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How some COVID-19 vaccines could cause rare blood clots
on April 14, 2021, after the CDC and Food and Drug Administration recommended that states hold off on using it pending a detailed review of six cases of the same kind of rare but serious event – a blood clot in the vessels that drain blood from the brain combined with a large drop in platelets, which increases the risk for bleeding.
This combination can lead to severe strokes that can lead to brain damage or death. Among the six cases reported, which came to light over the past 3 weeks, one person died, according to the CDC. All six were women and ranged in age from 18 to 48 years.
According to a report from the Vaccine Adverse Event Reporting System (VAERS), which is maintained by the Department of Health & Human Services, the woman who died was 45. She developed a gradually worsening headache about a week after receiving the Johnson & Johnson vaccine.
On March 17, the day she came to the hospital, she was dry heaving. Her headache had suddenly gotten much worse, and the left side of her body was weak, which are signs of a stroke. A CT scan revealed both bleeding in her brain and a clot in her cortical vein. She died the following day.
In addition to VAERS, which accepts reports from anyone, the CDC and FDA are monitoring at least eight other safety systems maintained by hospitals, research centers, long-term care facilities, and insurance companies for signs of trouble with the vaccines. VAERS data is searchable and open to the public. Most of these systems are not publicly available to protect patient privacy. It’s unclear which systems detected the six cases cited by federal regulators.
“These are very serious and potentially fatal problems occurring in a healthy young adult. It’s serious and we need to get to the bottom of it,” said Ed Belongia, MD, director of the Center for Clinical Epidemiology and Population Health at the Marshfield (Wis.) Clinic Research Institute. Dr. Belongia leads a research team that helps the CDC monitor vaccine safety and effectiveness.
“Safety is always the highest priority, and I think what we’ve seen here in the past 24 hours is our vaccine safety monitoring system is working,” he said.
Others agree. “I think what CDC and FDA have detected is a rare, but likely real adverse event associated with this vaccine,” said Paul Offit, MD, director of vaccine education at Children’s Hospital of Philadelphia.
Although much is still unknown about these events, they follow a similar pattern of blood clots reported with the AstraZeneca vaccine in Europe. That vaccine is now sold under the brand name Vaxzevria.
This has experts questioning whether all vaccines of this type may cause these rare clots.
“I think it’s likely a class effect,” said Dr. Offit, who was a member of the FDA advisory committee that reviewed clinical trial data on the J&J vaccine before it was authorized for use.
Adenovirus vaccines scrutinized
Both the Johnson & Johnson and Vaxzevria vaccines use an adenovirus to ferry genetic instructions for making the coronaviruses spike protein into our cells.
Adenoviruses are common, relatively simple viruses that normally cause mild cold or flu symptoms. The ones used in the vaccine are disabled so they can’t make us sick. They’re more like Trojan horses.
Once inside our cells, they release the DNA instructions they carry to make the spike protein of the new coronavirus. Those cells then crank out copies of the spike protein, which then get displayed on the outer surface of the cell membrane where they are recognized by the immune system.
The immune system then makes antibodies and other defenses against the spike so that, when the real coronavirus comes along, our bodies are ready to fight the infection.
There’s no question the vaccine works. In clinical trials, the Johnson & Johnson vaccine was 66% percent effective at preventing against moderate to severe COVID-19 infection, and none of the patients who got COVID-19 after vaccination had to be admitted to the hospital or died.
The idea behind using adenoviruses in vaccines isn’t a new one. In a kind of fight-fire-with-fire approach, the idea is to use a virus, which is good at infecting us, to fight a different kind of virus.
Researchers have been working on the concept for about 10 years, but the COVID-19 vaccines that use this technology are some of the first adenovirus-vector vaccines deployed in humans.
Only one other adenovirus vaccine, for Ebola, has been approved for use in humans. It was approved in Europe last year. Before the Johnson & Johnson vaccine, no other adenovirus vector has been available for use in humans in the United States.
There are six adenovirus-vector vaccines for COVID-19. In addition to AstraZeneca and Johnson & Johnson, there’s the Russian-developed vaccine Sputnik V, along with CanSino from China, and the Covishield vaccine in India.
Adenovirus vaccines are more stable than the mRNA vaccines. That makes them easier to store and transport.
But they have a significant downside, too. Because adenoviruses infect humans out in the world, we already make antibodies against them. So there’s always a danger that our immune systems might recognize and react to the vaccine, rendering it ineffective. For that reason, scientists try to carefully select the adenovirus vectors, or carriers, they use.
The two vaccines under investigation for blood clots are slightly different. The Johnson & Johnson vaccine uses the vector AD26, because most of the population lacks preexisting immunity to it. Vaxzevria uses an adenovirus that infects chimpanzees, called ChAdOx1.
Vaxzevria has been widely used in Europe but has not yet been authorized in the United States.
On April 7, the European Medicines Agency, Europe’s counterpart to the FDA, ruled that unusual blood clots with low blood platelets should be listed as rare side effects on the Vaxzevria vaccine.
The decision came after reviewing 62 cases of cerebral venous sinus thrombosis (CVST) linked to the vaccine and 25 cases of another rare type of clot, called a splanchnic vein thrombosis. Splanchnic veins drain blood from the major organs in the digestive system, including the stomach, liver, and intestines; 18 of those events were fatal.
The reports were culled from reporting in Europe and the United Kingdom, where around 25 million people have received the Vaxzevria vaccine, making these clots exceptionally rare, but serious.
So far, six cases of CVST have been reported in the United States, after more than 7 million doses of the Johnson & Johnson vaccines have been administered.
A key question for U.S. regulators will be the background rate for these types of rare combinations of clots and deplenished platelets. The background rate is the number of events that would be expected to occur naturally in a population of unvaccinated people. On a press call on April 13, Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, was asked about the frequency of this dangerous combination. He said the combination of low platelets and clots was so rare that it was hard to pinpoint, but might be somewhere between 2 and 14 cases per million people over the course of a year.
The first Johnson & Johnson doses were given in early March. That means the six cases came to light within the first few weeks of use of the vaccine in the United States, a very short amount of time.
“These were six cases per million people for 2 weeks, which is the same thing as 25 million per year, so it’s clearly above the background rate,” Dr. Offit said.
Studies suggest possible mechanism
On April 9, the New England Journal of Medicine published a detailed evaluation of the 11 patients in Germany and Austria who developed the rare clots after their Vaxzevria vaccines.
The study detected rare antibodies to a signaling protein called platelet factor 4, which helps to coordinate clot formation.
These same type of antibodies form in some people given the blood thinning drug heparin. In those reactions, which are also exceptionally rare, the same type of syndrome develops, leading to large, devastating clots that consume circulating platelets.
It’s not yet clear whether people who develop reactions to the vaccines already have some platelet factor 4 antibodies before they are vaccinated, or whether the vaccines somehow spur the body to make these antibodies, which then launch a kind of autoimmune attack.
The researchers on the paper gave the syndrome a name, vaccine-induced thrombotic thrombocytopenia (VITT).
It’s also not clear why more cases seem to be in women than in men. Andrew Eisenberger, MD, an associate professor of hematology and oncology at Columbia University, New York, said the most common causes of cerebral venous sinus thrombosis have to do with conditions that raise estrogen levels, like pregnancy and hormonal contraception.
“Estrogen naturally leads to changes in several clotting proteins in the blood that may predispose to abnormal blood clotting in a few different sites in the body,” he said. “The clotting changes we are encountering with some of COVID-19 vaccines are likely to be synergistic with the effects of estrogen on the blood.”
No matter the cause, the CDC on April 13 alerted doctors to keep a high index of suspicion for VITT in patients who have received the Johnson & Johnson vaccination within the last 2 weeks. In those patients, the usual course of treatment with blood thinning drugs like heparin may be harmful.
Symptoms to watch for include severe headache or backache, new neurologic symptoms, severe abdominal pain, shortness of breath, leg swelling, tiny red spots on the skin, or easy bruising.
Grappling with evidence
The CDC’s Advisory Committee on Immunization Practices will meet today in an emergency session to review the cases and see if any changes are needed to use of the J&J vaccine in the United States.
Last week, for example, the United Kingdom restricted the use of the AstraZeneca vaccine in people aged younger than 30 years, saying the risks and benefits of vaccination are “more finely balanced” for this age group.
With cases of COVID-19 rising again in the United States, and the Johnson & Johnson vaccine currently the most convenient form of protection against the virus, the committee will have to weigh the risks of that infection against the risk of rare clots caused by vaccination.
They will also likely have to rule out whether any of the cases had COVID. At least one study has reported CVST clots in three patients with confirmed COVID infections. In Europe, COVID infection did not seem to play a role in the formation of the clots with low platelets.
Hilda Bastian, PhD, a clinical trials expert who cofounded the Cochrane Collaboration, said it won’t be an easy task. Much will depend on how certain the committee members feel they know about all the events linked to the vaccine.
“That’s the really, really hard issue from my point of view for them right this moment. Have we missed any? Or how many are we likely to have missed?” asked Dr. Bastian, who lives in Australia.
“In a country that size with that fragmented [of] a health care system, how sure can you be that you know them all? That’s going to be a really difficult situation for them to grapple with, the quality of information that they’ve got,” she said.
A version of this article first appeared on Medscape.com.
on April 14, 2021, after the CDC and Food and Drug Administration recommended that states hold off on using it pending a detailed review of six cases of the same kind of rare but serious event – a blood clot in the vessels that drain blood from the brain combined with a large drop in platelets, which increases the risk for bleeding.
This combination can lead to severe strokes that can lead to brain damage or death. Among the six cases reported, which came to light over the past 3 weeks, one person died, according to the CDC. All six were women and ranged in age from 18 to 48 years.
According to a report from the Vaccine Adverse Event Reporting System (VAERS), which is maintained by the Department of Health & Human Services, the woman who died was 45. She developed a gradually worsening headache about a week after receiving the Johnson & Johnson vaccine.
On March 17, the day she came to the hospital, she was dry heaving. Her headache had suddenly gotten much worse, and the left side of her body was weak, which are signs of a stroke. A CT scan revealed both bleeding in her brain and a clot in her cortical vein. She died the following day.
In addition to VAERS, which accepts reports from anyone, the CDC and FDA are monitoring at least eight other safety systems maintained by hospitals, research centers, long-term care facilities, and insurance companies for signs of trouble with the vaccines. VAERS data is searchable and open to the public. Most of these systems are not publicly available to protect patient privacy. It’s unclear which systems detected the six cases cited by federal regulators.
“These are very serious and potentially fatal problems occurring in a healthy young adult. It’s serious and we need to get to the bottom of it,” said Ed Belongia, MD, director of the Center for Clinical Epidemiology and Population Health at the Marshfield (Wis.) Clinic Research Institute. Dr. Belongia leads a research team that helps the CDC monitor vaccine safety and effectiveness.
“Safety is always the highest priority, and I think what we’ve seen here in the past 24 hours is our vaccine safety monitoring system is working,” he said.
Others agree. “I think what CDC and FDA have detected is a rare, but likely real adverse event associated with this vaccine,” said Paul Offit, MD, director of vaccine education at Children’s Hospital of Philadelphia.
Although much is still unknown about these events, they follow a similar pattern of blood clots reported with the AstraZeneca vaccine in Europe. That vaccine is now sold under the brand name Vaxzevria.
This has experts questioning whether all vaccines of this type may cause these rare clots.
“I think it’s likely a class effect,” said Dr. Offit, who was a member of the FDA advisory committee that reviewed clinical trial data on the J&J vaccine before it was authorized for use.
Adenovirus vaccines scrutinized
Both the Johnson & Johnson and Vaxzevria vaccines use an adenovirus to ferry genetic instructions for making the coronaviruses spike protein into our cells.
Adenoviruses are common, relatively simple viruses that normally cause mild cold or flu symptoms. The ones used in the vaccine are disabled so they can’t make us sick. They’re more like Trojan horses.
Once inside our cells, they release the DNA instructions they carry to make the spike protein of the new coronavirus. Those cells then crank out copies of the spike protein, which then get displayed on the outer surface of the cell membrane where they are recognized by the immune system.
The immune system then makes antibodies and other defenses against the spike so that, when the real coronavirus comes along, our bodies are ready to fight the infection.
There’s no question the vaccine works. In clinical trials, the Johnson & Johnson vaccine was 66% percent effective at preventing against moderate to severe COVID-19 infection, and none of the patients who got COVID-19 after vaccination had to be admitted to the hospital or died.
The idea behind using adenoviruses in vaccines isn’t a new one. In a kind of fight-fire-with-fire approach, the idea is to use a virus, which is good at infecting us, to fight a different kind of virus.
Researchers have been working on the concept for about 10 years, but the COVID-19 vaccines that use this technology are some of the first adenovirus-vector vaccines deployed in humans.
Only one other adenovirus vaccine, for Ebola, has been approved for use in humans. It was approved in Europe last year. Before the Johnson & Johnson vaccine, no other adenovirus vector has been available for use in humans in the United States.
There are six adenovirus-vector vaccines for COVID-19. In addition to AstraZeneca and Johnson & Johnson, there’s the Russian-developed vaccine Sputnik V, along with CanSino from China, and the Covishield vaccine in India.
Adenovirus vaccines are more stable than the mRNA vaccines. That makes them easier to store and transport.
But they have a significant downside, too. Because adenoviruses infect humans out in the world, we already make antibodies against them. So there’s always a danger that our immune systems might recognize and react to the vaccine, rendering it ineffective. For that reason, scientists try to carefully select the adenovirus vectors, or carriers, they use.
The two vaccines under investigation for blood clots are slightly different. The Johnson & Johnson vaccine uses the vector AD26, because most of the population lacks preexisting immunity to it. Vaxzevria uses an adenovirus that infects chimpanzees, called ChAdOx1.
Vaxzevria has been widely used in Europe but has not yet been authorized in the United States.
On April 7, the European Medicines Agency, Europe’s counterpart to the FDA, ruled that unusual blood clots with low blood platelets should be listed as rare side effects on the Vaxzevria vaccine.
The decision came after reviewing 62 cases of cerebral venous sinus thrombosis (CVST) linked to the vaccine and 25 cases of another rare type of clot, called a splanchnic vein thrombosis. Splanchnic veins drain blood from the major organs in the digestive system, including the stomach, liver, and intestines; 18 of those events were fatal.
The reports were culled from reporting in Europe and the United Kingdom, where around 25 million people have received the Vaxzevria vaccine, making these clots exceptionally rare, but serious.
So far, six cases of CVST have been reported in the United States, after more than 7 million doses of the Johnson & Johnson vaccines have been administered.
A key question for U.S. regulators will be the background rate for these types of rare combinations of clots and deplenished platelets. The background rate is the number of events that would be expected to occur naturally in a population of unvaccinated people. On a press call on April 13, Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, was asked about the frequency of this dangerous combination. He said the combination of low platelets and clots was so rare that it was hard to pinpoint, but might be somewhere between 2 and 14 cases per million people over the course of a year.
The first Johnson & Johnson doses were given in early March. That means the six cases came to light within the first few weeks of use of the vaccine in the United States, a very short amount of time.
“These were six cases per million people for 2 weeks, which is the same thing as 25 million per year, so it’s clearly above the background rate,” Dr. Offit said.
Studies suggest possible mechanism
On April 9, the New England Journal of Medicine published a detailed evaluation of the 11 patients in Germany and Austria who developed the rare clots after their Vaxzevria vaccines.
The study detected rare antibodies to a signaling protein called platelet factor 4, which helps to coordinate clot formation.
These same type of antibodies form in some people given the blood thinning drug heparin. In those reactions, which are also exceptionally rare, the same type of syndrome develops, leading to large, devastating clots that consume circulating platelets.
It’s not yet clear whether people who develop reactions to the vaccines already have some platelet factor 4 antibodies before they are vaccinated, or whether the vaccines somehow spur the body to make these antibodies, which then launch a kind of autoimmune attack.
The researchers on the paper gave the syndrome a name, vaccine-induced thrombotic thrombocytopenia (VITT).
It’s also not clear why more cases seem to be in women than in men. Andrew Eisenberger, MD, an associate professor of hematology and oncology at Columbia University, New York, said the most common causes of cerebral venous sinus thrombosis have to do with conditions that raise estrogen levels, like pregnancy and hormonal contraception.
“Estrogen naturally leads to changes in several clotting proteins in the blood that may predispose to abnormal blood clotting in a few different sites in the body,” he said. “The clotting changes we are encountering with some of COVID-19 vaccines are likely to be synergistic with the effects of estrogen on the blood.”
No matter the cause, the CDC on April 13 alerted doctors to keep a high index of suspicion for VITT in patients who have received the Johnson & Johnson vaccination within the last 2 weeks. In those patients, the usual course of treatment with blood thinning drugs like heparin may be harmful.
Symptoms to watch for include severe headache or backache, new neurologic symptoms, severe abdominal pain, shortness of breath, leg swelling, tiny red spots on the skin, or easy bruising.
Grappling with evidence
The CDC’s Advisory Committee on Immunization Practices will meet today in an emergency session to review the cases and see if any changes are needed to use of the J&J vaccine in the United States.
Last week, for example, the United Kingdom restricted the use of the AstraZeneca vaccine in people aged younger than 30 years, saying the risks and benefits of vaccination are “more finely balanced” for this age group.
With cases of COVID-19 rising again in the United States, and the Johnson & Johnson vaccine currently the most convenient form of protection against the virus, the committee will have to weigh the risks of that infection against the risk of rare clots caused by vaccination.
They will also likely have to rule out whether any of the cases had COVID. At least one study has reported CVST clots in three patients with confirmed COVID infections. In Europe, COVID infection did not seem to play a role in the formation of the clots with low platelets.
Hilda Bastian, PhD, a clinical trials expert who cofounded the Cochrane Collaboration, said it won’t be an easy task. Much will depend on how certain the committee members feel they know about all the events linked to the vaccine.
“That’s the really, really hard issue from my point of view for them right this moment. Have we missed any? Or how many are we likely to have missed?” asked Dr. Bastian, who lives in Australia.
“In a country that size with that fragmented [of] a health care system, how sure can you be that you know them all? That’s going to be a really difficult situation for them to grapple with, the quality of information that they’ve got,” she said.
A version of this article first appeared on Medscape.com.
on April 14, 2021, after the CDC and Food and Drug Administration recommended that states hold off on using it pending a detailed review of six cases of the same kind of rare but serious event – a blood clot in the vessels that drain blood from the brain combined with a large drop in platelets, which increases the risk for bleeding.
This combination can lead to severe strokes that can lead to brain damage or death. Among the six cases reported, which came to light over the past 3 weeks, one person died, according to the CDC. All six were women and ranged in age from 18 to 48 years.
According to a report from the Vaccine Adverse Event Reporting System (VAERS), which is maintained by the Department of Health & Human Services, the woman who died was 45. She developed a gradually worsening headache about a week after receiving the Johnson & Johnson vaccine.
On March 17, the day she came to the hospital, she was dry heaving. Her headache had suddenly gotten much worse, and the left side of her body was weak, which are signs of a stroke. A CT scan revealed both bleeding in her brain and a clot in her cortical vein. She died the following day.
In addition to VAERS, which accepts reports from anyone, the CDC and FDA are monitoring at least eight other safety systems maintained by hospitals, research centers, long-term care facilities, and insurance companies for signs of trouble with the vaccines. VAERS data is searchable and open to the public. Most of these systems are not publicly available to protect patient privacy. It’s unclear which systems detected the six cases cited by federal regulators.
“These are very serious and potentially fatal problems occurring in a healthy young adult. It’s serious and we need to get to the bottom of it,” said Ed Belongia, MD, director of the Center for Clinical Epidemiology and Population Health at the Marshfield (Wis.) Clinic Research Institute. Dr. Belongia leads a research team that helps the CDC monitor vaccine safety and effectiveness.
“Safety is always the highest priority, and I think what we’ve seen here in the past 24 hours is our vaccine safety monitoring system is working,” he said.
Others agree. “I think what CDC and FDA have detected is a rare, but likely real adverse event associated with this vaccine,” said Paul Offit, MD, director of vaccine education at Children’s Hospital of Philadelphia.
Although much is still unknown about these events, they follow a similar pattern of blood clots reported with the AstraZeneca vaccine in Europe. That vaccine is now sold under the brand name Vaxzevria.
This has experts questioning whether all vaccines of this type may cause these rare clots.
“I think it’s likely a class effect,” said Dr. Offit, who was a member of the FDA advisory committee that reviewed clinical trial data on the J&J vaccine before it was authorized for use.
Adenovirus vaccines scrutinized
Both the Johnson & Johnson and Vaxzevria vaccines use an adenovirus to ferry genetic instructions for making the coronaviruses spike protein into our cells.
Adenoviruses are common, relatively simple viruses that normally cause mild cold or flu symptoms. The ones used in the vaccine are disabled so they can’t make us sick. They’re more like Trojan horses.
Once inside our cells, they release the DNA instructions they carry to make the spike protein of the new coronavirus. Those cells then crank out copies of the spike protein, which then get displayed on the outer surface of the cell membrane where they are recognized by the immune system.
The immune system then makes antibodies and other defenses against the spike so that, when the real coronavirus comes along, our bodies are ready to fight the infection.
There’s no question the vaccine works. In clinical trials, the Johnson & Johnson vaccine was 66% percent effective at preventing against moderate to severe COVID-19 infection, and none of the patients who got COVID-19 after vaccination had to be admitted to the hospital or died.
The idea behind using adenoviruses in vaccines isn’t a new one. In a kind of fight-fire-with-fire approach, the idea is to use a virus, which is good at infecting us, to fight a different kind of virus.
Researchers have been working on the concept for about 10 years, but the COVID-19 vaccines that use this technology are some of the first adenovirus-vector vaccines deployed in humans.
Only one other adenovirus vaccine, for Ebola, has been approved for use in humans. It was approved in Europe last year. Before the Johnson & Johnson vaccine, no other adenovirus vector has been available for use in humans in the United States.
There are six adenovirus-vector vaccines for COVID-19. In addition to AstraZeneca and Johnson & Johnson, there’s the Russian-developed vaccine Sputnik V, along with CanSino from China, and the Covishield vaccine in India.
Adenovirus vaccines are more stable than the mRNA vaccines. That makes them easier to store and transport.
But they have a significant downside, too. Because adenoviruses infect humans out in the world, we already make antibodies against them. So there’s always a danger that our immune systems might recognize and react to the vaccine, rendering it ineffective. For that reason, scientists try to carefully select the adenovirus vectors, or carriers, they use.
The two vaccines under investigation for blood clots are slightly different. The Johnson & Johnson vaccine uses the vector AD26, because most of the population lacks preexisting immunity to it. Vaxzevria uses an adenovirus that infects chimpanzees, called ChAdOx1.
Vaxzevria has been widely used in Europe but has not yet been authorized in the United States.
On April 7, the European Medicines Agency, Europe’s counterpart to the FDA, ruled that unusual blood clots with low blood platelets should be listed as rare side effects on the Vaxzevria vaccine.
The decision came after reviewing 62 cases of cerebral venous sinus thrombosis (CVST) linked to the vaccine and 25 cases of another rare type of clot, called a splanchnic vein thrombosis. Splanchnic veins drain blood from the major organs in the digestive system, including the stomach, liver, and intestines; 18 of those events were fatal.
The reports were culled from reporting in Europe and the United Kingdom, where around 25 million people have received the Vaxzevria vaccine, making these clots exceptionally rare, but serious.
So far, six cases of CVST have been reported in the United States, after more than 7 million doses of the Johnson & Johnson vaccines have been administered.
A key question for U.S. regulators will be the background rate for these types of rare combinations of clots and deplenished platelets. The background rate is the number of events that would be expected to occur naturally in a population of unvaccinated people. On a press call on April 13, Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, was asked about the frequency of this dangerous combination. He said the combination of low platelets and clots was so rare that it was hard to pinpoint, but might be somewhere between 2 and 14 cases per million people over the course of a year.
The first Johnson & Johnson doses were given in early March. That means the six cases came to light within the first few weeks of use of the vaccine in the United States, a very short amount of time.
“These were six cases per million people for 2 weeks, which is the same thing as 25 million per year, so it’s clearly above the background rate,” Dr. Offit said.
Studies suggest possible mechanism
On April 9, the New England Journal of Medicine published a detailed evaluation of the 11 patients in Germany and Austria who developed the rare clots after their Vaxzevria vaccines.
The study detected rare antibodies to a signaling protein called platelet factor 4, which helps to coordinate clot formation.
These same type of antibodies form in some people given the blood thinning drug heparin. In those reactions, which are also exceptionally rare, the same type of syndrome develops, leading to large, devastating clots that consume circulating platelets.
It’s not yet clear whether people who develop reactions to the vaccines already have some platelet factor 4 antibodies before they are vaccinated, or whether the vaccines somehow spur the body to make these antibodies, which then launch a kind of autoimmune attack.
The researchers on the paper gave the syndrome a name, vaccine-induced thrombotic thrombocytopenia (VITT).
It’s also not clear why more cases seem to be in women than in men. Andrew Eisenberger, MD, an associate professor of hematology and oncology at Columbia University, New York, said the most common causes of cerebral venous sinus thrombosis have to do with conditions that raise estrogen levels, like pregnancy and hormonal contraception.
“Estrogen naturally leads to changes in several clotting proteins in the blood that may predispose to abnormal blood clotting in a few different sites in the body,” he said. “The clotting changes we are encountering with some of COVID-19 vaccines are likely to be synergistic with the effects of estrogen on the blood.”
No matter the cause, the CDC on April 13 alerted doctors to keep a high index of suspicion for VITT in patients who have received the Johnson & Johnson vaccination within the last 2 weeks. In those patients, the usual course of treatment with blood thinning drugs like heparin may be harmful.
Symptoms to watch for include severe headache or backache, new neurologic symptoms, severe abdominal pain, shortness of breath, leg swelling, tiny red spots on the skin, or easy bruising.
Grappling with evidence
The CDC’s Advisory Committee on Immunization Practices will meet today in an emergency session to review the cases and see if any changes are needed to use of the J&J vaccine in the United States.
Last week, for example, the United Kingdom restricted the use of the AstraZeneca vaccine in people aged younger than 30 years, saying the risks and benefits of vaccination are “more finely balanced” for this age group.
With cases of COVID-19 rising again in the United States, and the Johnson & Johnson vaccine currently the most convenient form of protection against the virus, the committee will have to weigh the risks of that infection against the risk of rare clots caused by vaccination.
They will also likely have to rule out whether any of the cases had COVID. At least one study has reported CVST clots in three patients with confirmed COVID infections. In Europe, COVID infection did not seem to play a role in the formation of the clots with low platelets.
Hilda Bastian, PhD, a clinical trials expert who cofounded the Cochrane Collaboration, said it won’t be an easy task. Much will depend on how certain the committee members feel they know about all the events linked to the vaccine.
“That’s the really, really hard issue from my point of view for them right this moment. Have we missed any? Or how many are we likely to have missed?” asked Dr. Bastian, who lives in Australia.
“In a country that size with that fragmented [of] a health care system, how sure can you be that you know them all? That’s going to be a really difficult situation for them to grapple with, the quality of information that they’ve got,” she said.
A version of this article first appeared on Medscape.com.
Sarcoidosis: An FP’s primer on an enigmatic disease
Sarcoidosis is a multisystem inflammatory disease of unclear etiology that primarily affects the lungs. It can occur at any age but usually develops before the age of 50 years, with an initial peak incidence at 20 to 29 years and a second peak incidence after 50 years of age, especially among women in Scandinavia and Japan.1 Sarcoidosis affects men and women of all racial and ethnic groups throughout the world, but differences based on race, sex, and geography are noted.1
The highest rates are reported in northern European and African-American individuals, particularly in women.1,2 The adjusted annual incidence of sarcoidosis among African Americans is approximately 3 times that among White Americans3 and is more likely to be chronic and fatal in African Americans.3 The disease can be familial with a possible recessive inheritance mode with incomplete penetrance.4 Risk of sarcoidosis in monozygotic twins appears to be 80 times greater than that in the general population, which supports genetic factors accounting for two-thirds of disease susceptibility.5
Likely factors in the development of sarcoidosis
The exact cause of sarcoidosis is unknown, but we have insights into its pathogenesis and potential triggers.1,6-9 Genes involved are being identified: class I and II human leukocyte antigen (HLA) molecules are most consistently associated with risk of sarcoidosis. Environmental exposures can activate the innate immune system and precondition a susceptible individual to react to potential causative antigens in a highly polarized, antigen-specific Th1 immune response. The epithelioid granulomatous response involves local proinflammatory cytokine production and enhanced T-cell immunity at sites of inflammation.10 Granulomas generally form to confine pathogens, restrict inflammation, and protect surrounding tissue.11-13
ACCESS (A Case Control Etiologic Study of Sarcoidosis) identified several environmental exposures such as chemicals used in the agriculture industry, mold or mildew, and musty odors at work.14 Tobacco use was not associated with sarcoidosis.14 Recent studies have shown positive associations with service in the US Navy,15 metal working,16 firefighting,17 the handling of building supplies,18 and onsite exposure while assisting in rescue efforts at the World Trade Center disaster.19 Other data support the likelihood that specific environmental exposures associated with microbe-rich environments modestly increase the risk of sarcoidosis.14 Mycobacterial and propionibacterial DNA and RNA are potentially associated with sarcoidosis.20
Clinical manifestations are nonspecific
The diagnosis of sarcoidosis can be difficult and delayed due to diverse organ involvement and nonspecific presentations. TABLE 121-31 shows the diverse manifestations in a patient with suspected sarcoidosis. Around 50% of the patients are asymptomatic.23,24 Sarcoidosis is a diagnosis of exclusion, starting with a detailed history to rule out infections, occupational or environmental exposures, malignancies, and other possible disorders (TABLE 2).22
Diagnostic work-up
Radiologic studies
Chest x-ray (CXR) provides diagnostic and prognostic information in the evaluation of sarcoidosis using the Scadding classification system (FIGURE 1).21,25,32,33 Interobserver variability, especially between stages II and III and III and IV is the major limitation of this system.32 At presentation, radiographs are abnormal in approximately 90% of patients.34 Lymphadenopathy is the most common radiographic abnormality, occurring in more than two-thirds of cases, and pulmonary opacities (nodules and reticulation) with a middle to upper lobe predilection are present in 20% to 50% of patients.1,31,35 The nodules vary in size and can coalesce and cause alveolar collapse, thus producing consolidation.36 Linear opacities radiating laterally from the hilum into the middle and upper zones are characteristic in fibrotic disease.
Continue to: High-resoluton computed tomography
High-resolution computed tomography (HRCT). Micronodules in a perilymphatic distribution with upper lobe predominance combined with subcarinal and symmetrical hilar lymph node enlargement is practically diagnostic of sarcoidosis in the right clinical context. TABLE 321,23,25,32 and FIGURE 221,23,25,32 summarize the common CT chest findings of sarcoidosis.
Advanced imaging such as (18)F-fluorodeoxyglucose positron emission tomography (PET) and magnetic resonance imaging (MRI) are used in specialized settings for advanced pulmonary, cardiac, or neurosarcoidosis.
Tissue biopsy
Skin lesions (other than erythema nodosum), eye lesions, and peripheral lymph nodes are considered the safest extrapulmonary locations for biopsy.21,25 If pulmonary infiltrates or lymphadenopathy are present, or if extrapulmonary biopsy sites are not available, then flexible bronchoscopy with biopsy is the mainstay for tissue sampling.25
Bronchoalveolar lavage (BAL), transbronchial biopsy (TBB), endobronchial biopsy (EBB), and endobronchial ultrasound (EBUS) are invaluable modalities that have reduced the need for open lung biopsy. BAL in sarcoidosis can show lymphocytosis > 15% (nonspecific) and a CD4:CD8 lymphocyte ratio > 3.5 (specificity > 90%).21,22 TBB is more sensitive than EBB; however, sensitivity overall is heightened when both of them are combined. The advent of EBUS has increased the safety and efficiency of needle aspiration of mediastinal lymph nodes. Diagnostic yield of EBUS (~80%) is superior to that with TBB and EBB (~50%), especially in stage I and II sarcoidosis.37 The combination of EBUS with TBB improves the diagnostic yield to ~90%.37
The decision to obtain biopsy samples hinges on the nature of clinical and radiologic findings (FIGURE 3).22,25,26
Continue to: Laboratory studies
Laboratory studies
Multiple abnormalities may be seen in sarcoidosis, and specific lab tests may help support a diagnosis of sarcoidosis or detect organ-specific disease activity (TABLE 4).22,23,25,38 However, no consistently accurate biomarkers exist for use in clinical practice. An angiotensin-converting enzyme (ACE) level greater than 2 times the upper limit of normal may be helpful; however, sensitivity remains low, and genetic polymorphisms can influence the ACE level.25 Biomarkers sometimes used to assess disease activity are serum interleukin-2 receptor, neopterin, chitotriosidase, lysozyme, KL-6 glycoprotein, and amyloid A.21
Additional tests to assess specific features or organ involvement
Pulmonary function testing (PFT) is reviewed in detail below under “pulmonary sarcoidosis.”
Electrocardiogram (EKG)/transthoracic echocardiogram (TTE). EKG abnormalities—conduction disturbances, arrhythmias, or nonspecific ST segment and T-wave changes—are the most common nonspecific findings.30 TTE findings are also nonspecific but have value in assessing cardiac chamber size and function and myocardial involvement. TTE is indeed the most common screening modality for sarcoidosis-associated pulmonary hypertension (SAPH), which is definitively diagnosed by right heart catheterization (RHC). Further evaluation for cardiac sarcoidosis can be done with cardiac MRI or fluorodeoxyglucose PET in specialized settings.
Lumbar puncture (LP) may reveal lymphocytic infiltration in suspected neurosarcoidosis, but the finding is nonspecific and can reflect infection or malignancy. Oligoclonal bands may also be seen in about one-third of neurosarcoidosis cases, and it is imperative to rule out multiple sclerosis.28
Pulmonary sarcoidosis
Pulmonary sarcoidosis accounts for most of the morbidity, mortality, and health care use associated with sarcoidosis.39,40
Continue to: Pathology of early and advanced pulmonary sarcoidosis
Pathology of early and advanced pulmonary sarcoidosis
Sarcoidosis is characterized by coalescing, tightly clustered, nonnecrotizing granulomas in the lung (FIGURE 4), most often located along the lymphatic routes of the pleura, interlobular septa, and bronchovascular bundles.41 Granulomas contain epithelioid cells or multinucleated giant cells surrounded by a chronic lymphocytic infiltrate. Typically, intracytoplasmic inclusions, such as Schaumann bodies, asteroid bodies, and blue bodies of calcium oxalates are noted within giant cells.
In chronic disease, lymphocytic infiltrate vanishes and granulomas tend to become increasingly fibrotic and enlarge to form hyalinized nodules rich with densely eosinophilic collagen. In 10% to 30% of cases, the lungs undergo progressive fibrosis.40 Nonresolving inflammation appears to be the major cause of fibrosis and the peribronchovascular localization leading to marked bronchial distortion.
Clinical features, monitoring, and outcomes
Pulmonary involvement occurs in most patients with sarcoidosis, and subclinical pulmonary disease is generally present, even when extrathoracic manifestations predominate.23 Dry cough, dyspnea, and chest discomfort are the most common symptoms. Chest auscultation is usually unremarkable. Wheezing is more common in those with fibrosis and is attributed to airway-centric fibrosis.42 There is often a substantial delay between the onset of symptoms and the diagnosis of pulmonary sarcoidosis, as symptoms are nonspecific and might be mistaken for more common pulmonary diseases, such as asthma or chronic bronchitis.43
Since sarcoidosis can affect pulmonary parenchyma, interstitium, large and small airways, pulmonary vasculature, and respiratory muscles, the pattern of lung function impairment on PFT varies from normal to obstruction, restriction, isolated diffusion defect, or a combination of these. The typical physiologic abnormality is a restrictive ventilatory defect with a decreased diffusing capacity of the lung for carbon monoxide (DLCO). Extent of disease seen on HRCT correlates with level of restriction.44 Airway obstruction can be multifactorial and due to airway distortion (more likely to occur in fibrotic lung disease) and luminal disease.45-48 The 6-minute walk test and DLCO can also aid in the diagnosis of SAPH and advanced parenchymal lung disease.
While monitoring is done clinically and with testing (PFT and imaging) as needed, the optimal approach is unclear. Nevertheless, longitudinal monitoring with testing may provide useful management and prognostic information.40 Pulmonary function can remain stable in fibrotic sarcoidosis over extended periods and actually can improve in some patients.49 Serial spirometry, particularly forced vital capacity, is the most reliable tool for monitoring; when a decline in measurement occurs, chest radiography can elucidate the mechanism.50,51
Continue to: Because sarcoidosis is a multisystem disease...
Because sarcoidosis is a multisystem disease, caution needs to be exercised when evaluating a patient’s new or worsening respiratory symptoms to accurately determine the cause of symptoms and direct therapy accordingly. In addition to refractory inflammatory pulmonary disease, airway disease, infection, fibrosis, and SAPH, one needs to consider extrapulmonary involvement or complications such as cardiac or neurologic disease, musculoskeletal disease, depression, or fatigue. Adverse medication effects, deconditioning, or unrelated (or possibly related) disorders (eg pulmonary embolism) may be to blame.
Determining prognosis
Prognosis of sarcoidosis varies and depends on epidemiologic factors, clinical presentation, and course, as well as specific organ involvement. Patients may develop life-threatening pulmonary, cardiac, or neurologic complications. End-stage disease may require organ transplantation for eligible patients.
Most patients with pulmonary sarcoidosis experience clinical remission with minimal residual organ impairment and a favorable long-term outcome. Advanced pulmonary disease (known as APS) occurs in a small proportion of patients with sarcoidosis but accounts for most of the poor outcomes in sarcoidosis.40 APS is variably defined, but it generally includes pulmonary fibrosis, SAPH, and respiratory infection.
One percent to 5% of patients with sarcoidosis die from complications, and mortality is higher in women and African Americans.52 Mortality and morbidity may be increasing.53 The reasons behind these trends are unclear but could include true increases in disease incidence, better detection rates, greater severity of disease, or an aging population. Increased hospitalizations and health care use might be due to organ damage from granulomatous inflammation (and resultant fibrosis), complications associated with treatment, and psychosocial effects of the disease/treatment.
Management
Management consists primarily of anti-inflammatory or immunosuppressive therapies but can also include measures to address specific complications (such as fatigue) and organ transplant, as well as efforts to counter adverse medication effects. Other supportive and preventive measures may include, on a case-by-case basis, oxygen supplementation, vaccinations, or pulmonary rehabilitation. Details of these are found in other, more in-depth reviews on treatment; we will briefly review anti-inflammatory therapy, which forms the cornerstone of treatment in most patients with sarcoidosis.
Continue to: General approach to treatment decisions
General approach to treatment decisions. Anti-inflammatory therapy is used to reduce granulomatous inflammation, thereby preserving organ function and reducing symptoms. A decision to begin treatment is one shared with the patient and is based on symptoms and potential danger of organ system failure.54 Patients who are symptomatic or have progressive disease or physiologic impairment are generally candidates for treatment. Monitoring usually suffices for those who have minimal symptoms, stable disease, and preserved organ function.
Patients with pulmonary sarcoidosis at CXR stage 0 should not receive treatment, given that large, randomized trials have shown no meaningful benefit and that these patients have a high likelihood of spontaneous remission and excellent long-term prognosis.55-58 However, a subgroup of patients classified as stage 0/I on CXR may show parenchymal disease on HRCT,59 and, if more symptomatic, could be considered for treatment. For patients with stage II to IV pulmonary sarcoidosis with symptoms, there is good evidence that treatment may improve lung function and reduce dyspnea and fatigue.57,60-62
Corticosteroids are first-line treatment for most patients. Based on expert opinion, treatment of pulmonary sarcoidosis is generally started with oral prednisone (or an equivalent corticosteroid). A starting dose of 20 to 40 mg/d generally is sufficient for most patients. If the patient responds to initial treatment, prednisone dose is tapered over a period of months. If symptoms worsen during tapering, the minimum effective dose is maintained without further attempts at tapering. Treatment is continued for at least 3 to 6 months but it might be needed for longer durations; unfortunately, evidence-based guidelines are lacking.63 Once the patient goes into remission, close monitoring is done for possible relapses. Inhaled corticosteroids alone have not reduced symptoms or improved lung function in patients with pulmonary sarcoidosis.64-66
Steroid-sparing agents are added for many patients. For patients receiving chronic prednisone therapy (≥ 10 mg for > 6 months), steroid-sparing agents are considered to minimize the adverse effects of steroids or to better control the inflammatory activity of sarcoidosis. These agents must be carefully selected, and clinical and laboratory monitoring need to be done throughout therapy. TABLE 558,64,67-81
The management might be complicated for extrapulmonary, multi-organ, and advanced sarcoidosis (advanced pulmonary sarcoidosis, cardiac disease, neurosarcoidosis, lupus pernio, etc) when specialized testing, as well as a combination of corticosteroids and steroid-sparing agents (with higher doses or prolonged courses), might be needed. This should be performed at an expert sarcoidosis center, ideally in a multidisciplinary setting involving pulmonologists and/or rheumatologists, chest radiologists, and specialists as indicated, based on specific organ involvement.
Continue to: Research and future directions
Research and future directions
Key goals for research are identifying more accurate biomarkers of disease, improving diagnosis of multi-organ disease, determining validated endpoints of clinical trials in sarcoidosis, and developing treatments for refractory cases.
There is optimism and opportunity in the field of sarcoidosis overall. An example of an advancement is in the area of APS, as the severity and importance of this phenotype has been better understood. Worldwide registries and trials of pulmonary vasodilator therapy (bosentan, sildenafil, epoprostenol, and inhaled iloprost) in patients with SAPH without left ventricular dysfunction are promising.82-85 However, no benefit in survival has been shown.
RioSAPH is a double-blind, placebo-controlled trial of Riociguat (a stimulator of soluble guanylate cyclase) for SAPH (NCT02625558) that is closed to enrollment and undergoing data review. Similarly, results of the phase IV study of pirfenidone, an antifibrotic agent that was shown to decrease disease progression and deaths in idiopathic pulmonary fibrosis,86 are awaited in the near future.
Other potential directions being explored are multicenter patient registries and randomized controlled trials, analyses of existing databases, use of biobanking, and patient-centered outcome measures. Hopefully, the care of patients with sarcoidosis will become more evidence based with ongoing and upcoming research in this field.
CORRESPONDENCE
Rohit Gupta, MBBS, FCCP, 3401 North Broad Street, 7 Parkinson Pavilion, Philadelphia, PA 19140; rohit.gupta@tuhs.temple.edu
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2. Hillerdal G, Nöu E, Osterman K, et al. Sarcoidosis: epidemiology and prognosis. A 15-year European study. Am Rev Respir Dis. 1984;130:29-32.
3. Mirsaeidi M, Machado RF, Schraufnagel D, et al. Racial difference in sarcoidosis mortality in the United States. Chest. 2015;147:438-449.
4. Rybicki BA, Iannuzzi MC, Frederick MM, et al. Familial aggregation of sarcoidosis. A case-control etiologic study of sarcoidosis (ACCESS). Am J Resp Crit Care Med. 2001;164:2085-2091.
5. Sverrild A, Backer V, Kyvik KO, et al. Heredity in sarcoidosis:a registry-based twin study. Thorax. 2008;63:894.
6. Vuyst P, Dumortier P, Schandené L, et al. Sarcoidlike lung granulomatosis induced by aluminum dusts. Am Rev Respir Dis. 1987;135:493-497.
7. Werfel U, Schneider J, Rödelsperger K, et al. Sarcoid granulomatosis after zirconium exposure with multiple organ involvement. European Respir J. 1998;12:750.
8. Newman KL, Newman LS. Occupational causes of sarcoidosis. Curr Opin Allergy Clin Immunol. 2012;12:145-150.
9. Zissel G, Müller-Quernheim J. Specific antigen(s) in sarcoidosis:a link to autoimmunity? Eur Respir J. 2016;47:707-709.
10. Chen ES, Moller DR. Etiology of sarcoidosis. Clin Chest Med. 2008;29:365-377.
11. Agostini C, Adami F, Semenzato G. New pathogenetic insights into the sarcoid granuloma. Curr Opin Rheumatol. 2000;12:71-76.
12. Valentonyte R, Hampe J, Huse K, et al. Sarcoidosis is associated with a truncating splice site mutation in BTNL2. Nat Genet. 2005;37:357-364.
13. Rybicki BA, Walewski JL, Maliarik MJ, et al. The BTNL2 gene and sarcoidosis susceptibility in African Americans and Whites. Am J Hum Genet. 2005;77:491-499.
14. Newman LS, Rose CS, Bresnitz EA, et al. A case control etiologic study of sarcoidosis: environmental and occupational risk factors. Am J Respir Crit Care Med. 2004;170:1324-1330.
15. Gorham ED, Garland CF, Garland FC, et al. Trends and occupational associations in incidence of hospitalized pulmonary sarcoidosis and other lung diseases in Navy personnel: a 27-year historical prospective study, 1975-2001. Chest. 2004;126:1431-1438.
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17. Prezant DJ, Dhala A, Goldstein A, et al. The incidence, prevalence, and severity of sarcoidosis in New York City firefighters. Chest. 1999;116:1183-1193.
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20. Eishi Y, Suga M, Ishige I, et al. Quantitative analysis of mycobacterial and propionibacterial DNA in lymph nodes of Japanese and European patients with sarcoidosis. J Clin Microbiol. 2002;40:198-204.
21. Valeyre D, Prasse A, Nunes H, et al. Sarcoidosis. Lancet. 2014;383:1155-1167.
22. Crouser ED, Maier LA, Wilson KC, et al. Diagnosis and detection of sarcoidosis. An official American Thoracic Society clinical practice guideline. Am J Respir Crit Care Med. 2020;201:e26-51.
23. Judson MA, ed. Pulmonary Sarcoidosis: A Guide for the Practicing Clinician. Springer; 2014.
24. Govender P, Berman JS. The diagnosis of sarcoidosis. Clin Chest Med. 2015;36:585-602.
25. Valeyre D, Bernaudin J-F, Uzunhan Y, et al. Clinical presentation of sarcoidosis and diagnostic work-up. Semin Resp Crit Care Med. 2014;35:336-351.
26. Judson MA. The clinical features of sarcoidosis: a comprehensive review. Clin Rev Allergy Immunol. 2015;49:63-78.
27. Wanat KA, Rosenbach M. Cutaneous sarcoidosis. Clin Chest Med. 2015;36:685-702.
28. Culver DA, Neto ML, Moss BP, et al. Neurosarcoidosis. Semin Resp Crit Care Med. 2017;38:499-513.
29. Pasadhika S, Rosenbaum JT. Ocular sarcoidosis. Clin Chest Med. 2015;36:669-683.
30. Sayah DM, Bradfield JS, Moriarty JM, et al. Cardiac involvement in sarcoidosis: evolving concepts in diagnosis and treatment. Semin Resp Crit Care Med. 2017;38:477-498.
31. Baughman RP, Teirstein AS, Judson MA, et al. Clinical characteristics of patients in a case control study of sarcoidosis. Am J Resp Crit Care. 2012;164:1885-1889.
32. Keijsers RG, Veltkamp M, Grutters JC. Chest imaging. Clin Chest Med. 2015;36:603-619.
33. Scadding J. Prognosis of intrathoracic sarcoidosis in England. A review of 136 cases after five years’ observation. Brit Med J. 1961;2:1165-1172.
34. Miller B, Putman C. The chest radiograph and sarcoidosis. Reevaluation of the chest radiograph in assessing activity of sarcoidosis: a preliminary communication. Sarcoidosis. 1985;2:85-90.
35. Loddenkemper R, Kloppenborg A, Schoenfeld N, et al. Clinical findings in 715 patients with newly detected pulmonary sarcoidosis--results of a cooperative study in former West Germany and Switzerland. WATL Study Group. Wissenschaftliche Arbeitsgemeinschaft für die Therapie von Lungenkrankheitan. Sarcoidosis Vasc Diffuse Lung Dis. 1998;15:178-182.
36. Calandriello L, Walsh SLF. Imaging for sarcoidosis. Semin Resp Crit Care Med. 2017;38:417-436.
37. Gupta D, Dadhwal DS, Agarwal R, et al. Endobronchial ultrasound-guided transbronchial needle aspiration vs conventional transbronchial needle aspiration in the diagnosis of sarcoidosis. Chest. 2014;146:547-556.
38. Baydur A. Recent developments in the physiological assessment of sarcoidosis: clinical implications. Curr Opin Pulm Med. 2012;18:499-505.
39. Jamilloux Y, Maucort-Boulch D, Kerever S, et al. Sarcoidosis-related mortality in France: a multiple-cause-of-death analysis. Eur Respir J. 2016;48:1700-1709.
40. Gupta R, Baughman RP. Advanced pulmonary sarcoidosis. Semin Respir Crit Care Med. 2020;41:700-715.
41. Rossi G, Cavazza A, Colby TV. Pathology of sarcoidosis. Clin Rev Allergy Immunol. 2015;49:36-44.
42. Hansell D, Milne D, Wilsher M, et al. Pulmonary sarcoidosis: morphologic associations of airflow obstruction at thin-section CT. Radiology. 1998;209:697-704.
43. Judson MA, Thompson BW, Rabin DL, et al. The diagnostic pathway to sarcoidosis. Chest. 2003;123:406-412.
44. Müller NL, Mawson JB, Mathieson JR, et al. Sarcoidosis: correlation of extent of disease at CT with clinical, functional, and radiographic findings. Radiology. 1989;171:613-618.
45. Harrison BDW, Shaylor JM, Stokes TC, et al. Airflow limitation in sarcoidosis—a study of pulmonary function in 107 patients with newly diagnosed disease. Resp Med. 1991;85:59-64.
46. Polychronopoulos VS, Prakash UBS. Airway Involvement in sarcoidosis. Chest. 2009;136:1371-1380.
47. Chambellan A, Turbie P, Nunes H, et al. Endoluminal stenosis of proximal bronchi in sarcoidosis: bronchoscopy, function, and evolution. Chest. 2005;127:472-481.
48. Handa T, Nagai S, Fushimi Y, et al. Clinical and radiographic indices associated with airflow limitation in patients with sarcoidosis. Chest. 2006;130:1851-1856.
49. Nardi A, Brillet P-Y, Letoumelin P, et al. Stage IV sarcoidosis: comparison of survival with the general population and causes of death. Eur Respir J. 2011;38:1368-1373.
50. Zappala CJ, Desai SR, Copley SJ, et al. Accuracy of individual variables in the monitoring of long-term change in pulmonary sarcoidosis as judged by serial high-resolution CT scan data. Chest. 2014;145:101-107.
51. Gafà G, Sverzellati N, Bonati E, et al. Follow-up in pulmonary sarcoidosis: comparison between HRCT and pulmonary function tests. Radiol Med. 2012;117:968-978.
52. Gerke AK. Morbidity and mortality in sarcoidosis. Curr Opin Pulm Med. 2014;20:472-478.
53. Kearney GD, Obi ON, Maddipati V, et al. Sarcoidosis deaths in the United States: 1999–2016. Respir Med. 2019;149:30-35.
54. Baughman RP, Judson M, Wells A. The indications for the treatment of sarcoidosis: Wells Law. Sarcoidosis Vasc Diffuse Lung Dis. 2017;34:280-282.
55. Nagai S, Shigematsu M, Hamada K, et al. Clinical courses and prognoses of pulmonary sarcoidosis. Curr Opin Pulm Med. 1999;5:293-298.
56. Neville E, Walker AN, James DG. Prognostic factors predicting the outcome of sarcoidosis: an analysis of 818 patients. Q J Med. 1983;52:525-533.
57. Bradley B, Branley HM, Egan JJ, et al. Interstitial lung disease guideline: the British Thoracic Society in collaboration with the Thoracic Society of Australia and the Irish Thoracic Society. Thorax. 2008;63(suppl 5):v1-v58.
58. Pietinalho A, Tukiainen P, Haahtela T, et al. Oral prednisolone followed by inhaled budesonide in newly diagnosed pulmonary sarcoidosis: a double-blind, placebo-controlled multicenter study. Finnish Pulmonary Sarcoidosis Group. Chest. 1999;116:424-431.
59. Oberstein A, von Zitzewitz H, Schweden F, et al. Non invasive evaluation of the inflammatory activity in sarcoidosis with high-resolution computed tomography. Sarcoidosis Vasc Diffuse Lung Dis. 1997;14:65-72.
60. Gibson G, Prescott RJ, Muers MF, et al. British Thoracic Society Sarcoidosis study: effects of long term corticosteroid treatment. Thorax. 1996;51:238-247.
61. Baughman RP, Nunes H. Therapy for sarcoidosis: evidence-based recommendations. Expert Rev Clin Immunol. 2012;8:95-103.
62. Pietinalho A, Tukiainen P, Haahtela T, et al. Early treatment of stage II sarcoidosis improves 5-year pulmonary function. Chest. 2002;121:24-31.
63. Rahaghi FF, Baughman RP, Saketkoo LA, et al. Delphi consensus recommendations for a treatment algorithm in pulmonary sarcoidosis. Eur Respir Rev. 2020;29:190146.
64. Baughman RP, Iannuzzi MC, Lower EE, et al. Use of fluticasone in acute symptomatic pulmonary sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis. 2002;19:198-204.
65. du Bois RM, Greenhalgh PM, Southcott AM, et al. Randomized trial of inhaled fluticasone propionate in chronic stable pulmonary sarcoidosis: a pilot study. Eur Respir J. 1999;13:1345-1350.
66. Milman N, Graudal N, Grode G, Munch E. No effect of high‐dose inhaled steroids in pulmonary sarcoidosis: a double‐blind, placebo‐controlled study. J Intern Med. 1994;236:285-290.
67. Baughman RP, Winget DB, Lower EE. Methotrexate is steroid sparing in acute sarcoidosis: results of a double blind, randomized trial. Sarcoidosis Vasc Diffuse Lung Dis. 2000;17:60-66.
68. Vorselaars ADM, Wuyts WA, Vorselaars VMM, et al. Methotrexate vs azathioprine in second-line therapy of sarcoidosis. Chest. 2013;144:805-812.
69. Sahoo D, Bandyopadhyay D, Xu M, et al. Effectiveness and safety of leflunomide for pulmonary and extrapulmonary sarcoidosis. Eur Respir J. 2011;38:1145-1150.
70. Baughman RP, Drent M, Kavuru M, et al. Infliximab therapy in patients with chronic sarcoidosis and pulmonary involvement. Am J Resp Crit Care Med . 2006;174:795-802.
71. Rossman MD, Newman LS, Baughman RP, et al. A double-blinded, randomized, placebo-controlled trial of infliximab in subjects with active pulmonary sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis . 2006;23:201-208.
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74. Hamzeh N, Voelker A, Forssén A, et al. Efficacy of mycophenolate mofetil in sarcoidosis. Respir Med . 2014;108:1663-1669.
75. Brill A-K, Ott SR, Geiser T. Effect and safety of mycophenolate mofetil in chronic pulmonary sarcoidosis: a retrospective study. Respiration . 2013;86:376-383.
76. Baughman RP, Lower EE. Leflunomide for chronic sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis . 2004;21:43-48.
77. Sweiss NJ, Noth I, Mirsaeidi M, et al. Efficacy results of a 52-week trial of adalimumab in the treatment of refractory sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis . 2014;31:46-54.
78. Sweiss NJ, Lower EE, Mirsaeidi M, et al. Rituximab in the treatment of refractory pulmonary sarcoidosis. Eur Respir J . 2014;43:1525-1528.
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80. Drake WP, Oswald-Richter K, Richmond BW, et al. Oral antimycobacterial therapy in chronic cutaneous sarcoidosis: a randomized, single-masked, placebo-controlled study. Jama Dermatol . 2013;149:1040-1049.
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Sarcoidosis is a multisystem inflammatory disease of unclear etiology that primarily affects the lungs. It can occur at any age but usually develops before the age of 50 years, with an initial peak incidence at 20 to 29 years and a second peak incidence after 50 years of age, especially among women in Scandinavia and Japan.1 Sarcoidosis affects men and women of all racial and ethnic groups throughout the world, but differences based on race, sex, and geography are noted.1
The highest rates are reported in northern European and African-American individuals, particularly in women.1,2 The adjusted annual incidence of sarcoidosis among African Americans is approximately 3 times that among White Americans3 and is more likely to be chronic and fatal in African Americans.3 The disease can be familial with a possible recessive inheritance mode with incomplete penetrance.4 Risk of sarcoidosis in monozygotic twins appears to be 80 times greater than that in the general population, which supports genetic factors accounting for two-thirds of disease susceptibility.5
Likely factors in the development of sarcoidosis
The exact cause of sarcoidosis is unknown, but we have insights into its pathogenesis and potential triggers.1,6-9 Genes involved are being identified: class I and II human leukocyte antigen (HLA) molecules are most consistently associated with risk of sarcoidosis. Environmental exposures can activate the innate immune system and precondition a susceptible individual to react to potential causative antigens in a highly polarized, antigen-specific Th1 immune response. The epithelioid granulomatous response involves local proinflammatory cytokine production and enhanced T-cell immunity at sites of inflammation.10 Granulomas generally form to confine pathogens, restrict inflammation, and protect surrounding tissue.11-13
ACCESS (A Case Control Etiologic Study of Sarcoidosis) identified several environmental exposures such as chemicals used in the agriculture industry, mold or mildew, and musty odors at work.14 Tobacco use was not associated with sarcoidosis.14 Recent studies have shown positive associations with service in the US Navy,15 metal working,16 firefighting,17 the handling of building supplies,18 and onsite exposure while assisting in rescue efforts at the World Trade Center disaster.19 Other data support the likelihood that specific environmental exposures associated with microbe-rich environments modestly increase the risk of sarcoidosis.14 Mycobacterial and propionibacterial DNA and RNA are potentially associated with sarcoidosis.20
Clinical manifestations are nonspecific
The diagnosis of sarcoidosis can be difficult and delayed due to diverse organ involvement and nonspecific presentations. TABLE 121-31 shows the diverse manifestations in a patient with suspected sarcoidosis. Around 50% of the patients are asymptomatic.23,24 Sarcoidosis is a diagnosis of exclusion, starting with a detailed history to rule out infections, occupational or environmental exposures, malignancies, and other possible disorders (TABLE 2).22
Diagnostic work-up
Radiologic studies
Chest x-ray (CXR) provides diagnostic and prognostic information in the evaluation of sarcoidosis using the Scadding classification system (FIGURE 1).21,25,32,33 Interobserver variability, especially between stages II and III and III and IV is the major limitation of this system.32 At presentation, radiographs are abnormal in approximately 90% of patients.34 Lymphadenopathy is the most common radiographic abnormality, occurring in more than two-thirds of cases, and pulmonary opacities (nodules and reticulation) with a middle to upper lobe predilection are present in 20% to 50% of patients.1,31,35 The nodules vary in size and can coalesce and cause alveolar collapse, thus producing consolidation.36 Linear opacities radiating laterally from the hilum into the middle and upper zones are characteristic in fibrotic disease.
Continue to: High-resoluton computed tomography
High-resolution computed tomography (HRCT). Micronodules in a perilymphatic distribution with upper lobe predominance combined with subcarinal and symmetrical hilar lymph node enlargement is practically diagnostic of sarcoidosis in the right clinical context. TABLE 321,23,25,32 and FIGURE 221,23,25,32 summarize the common CT chest findings of sarcoidosis.
Advanced imaging such as (18)F-fluorodeoxyglucose positron emission tomography (PET) and magnetic resonance imaging (MRI) are used in specialized settings for advanced pulmonary, cardiac, or neurosarcoidosis.
Tissue biopsy
Skin lesions (other than erythema nodosum), eye lesions, and peripheral lymph nodes are considered the safest extrapulmonary locations for biopsy.21,25 If pulmonary infiltrates or lymphadenopathy are present, or if extrapulmonary biopsy sites are not available, then flexible bronchoscopy with biopsy is the mainstay for tissue sampling.25
Bronchoalveolar lavage (BAL), transbronchial biopsy (TBB), endobronchial biopsy (EBB), and endobronchial ultrasound (EBUS) are invaluable modalities that have reduced the need for open lung biopsy. BAL in sarcoidosis can show lymphocytosis > 15% (nonspecific) and a CD4:CD8 lymphocyte ratio > 3.5 (specificity > 90%).21,22 TBB is more sensitive than EBB; however, sensitivity overall is heightened when both of them are combined. The advent of EBUS has increased the safety and efficiency of needle aspiration of mediastinal lymph nodes. Diagnostic yield of EBUS (~80%) is superior to that with TBB and EBB (~50%), especially in stage I and II sarcoidosis.37 The combination of EBUS with TBB improves the diagnostic yield to ~90%.37
The decision to obtain biopsy samples hinges on the nature of clinical and radiologic findings (FIGURE 3).22,25,26
Continue to: Laboratory studies
Laboratory studies
Multiple abnormalities may be seen in sarcoidosis, and specific lab tests may help support a diagnosis of sarcoidosis or detect organ-specific disease activity (TABLE 4).22,23,25,38 However, no consistently accurate biomarkers exist for use in clinical practice. An angiotensin-converting enzyme (ACE) level greater than 2 times the upper limit of normal may be helpful; however, sensitivity remains low, and genetic polymorphisms can influence the ACE level.25 Biomarkers sometimes used to assess disease activity are serum interleukin-2 receptor, neopterin, chitotriosidase, lysozyme, KL-6 glycoprotein, and amyloid A.21
Additional tests to assess specific features or organ involvement
Pulmonary function testing (PFT) is reviewed in detail below under “pulmonary sarcoidosis.”
Electrocardiogram (EKG)/transthoracic echocardiogram (TTE). EKG abnormalities—conduction disturbances, arrhythmias, or nonspecific ST segment and T-wave changes—are the most common nonspecific findings.30 TTE findings are also nonspecific but have value in assessing cardiac chamber size and function and myocardial involvement. TTE is indeed the most common screening modality for sarcoidosis-associated pulmonary hypertension (SAPH), which is definitively diagnosed by right heart catheterization (RHC). Further evaluation for cardiac sarcoidosis can be done with cardiac MRI or fluorodeoxyglucose PET in specialized settings.
Lumbar puncture (LP) may reveal lymphocytic infiltration in suspected neurosarcoidosis, but the finding is nonspecific and can reflect infection or malignancy. Oligoclonal bands may also be seen in about one-third of neurosarcoidosis cases, and it is imperative to rule out multiple sclerosis.28
Pulmonary sarcoidosis
Pulmonary sarcoidosis accounts for most of the morbidity, mortality, and health care use associated with sarcoidosis.39,40
Continue to: Pathology of early and advanced pulmonary sarcoidosis
Pathology of early and advanced pulmonary sarcoidosis
Sarcoidosis is characterized by coalescing, tightly clustered, nonnecrotizing granulomas in the lung (FIGURE 4), most often located along the lymphatic routes of the pleura, interlobular septa, and bronchovascular bundles.41 Granulomas contain epithelioid cells or multinucleated giant cells surrounded by a chronic lymphocytic infiltrate. Typically, intracytoplasmic inclusions, such as Schaumann bodies, asteroid bodies, and blue bodies of calcium oxalates are noted within giant cells.
In chronic disease, lymphocytic infiltrate vanishes and granulomas tend to become increasingly fibrotic and enlarge to form hyalinized nodules rich with densely eosinophilic collagen. In 10% to 30% of cases, the lungs undergo progressive fibrosis.40 Nonresolving inflammation appears to be the major cause of fibrosis and the peribronchovascular localization leading to marked bronchial distortion.
Clinical features, monitoring, and outcomes
Pulmonary involvement occurs in most patients with sarcoidosis, and subclinical pulmonary disease is generally present, even when extrathoracic manifestations predominate.23 Dry cough, dyspnea, and chest discomfort are the most common symptoms. Chest auscultation is usually unremarkable. Wheezing is more common in those with fibrosis and is attributed to airway-centric fibrosis.42 There is often a substantial delay between the onset of symptoms and the diagnosis of pulmonary sarcoidosis, as symptoms are nonspecific and might be mistaken for more common pulmonary diseases, such as asthma or chronic bronchitis.43
Since sarcoidosis can affect pulmonary parenchyma, interstitium, large and small airways, pulmonary vasculature, and respiratory muscles, the pattern of lung function impairment on PFT varies from normal to obstruction, restriction, isolated diffusion defect, or a combination of these. The typical physiologic abnormality is a restrictive ventilatory defect with a decreased diffusing capacity of the lung for carbon monoxide (DLCO). Extent of disease seen on HRCT correlates with level of restriction.44 Airway obstruction can be multifactorial and due to airway distortion (more likely to occur in fibrotic lung disease) and luminal disease.45-48 The 6-minute walk test and DLCO can also aid in the diagnosis of SAPH and advanced parenchymal lung disease.
While monitoring is done clinically and with testing (PFT and imaging) as needed, the optimal approach is unclear. Nevertheless, longitudinal monitoring with testing may provide useful management and prognostic information.40 Pulmonary function can remain stable in fibrotic sarcoidosis over extended periods and actually can improve in some patients.49 Serial spirometry, particularly forced vital capacity, is the most reliable tool for monitoring; when a decline in measurement occurs, chest radiography can elucidate the mechanism.50,51
Continue to: Because sarcoidosis is a multisystem disease...
Because sarcoidosis is a multisystem disease, caution needs to be exercised when evaluating a patient’s new or worsening respiratory symptoms to accurately determine the cause of symptoms and direct therapy accordingly. In addition to refractory inflammatory pulmonary disease, airway disease, infection, fibrosis, and SAPH, one needs to consider extrapulmonary involvement or complications such as cardiac or neurologic disease, musculoskeletal disease, depression, or fatigue. Adverse medication effects, deconditioning, or unrelated (or possibly related) disorders (eg pulmonary embolism) may be to blame.
Determining prognosis
Prognosis of sarcoidosis varies and depends on epidemiologic factors, clinical presentation, and course, as well as specific organ involvement. Patients may develop life-threatening pulmonary, cardiac, or neurologic complications. End-stage disease may require organ transplantation for eligible patients.
Most patients with pulmonary sarcoidosis experience clinical remission with minimal residual organ impairment and a favorable long-term outcome. Advanced pulmonary disease (known as APS) occurs in a small proportion of patients with sarcoidosis but accounts for most of the poor outcomes in sarcoidosis.40 APS is variably defined, but it generally includes pulmonary fibrosis, SAPH, and respiratory infection.
One percent to 5% of patients with sarcoidosis die from complications, and mortality is higher in women and African Americans.52 Mortality and morbidity may be increasing.53 The reasons behind these trends are unclear but could include true increases in disease incidence, better detection rates, greater severity of disease, or an aging population. Increased hospitalizations and health care use might be due to organ damage from granulomatous inflammation (and resultant fibrosis), complications associated with treatment, and psychosocial effects of the disease/treatment.
Management
Management consists primarily of anti-inflammatory or immunosuppressive therapies but can also include measures to address specific complications (such as fatigue) and organ transplant, as well as efforts to counter adverse medication effects. Other supportive and preventive measures may include, on a case-by-case basis, oxygen supplementation, vaccinations, or pulmonary rehabilitation. Details of these are found in other, more in-depth reviews on treatment; we will briefly review anti-inflammatory therapy, which forms the cornerstone of treatment in most patients with sarcoidosis.
Continue to: General approach to treatment decisions
General approach to treatment decisions. Anti-inflammatory therapy is used to reduce granulomatous inflammation, thereby preserving organ function and reducing symptoms. A decision to begin treatment is one shared with the patient and is based on symptoms and potential danger of organ system failure.54 Patients who are symptomatic or have progressive disease or physiologic impairment are generally candidates for treatment. Monitoring usually suffices for those who have minimal symptoms, stable disease, and preserved organ function.
Patients with pulmonary sarcoidosis at CXR stage 0 should not receive treatment, given that large, randomized trials have shown no meaningful benefit and that these patients have a high likelihood of spontaneous remission and excellent long-term prognosis.55-58 However, a subgroup of patients classified as stage 0/I on CXR may show parenchymal disease on HRCT,59 and, if more symptomatic, could be considered for treatment. For patients with stage II to IV pulmonary sarcoidosis with symptoms, there is good evidence that treatment may improve lung function and reduce dyspnea and fatigue.57,60-62
Corticosteroids are first-line treatment for most patients. Based on expert opinion, treatment of pulmonary sarcoidosis is generally started with oral prednisone (or an equivalent corticosteroid). A starting dose of 20 to 40 mg/d generally is sufficient for most patients. If the patient responds to initial treatment, prednisone dose is tapered over a period of months. If symptoms worsen during tapering, the minimum effective dose is maintained without further attempts at tapering. Treatment is continued for at least 3 to 6 months but it might be needed for longer durations; unfortunately, evidence-based guidelines are lacking.63 Once the patient goes into remission, close monitoring is done for possible relapses. Inhaled corticosteroids alone have not reduced symptoms or improved lung function in patients with pulmonary sarcoidosis.64-66
Steroid-sparing agents are added for many patients. For patients receiving chronic prednisone therapy (≥ 10 mg for > 6 months), steroid-sparing agents are considered to minimize the adverse effects of steroids or to better control the inflammatory activity of sarcoidosis. These agents must be carefully selected, and clinical and laboratory monitoring need to be done throughout therapy. TABLE 558,64,67-81
The management might be complicated for extrapulmonary, multi-organ, and advanced sarcoidosis (advanced pulmonary sarcoidosis, cardiac disease, neurosarcoidosis, lupus pernio, etc) when specialized testing, as well as a combination of corticosteroids and steroid-sparing agents (with higher doses or prolonged courses), might be needed. This should be performed at an expert sarcoidosis center, ideally in a multidisciplinary setting involving pulmonologists and/or rheumatologists, chest radiologists, and specialists as indicated, based on specific organ involvement.
Continue to: Research and future directions
Research and future directions
Key goals for research are identifying more accurate biomarkers of disease, improving diagnosis of multi-organ disease, determining validated endpoints of clinical trials in sarcoidosis, and developing treatments for refractory cases.
There is optimism and opportunity in the field of sarcoidosis overall. An example of an advancement is in the area of APS, as the severity and importance of this phenotype has been better understood. Worldwide registries and trials of pulmonary vasodilator therapy (bosentan, sildenafil, epoprostenol, and inhaled iloprost) in patients with SAPH without left ventricular dysfunction are promising.82-85 However, no benefit in survival has been shown.
RioSAPH is a double-blind, placebo-controlled trial of Riociguat (a stimulator of soluble guanylate cyclase) for SAPH (NCT02625558) that is closed to enrollment and undergoing data review. Similarly, results of the phase IV study of pirfenidone, an antifibrotic agent that was shown to decrease disease progression and deaths in idiopathic pulmonary fibrosis,86 are awaited in the near future.
Other potential directions being explored are multicenter patient registries and randomized controlled trials, analyses of existing databases, use of biobanking, and patient-centered outcome measures. Hopefully, the care of patients with sarcoidosis will become more evidence based with ongoing and upcoming research in this field.
CORRESPONDENCE
Rohit Gupta, MBBS, FCCP, 3401 North Broad Street, 7 Parkinson Pavilion, Philadelphia, PA 19140; rohit.gupta@tuhs.temple.edu
Sarcoidosis is a multisystem inflammatory disease of unclear etiology that primarily affects the lungs. It can occur at any age but usually develops before the age of 50 years, with an initial peak incidence at 20 to 29 years and a second peak incidence after 50 years of age, especially among women in Scandinavia and Japan.1 Sarcoidosis affects men and women of all racial and ethnic groups throughout the world, but differences based on race, sex, and geography are noted.1
The highest rates are reported in northern European and African-American individuals, particularly in women.1,2 The adjusted annual incidence of sarcoidosis among African Americans is approximately 3 times that among White Americans3 and is more likely to be chronic and fatal in African Americans.3 The disease can be familial with a possible recessive inheritance mode with incomplete penetrance.4 Risk of sarcoidosis in monozygotic twins appears to be 80 times greater than that in the general population, which supports genetic factors accounting for two-thirds of disease susceptibility.5
Likely factors in the development of sarcoidosis
The exact cause of sarcoidosis is unknown, but we have insights into its pathogenesis and potential triggers.1,6-9 Genes involved are being identified: class I and II human leukocyte antigen (HLA) molecules are most consistently associated with risk of sarcoidosis. Environmental exposures can activate the innate immune system and precondition a susceptible individual to react to potential causative antigens in a highly polarized, antigen-specific Th1 immune response. The epithelioid granulomatous response involves local proinflammatory cytokine production and enhanced T-cell immunity at sites of inflammation.10 Granulomas generally form to confine pathogens, restrict inflammation, and protect surrounding tissue.11-13
ACCESS (A Case Control Etiologic Study of Sarcoidosis) identified several environmental exposures such as chemicals used in the agriculture industry, mold or mildew, and musty odors at work.14 Tobacco use was not associated with sarcoidosis.14 Recent studies have shown positive associations with service in the US Navy,15 metal working,16 firefighting,17 the handling of building supplies,18 and onsite exposure while assisting in rescue efforts at the World Trade Center disaster.19 Other data support the likelihood that specific environmental exposures associated with microbe-rich environments modestly increase the risk of sarcoidosis.14 Mycobacterial and propionibacterial DNA and RNA are potentially associated with sarcoidosis.20
Clinical manifestations are nonspecific
The diagnosis of sarcoidosis can be difficult and delayed due to diverse organ involvement and nonspecific presentations. TABLE 121-31 shows the diverse manifestations in a patient with suspected sarcoidosis. Around 50% of the patients are asymptomatic.23,24 Sarcoidosis is a diagnosis of exclusion, starting with a detailed history to rule out infections, occupational or environmental exposures, malignancies, and other possible disorders (TABLE 2).22
Diagnostic work-up
Radiologic studies
Chest x-ray (CXR) provides diagnostic and prognostic information in the evaluation of sarcoidosis using the Scadding classification system (FIGURE 1).21,25,32,33 Interobserver variability, especially between stages II and III and III and IV is the major limitation of this system.32 At presentation, radiographs are abnormal in approximately 90% of patients.34 Lymphadenopathy is the most common radiographic abnormality, occurring in more than two-thirds of cases, and pulmonary opacities (nodules and reticulation) with a middle to upper lobe predilection are present in 20% to 50% of patients.1,31,35 The nodules vary in size and can coalesce and cause alveolar collapse, thus producing consolidation.36 Linear opacities radiating laterally from the hilum into the middle and upper zones are characteristic in fibrotic disease.
Continue to: High-resoluton computed tomography
High-resolution computed tomography (HRCT). Micronodules in a perilymphatic distribution with upper lobe predominance combined with subcarinal and symmetrical hilar lymph node enlargement is practically diagnostic of sarcoidosis in the right clinical context. TABLE 321,23,25,32 and FIGURE 221,23,25,32 summarize the common CT chest findings of sarcoidosis.
Advanced imaging such as (18)F-fluorodeoxyglucose positron emission tomography (PET) and magnetic resonance imaging (MRI) are used in specialized settings for advanced pulmonary, cardiac, or neurosarcoidosis.
Tissue biopsy
Skin lesions (other than erythema nodosum), eye lesions, and peripheral lymph nodes are considered the safest extrapulmonary locations for biopsy.21,25 If pulmonary infiltrates or lymphadenopathy are present, or if extrapulmonary biopsy sites are not available, then flexible bronchoscopy with biopsy is the mainstay for tissue sampling.25
Bronchoalveolar lavage (BAL), transbronchial biopsy (TBB), endobronchial biopsy (EBB), and endobronchial ultrasound (EBUS) are invaluable modalities that have reduced the need for open lung biopsy. BAL in sarcoidosis can show lymphocytosis > 15% (nonspecific) and a CD4:CD8 lymphocyte ratio > 3.5 (specificity > 90%).21,22 TBB is more sensitive than EBB; however, sensitivity overall is heightened when both of them are combined. The advent of EBUS has increased the safety and efficiency of needle aspiration of mediastinal lymph nodes. Diagnostic yield of EBUS (~80%) is superior to that with TBB and EBB (~50%), especially in stage I and II sarcoidosis.37 The combination of EBUS with TBB improves the diagnostic yield to ~90%.37
The decision to obtain biopsy samples hinges on the nature of clinical and radiologic findings (FIGURE 3).22,25,26
Continue to: Laboratory studies
Laboratory studies
Multiple abnormalities may be seen in sarcoidosis, and specific lab tests may help support a diagnosis of sarcoidosis or detect organ-specific disease activity (TABLE 4).22,23,25,38 However, no consistently accurate biomarkers exist for use in clinical practice. An angiotensin-converting enzyme (ACE) level greater than 2 times the upper limit of normal may be helpful; however, sensitivity remains low, and genetic polymorphisms can influence the ACE level.25 Biomarkers sometimes used to assess disease activity are serum interleukin-2 receptor, neopterin, chitotriosidase, lysozyme, KL-6 glycoprotein, and amyloid A.21
Additional tests to assess specific features or organ involvement
Pulmonary function testing (PFT) is reviewed in detail below under “pulmonary sarcoidosis.”
Electrocardiogram (EKG)/transthoracic echocardiogram (TTE). EKG abnormalities—conduction disturbances, arrhythmias, or nonspecific ST segment and T-wave changes—are the most common nonspecific findings.30 TTE findings are also nonspecific but have value in assessing cardiac chamber size and function and myocardial involvement. TTE is indeed the most common screening modality for sarcoidosis-associated pulmonary hypertension (SAPH), which is definitively diagnosed by right heart catheterization (RHC). Further evaluation for cardiac sarcoidosis can be done with cardiac MRI or fluorodeoxyglucose PET in specialized settings.
Lumbar puncture (LP) may reveal lymphocytic infiltration in suspected neurosarcoidosis, but the finding is nonspecific and can reflect infection or malignancy. Oligoclonal bands may also be seen in about one-third of neurosarcoidosis cases, and it is imperative to rule out multiple sclerosis.28
Pulmonary sarcoidosis
Pulmonary sarcoidosis accounts for most of the morbidity, mortality, and health care use associated with sarcoidosis.39,40
Continue to: Pathology of early and advanced pulmonary sarcoidosis
Pathology of early and advanced pulmonary sarcoidosis
Sarcoidosis is characterized by coalescing, tightly clustered, nonnecrotizing granulomas in the lung (FIGURE 4), most often located along the lymphatic routes of the pleura, interlobular septa, and bronchovascular bundles.41 Granulomas contain epithelioid cells or multinucleated giant cells surrounded by a chronic lymphocytic infiltrate. Typically, intracytoplasmic inclusions, such as Schaumann bodies, asteroid bodies, and blue bodies of calcium oxalates are noted within giant cells.
In chronic disease, lymphocytic infiltrate vanishes and granulomas tend to become increasingly fibrotic and enlarge to form hyalinized nodules rich with densely eosinophilic collagen. In 10% to 30% of cases, the lungs undergo progressive fibrosis.40 Nonresolving inflammation appears to be the major cause of fibrosis and the peribronchovascular localization leading to marked bronchial distortion.
Clinical features, monitoring, and outcomes
Pulmonary involvement occurs in most patients with sarcoidosis, and subclinical pulmonary disease is generally present, even when extrathoracic manifestations predominate.23 Dry cough, dyspnea, and chest discomfort are the most common symptoms. Chest auscultation is usually unremarkable. Wheezing is more common in those with fibrosis and is attributed to airway-centric fibrosis.42 There is often a substantial delay between the onset of symptoms and the diagnosis of pulmonary sarcoidosis, as symptoms are nonspecific and might be mistaken for more common pulmonary diseases, such as asthma or chronic bronchitis.43
Since sarcoidosis can affect pulmonary parenchyma, interstitium, large and small airways, pulmonary vasculature, and respiratory muscles, the pattern of lung function impairment on PFT varies from normal to obstruction, restriction, isolated diffusion defect, or a combination of these. The typical physiologic abnormality is a restrictive ventilatory defect with a decreased diffusing capacity of the lung for carbon monoxide (DLCO). Extent of disease seen on HRCT correlates with level of restriction.44 Airway obstruction can be multifactorial and due to airway distortion (more likely to occur in fibrotic lung disease) and luminal disease.45-48 The 6-minute walk test and DLCO can also aid in the diagnosis of SAPH and advanced parenchymal lung disease.
While monitoring is done clinically and with testing (PFT and imaging) as needed, the optimal approach is unclear. Nevertheless, longitudinal monitoring with testing may provide useful management and prognostic information.40 Pulmonary function can remain stable in fibrotic sarcoidosis over extended periods and actually can improve in some patients.49 Serial spirometry, particularly forced vital capacity, is the most reliable tool for monitoring; when a decline in measurement occurs, chest radiography can elucidate the mechanism.50,51
Continue to: Because sarcoidosis is a multisystem disease...
Because sarcoidosis is a multisystem disease, caution needs to be exercised when evaluating a patient’s new or worsening respiratory symptoms to accurately determine the cause of symptoms and direct therapy accordingly. In addition to refractory inflammatory pulmonary disease, airway disease, infection, fibrosis, and SAPH, one needs to consider extrapulmonary involvement or complications such as cardiac or neurologic disease, musculoskeletal disease, depression, or fatigue. Adverse medication effects, deconditioning, or unrelated (or possibly related) disorders (eg pulmonary embolism) may be to blame.
Determining prognosis
Prognosis of sarcoidosis varies and depends on epidemiologic factors, clinical presentation, and course, as well as specific organ involvement. Patients may develop life-threatening pulmonary, cardiac, or neurologic complications. End-stage disease may require organ transplantation for eligible patients.
Most patients with pulmonary sarcoidosis experience clinical remission with minimal residual organ impairment and a favorable long-term outcome. Advanced pulmonary disease (known as APS) occurs in a small proportion of patients with sarcoidosis but accounts for most of the poor outcomes in sarcoidosis.40 APS is variably defined, but it generally includes pulmonary fibrosis, SAPH, and respiratory infection.
One percent to 5% of patients with sarcoidosis die from complications, and mortality is higher in women and African Americans.52 Mortality and morbidity may be increasing.53 The reasons behind these trends are unclear but could include true increases in disease incidence, better detection rates, greater severity of disease, or an aging population. Increased hospitalizations and health care use might be due to organ damage from granulomatous inflammation (and resultant fibrosis), complications associated with treatment, and psychosocial effects of the disease/treatment.
Management
Management consists primarily of anti-inflammatory or immunosuppressive therapies but can also include measures to address specific complications (such as fatigue) and organ transplant, as well as efforts to counter adverse medication effects. Other supportive and preventive measures may include, on a case-by-case basis, oxygen supplementation, vaccinations, or pulmonary rehabilitation. Details of these are found in other, more in-depth reviews on treatment; we will briefly review anti-inflammatory therapy, which forms the cornerstone of treatment in most patients with sarcoidosis.
Continue to: General approach to treatment decisions
General approach to treatment decisions. Anti-inflammatory therapy is used to reduce granulomatous inflammation, thereby preserving organ function and reducing symptoms. A decision to begin treatment is one shared with the patient and is based on symptoms and potential danger of organ system failure.54 Patients who are symptomatic or have progressive disease or physiologic impairment are generally candidates for treatment. Monitoring usually suffices for those who have minimal symptoms, stable disease, and preserved organ function.
Patients with pulmonary sarcoidosis at CXR stage 0 should not receive treatment, given that large, randomized trials have shown no meaningful benefit and that these patients have a high likelihood of spontaneous remission and excellent long-term prognosis.55-58 However, a subgroup of patients classified as stage 0/I on CXR may show parenchymal disease on HRCT,59 and, if more symptomatic, could be considered for treatment. For patients with stage II to IV pulmonary sarcoidosis with symptoms, there is good evidence that treatment may improve lung function and reduce dyspnea and fatigue.57,60-62
Corticosteroids are first-line treatment for most patients. Based on expert opinion, treatment of pulmonary sarcoidosis is generally started with oral prednisone (or an equivalent corticosteroid). A starting dose of 20 to 40 mg/d generally is sufficient for most patients. If the patient responds to initial treatment, prednisone dose is tapered over a period of months. If symptoms worsen during tapering, the minimum effective dose is maintained without further attempts at tapering. Treatment is continued for at least 3 to 6 months but it might be needed for longer durations; unfortunately, evidence-based guidelines are lacking.63 Once the patient goes into remission, close monitoring is done for possible relapses. Inhaled corticosteroids alone have not reduced symptoms or improved lung function in patients with pulmonary sarcoidosis.64-66
Steroid-sparing agents are added for many patients. For patients receiving chronic prednisone therapy (≥ 10 mg for > 6 months), steroid-sparing agents are considered to minimize the adverse effects of steroids or to better control the inflammatory activity of sarcoidosis. These agents must be carefully selected, and clinical and laboratory monitoring need to be done throughout therapy. TABLE 558,64,67-81
The management might be complicated for extrapulmonary, multi-organ, and advanced sarcoidosis (advanced pulmonary sarcoidosis, cardiac disease, neurosarcoidosis, lupus pernio, etc) when specialized testing, as well as a combination of corticosteroids and steroid-sparing agents (with higher doses or prolonged courses), might be needed. This should be performed at an expert sarcoidosis center, ideally in a multidisciplinary setting involving pulmonologists and/or rheumatologists, chest radiologists, and specialists as indicated, based on specific organ involvement.
Continue to: Research and future directions
Research and future directions
Key goals for research are identifying more accurate biomarkers of disease, improving diagnosis of multi-organ disease, determining validated endpoints of clinical trials in sarcoidosis, and developing treatments for refractory cases.
There is optimism and opportunity in the field of sarcoidosis overall. An example of an advancement is in the area of APS, as the severity and importance of this phenotype has been better understood. Worldwide registries and trials of pulmonary vasodilator therapy (bosentan, sildenafil, epoprostenol, and inhaled iloprost) in patients with SAPH without left ventricular dysfunction are promising.82-85 However, no benefit in survival has been shown.
RioSAPH is a double-blind, placebo-controlled trial of Riociguat (a stimulator of soluble guanylate cyclase) for SAPH (NCT02625558) that is closed to enrollment and undergoing data review. Similarly, results of the phase IV study of pirfenidone, an antifibrotic agent that was shown to decrease disease progression and deaths in idiopathic pulmonary fibrosis,86 are awaited in the near future.
Other potential directions being explored are multicenter patient registries and randomized controlled trials, analyses of existing databases, use of biobanking, and patient-centered outcome measures. Hopefully, the care of patients with sarcoidosis will become more evidence based with ongoing and upcoming research in this field.
CORRESPONDENCE
Rohit Gupta, MBBS, FCCP, 3401 North Broad Street, 7 Parkinson Pavilion, Philadelphia, PA 19140; rohit.gupta@tuhs.temple.edu
1. Costabel U, Hunninghake G. ATS/ERS/WASOG statement on sarcoidosis. Sarcoidosis Statement Committee. American Thoracic Society. European Respiratory Society. World Association for Sarcoidosis and Other Granulomatous Disorders. Eur Respir J. 1999;14:735-737.
2. Hillerdal G, Nöu E, Osterman K, et al. Sarcoidosis: epidemiology and prognosis. A 15-year European study. Am Rev Respir Dis. 1984;130:29-32.
3. Mirsaeidi M, Machado RF, Schraufnagel D, et al. Racial difference in sarcoidosis mortality in the United States. Chest. 2015;147:438-449.
4. Rybicki BA, Iannuzzi MC, Frederick MM, et al. Familial aggregation of sarcoidosis. A case-control etiologic study of sarcoidosis (ACCESS). Am J Resp Crit Care Med. 2001;164:2085-2091.
5. Sverrild A, Backer V, Kyvik KO, et al. Heredity in sarcoidosis:a registry-based twin study. Thorax. 2008;63:894.
6. Vuyst P, Dumortier P, Schandené L, et al. Sarcoidlike lung granulomatosis induced by aluminum dusts. Am Rev Respir Dis. 1987;135:493-497.
7. Werfel U, Schneider J, Rödelsperger K, et al. Sarcoid granulomatosis after zirconium exposure with multiple organ involvement. European Respir J. 1998;12:750.
8. Newman KL, Newman LS. Occupational causes of sarcoidosis. Curr Opin Allergy Clin Immunol. 2012;12:145-150.
9. Zissel G, Müller-Quernheim J. Specific antigen(s) in sarcoidosis:a link to autoimmunity? Eur Respir J. 2016;47:707-709.
10. Chen ES, Moller DR. Etiology of sarcoidosis. Clin Chest Med. 2008;29:365-377.
11. Agostini C, Adami F, Semenzato G. New pathogenetic insights into the sarcoid granuloma. Curr Opin Rheumatol. 2000;12:71-76.
12. Valentonyte R, Hampe J, Huse K, et al. Sarcoidosis is associated with a truncating splice site mutation in BTNL2. Nat Genet. 2005;37:357-364.
13. Rybicki BA, Walewski JL, Maliarik MJ, et al. The BTNL2 gene and sarcoidosis susceptibility in African Americans and Whites. Am J Hum Genet. 2005;77:491-499.
14. Newman LS, Rose CS, Bresnitz EA, et al. A case control etiologic study of sarcoidosis: environmental and occupational risk factors. Am J Respir Crit Care Med. 2004;170:1324-1330.
15. Gorham ED, Garland CF, Garland FC, et al. Trends and occupational associations in incidence of hospitalized pulmonary sarcoidosis and other lung diseases in Navy personnel: a 27-year historical prospective study, 1975-2001. Chest. 2004;126:1431-1438.
16. Kucera GP, Rybicki BA, Kirkey KL, et al. Occupational risk factors for sarcoidosis in African-American siblings. Chest. 2003;123:1527-1535.
17. Prezant DJ, Dhala A, Goldstein A, et al. The incidence, prevalence, and severity of sarcoidosis in New York City firefighters. Chest. 1999;116:1183-1193.
18. Barnard J, Rose C, Newman L, et al. Job and industry classifications associated with sarcoidosis in A Case–Control Etiologic Study of Sarcoidosis (ACCESS). J Occup Environ Med. 2005;47:226-234.
19. Izbicki G, Chavko R, Banauch GI, et al. World Trade Center “sarcoid-like” granulomatous pulmonary disease in New York City Fire Department rescue workers. Chest. 2007;131:1414-1423.
20. Eishi Y, Suga M, Ishige I, et al. Quantitative analysis of mycobacterial and propionibacterial DNA in lymph nodes of Japanese and European patients with sarcoidosis. J Clin Microbiol. 2002;40:198-204.
21. Valeyre D, Prasse A, Nunes H, et al. Sarcoidosis. Lancet. 2014;383:1155-1167.
22. Crouser ED, Maier LA, Wilson KC, et al. Diagnosis and detection of sarcoidosis. An official American Thoracic Society clinical practice guideline. Am J Respir Crit Care Med. 2020;201:e26-51.
23. Judson MA, ed. Pulmonary Sarcoidosis: A Guide for the Practicing Clinician. Springer; 2014.
24. Govender P, Berman JS. The diagnosis of sarcoidosis. Clin Chest Med. 2015;36:585-602.
25. Valeyre D, Bernaudin J-F, Uzunhan Y, et al. Clinical presentation of sarcoidosis and diagnostic work-up. Semin Resp Crit Care Med. 2014;35:336-351.
26. Judson MA. The clinical features of sarcoidosis: a comprehensive review. Clin Rev Allergy Immunol. 2015;49:63-78.
27. Wanat KA, Rosenbach M. Cutaneous sarcoidosis. Clin Chest Med. 2015;36:685-702.
28. Culver DA, Neto ML, Moss BP, et al. Neurosarcoidosis. Semin Resp Crit Care Med. 2017;38:499-513.
29. Pasadhika S, Rosenbaum JT. Ocular sarcoidosis. Clin Chest Med. 2015;36:669-683.
30. Sayah DM, Bradfield JS, Moriarty JM, et al. Cardiac involvement in sarcoidosis: evolving concepts in diagnosis and treatment. Semin Resp Crit Care Med. 2017;38:477-498.
31. Baughman RP, Teirstein AS, Judson MA, et al. Clinical characteristics of patients in a case control study of sarcoidosis. Am J Resp Crit Care. 2012;164:1885-1889.
32. Keijsers RG, Veltkamp M, Grutters JC. Chest imaging. Clin Chest Med. 2015;36:603-619.
33. Scadding J. Prognosis of intrathoracic sarcoidosis in England. A review of 136 cases after five years’ observation. Brit Med J. 1961;2:1165-1172.
34. Miller B, Putman C. The chest radiograph and sarcoidosis. Reevaluation of the chest radiograph in assessing activity of sarcoidosis: a preliminary communication. Sarcoidosis. 1985;2:85-90.
35. Loddenkemper R, Kloppenborg A, Schoenfeld N, et al. Clinical findings in 715 patients with newly detected pulmonary sarcoidosis--results of a cooperative study in former West Germany and Switzerland. WATL Study Group. Wissenschaftliche Arbeitsgemeinschaft für die Therapie von Lungenkrankheitan. Sarcoidosis Vasc Diffuse Lung Dis. 1998;15:178-182.
36. Calandriello L, Walsh SLF. Imaging for sarcoidosis. Semin Resp Crit Care Med. 2017;38:417-436.
37. Gupta D, Dadhwal DS, Agarwal R, et al. Endobronchial ultrasound-guided transbronchial needle aspiration vs conventional transbronchial needle aspiration in the diagnosis of sarcoidosis. Chest. 2014;146:547-556.
38. Baydur A. Recent developments in the physiological assessment of sarcoidosis: clinical implications. Curr Opin Pulm Med. 2012;18:499-505.
39. Jamilloux Y, Maucort-Boulch D, Kerever S, et al. Sarcoidosis-related mortality in France: a multiple-cause-of-death analysis. Eur Respir J. 2016;48:1700-1709.
40. Gupta R, Baughman RP. Advanced pulmonary sarcoidosis. Semin Respir Crit Care Med. 2020;41:700-715.
41. Rossi G, Cavazza A, Colby TV. Pathology of sarcoidosis. Clin Rev Allergy Immunol. 2015;49:36-44.
42. Hansell D, Milne D, Wilsher M, et al. Pulmonary sarcoidosis: morphologic associations of airflow obstruction at thin-section CT. Radiology. 1998;209:697-704.
43. Judson MA, Thompson BW, Rabin DL, et al. The diagnostic pathway to sarcoidosis. Chest. 2003;123:406-412.
44. Müller NL, Mawson JB, Mathieson JR, et al. Sarcoidosis: correlation of extent of disease at CT with clinical, functional, and radiographic findings. Radiology. 1989;171:613-618.
45. Harrison BDW, Shaylor JM, Stokes TC, et al. Airflow limitation in sarcoidosis—a study of pulmonary function in 107 patients with newly diagnosed disease. Resp Med. 1991;85:59-64.
46. Polychronopoulos VS, Prakash UBS. Airway Involvement in sarcoidosis. Chest. 2009;136:1371-1380.
47. Chambellan A, Turbie P, Nunes H, et al. Endoluminal stenosis of proximal bronchi in sarcoidosis: bronchoscopy, function, and evolution. Chest. 2005;127:472-481.
48. Handa T, Nagai S, Fushimi Y, et al. Clinical and radiographic indices associated with airflow limitation in patients with sarcoidosis. Chest. 2006;130:1851-1856.
49. Nardi A, Brillet P-Y, Letoumelin P, et al. Stage IV sarcoidosis: comparison of survival with the general population and causes of death. Eur Respir J. 2011;38:1368-1373.
50. Zappala CJ, Desai SR, Copley SJ, et al. Accuracy of individual variables in the monitoring of long-term change in pulmonary sarcoidosis as judged by serial high-resolution CT scan data. Chest. 2014;145:101-107.
51. Gafà G, Sverzellati N, Bonati E, et al. Follow-up in pulmonary sarcoidosis: comparison between HRCT and pulmonary function tests. Radiol Med. 2012;117:968-978.
52. Gerke AK. Morbidity and mortality in sarcoidosis. Curr Opin Pulm Med. 2014;20:472-478.
53. Kearney GD, Obi ON, Maddipati V, et al. Sarcoidosis deaths in the United States: 1999–2016. Respir Med. 2019;149:30-35.
54. Baughman RP, Judson M, Wells A. The indications for the treatment of sarcoidosis: Wells Law. Sarcoidosis Vasc Diffuse Lung Dis. 2017;34:280-282.
55. Nagai S, Shigematsu M, Hamada K, et al. Clinical courses and prognoses of pulmonary sarcoidosis. Curr Opin Pulm Med. 1999;5:293-298.
56. Neville E, Walker AN, James DG. Prognostic factors predicting the outcome of sarcoidosis: an analysis of 818 patients. Q J Med. 1983;52:525-533.
57. Bradley B, Branley HM, Egan JJ, et al. Interstitial lung disease guideline: the British Thoracic Society in collaboration with the Thoracic Society of Australia and the Irish Thoracic Society. Thorax. 2008;63(suppl 5):v1-v58.
58. Pietinalho A, Tukiainen P, Haahtela T, et al. Oral prednisolone followed by inhaled budesonide in newly diagnosed pulmonary sarcoidosis: a double-blind, placebo-controlled multicenter study. Finnish Pulmonary Sarcoidosis Group. Chest. 1999;116:424-431.
59. Oberstein A, von Zitzewitz H, Schweden F, et al. Non invasive evaluation of the inflammatory activity in sarcoidosis with high-resolution computed tomography. Sarcoidosis Vasc Diffuse Lung Dis. 1997;14:65-72.
60. Gibson G, Prescott RJ, Muers MF, et al. British Thoracic Society Sarcoidosis study: effects of long term corticosteroid treatment. Thorax. 1996;51:238-247.
61. Baughman RP, Nunes H. Therapy for sarcoidosis: evidence-based recommendations. Expert Rev Clin Immunol. 2012;8:95-103.
62. Pietinalho A, Tukiainen P, Haahtela T, et al. Early treatment of stage II sarcoidosis improves 5-year pulmonary function. Chest. 2002;121:24-31.
63. Rahaghi FF, Baughman RP, Saketkoo LA, et al. Delphi consensus recommendations for a treatment algorithm in pulmonary sarcoidosis. Eur Respir Rev. 2020;29:190146.
64. Baughman RP, Iannuzzi MC, Lower EE, et al. Use of fluticasone in acute symptomatic pulmonary sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis. 2002;19:198-204.
65. du Bois RM, Greenhalgh PM, Southcott AM, et al. Randomized trial of inhaled fluticasone propionate in chronic stable pulmonary sarcoidosis: a pilot study. Eur Respir J. 1999;13:1345-1350.
66. Milman N, Graudal N, Grode G, Munch E. No effect of high‐dose inhaled steroids in pulmonary sarcoidosis: a double‐blind, placebo‐controlled study. J Intern Med. 1994;236:285-290.
67. Baughman RP, Winget DB, Lower EE. Methotrexate is steroid sparing in acute sarcoidosis: results of a double blind, randomized trial. Sarcoidosis Vasc Diffuse Lung Dis. 2000;17:60-66.
68. Vorselaars ADM, Wuyts WA, Vorselaars VMM, et al. Methotrexate vs azathioprine in second-line therapy of sarcoidosis. Chest. 2013;144:805-812.
69. Sahoo D, Bandyopadhyay D, Xu M, et al. Effectiveness and safety of leflunomide for pulmonary and extrapulmonary sarcoidosis. Eur Respir J. 2011;38:1145-1150.
70. Baughman RP, Drent M, Kavuru M, et al. Infliximab therapy in patients with chronic sarcoidosis and pulmonary involvement. Am J Resp Crit Care Med . 2006;174:795-802.
71. Rossman MD, Newman LS, Baughman RP, et al. A double-blinded, randomized, placebo-controlled trial of infliximab in subjects with active pulmonary sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis . 2006;23:201-208.
72. Selroos O, Sellergren T. Corticosteroid therapy of pulmonary sarcoidosis. A prospective evaluation of alternate day and daily dosage in stage II disease. Scand J Respir Dis . 1979;60:215-221.
73. Israel HL, Fouts DW, Beggs RA. A controlled trial of prednisone treatment of sarcoidosis. Am Rev Respir Dis . 1973;107:609-614.
74. Hamzeh N, Voelker A, Forssén A, et al. Efficacy of mycophenolate mofetil in sarcoidosis. Respir Med . 2014;108:1663-1669.
75. Brill A-K, Ott SR, Geiser T. Effect and safety of mycophenolate mofetil in chronic pulmonary sarcoidosis: a retrospective study. Respiration . 2013;86:376-383.
76. Baughman RP, Lower EE. Leflunomide for chronic sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis . 2004;21:43-48.
77. Sweiss NJ, Noth I, Mirsaeidi M, et al. Efficacy results of a 52-week trial of adalimumab in the treatment of refractory sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis . 2014;31:46-54.
78. Sweiss NJ, Lower EE, Mirsaeidi M, et al. Rituximab in the treatment of refractory pulmonary sarcoidosis. Eur Respir J . 2014;43:1525-1528.
79. Thatayatikom A, Thatayatikom S, White AJ. Infliximab treatment for severe granulomatous disease in common variable immunodeficiency: a case report and review of the literature. Ann Allergy Asthma Immunol . 2005;95:293-300.
80. Drake WP, Oswald-Richter K, Richmond BW, et al. Oral antimycobacterial therapy in chronic cutaneous sarcoidosis: a randomized, single-masked, placebo-controlled study. Jama Dermatol . 2013;149:1040-1049.
81. Drake WP, Richmond BW, Oswald-Richter K, et al. Effects of broad-spectrum antimycobacterial therapy on chronic pulmonary sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis . 2013;30:201-211.
82. Baughman RP, Culver DA, Cordova FC, et al. Bosentan for sarcoidosis-associated pulmonary hypertension: a double-blind placebo controlled randomized trial. Chest . 2014;145:810-817.
83. Baughman RP, Shlobin OA, Wells AU, et al. Clinical features of sarcoidosis associated pulmonary hypertension: results of a multi-national registry. Respir Med . 2018;139:72-78.
84. Fisher KA, Serlin DM, Wilson KC, et al. Sarcoidosis-associated pulmonary hypertension outcome with long-term epoprostenol treatment. Chest . 2006;130:1481-1488.
85. Baughman RP, Judson MA, Lower EE, et al. Inhaled iloprost for sarcoidosis associated pulmonary hypertension. Sarcoidosis Vasc Diffuse Lung Dis . 2009;26:110-120.
86. King TE, Bradford WZ, Castro-Bernardini S, et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med . 2014;370:2083-2092.
1. Costabel U, Hunninghake G. ATS/ERS/WASOG statement on sarcoidosis. Sarcoidosis Statement Committee. American Thoracic Society. European Respiratory Society. World Association for Sarcoidosis and Other Granulomatous Disorders. Eur Respir J. 1999;14:735-737.
2. Hillerdal G, Nöu E, Osterman K, et al. Sarcoidosis: epidemiology and prognosis. A 15-year European study. Am Rev Respir Dis. 1984;130:29-32.
3. Mirsaeidi M, Machado RF, Schraufnagel D, et al. Racial difference in sarcoidosis mortality in the United States. Chest. 2015;147:438-449.
4. Rybicki BA, Iannuzzi MC, Frederick MM, et al. Familial aggregation of sarcoidosis. A case-control etiologic study of sarcoidosis (ACCESS). Am J Resp Crit Care Med. 2001;164:2085-2091.
5. Sverrild A, Backer V, Kyvik KO, et al. Heredity in sarcoidosis:a registry-based twin study. Thorax. 2008;63:894.
6. Vuyst P, Dumortier P, Schandené L, et al. Sarcoidlike lung granulomatosis induced by aluminum dusts. Am Rev Respir Dis. 1987;135:493-497.
7. Werfel U, Schneider J, Rödelsperger K, et al. Sarcoid granulomatosis after zirconium exposure with multiple organ involvement. European Respir J. 1998;12:750.
8. Newman KL, Newman LS. Occupational causes of sarcoidosis. Curr Opin Allergy Clin Immunol. 2012;12:145-150.
9. Zissel G, Müller-Quernheim J. Specific antigen(s) in sarcoidosis:a link to autoimmunity? Eur Respir J. 2016;47:707-709.
10. Chen ES, Moller DR. Etiology of sarcoidosis. Clin Chest Med. 2008;29:365-377.
11. Agostini C, Adami F, Semenzato G. New pathogenetic insights into the sarcoid granuloma. Curr Opin Rheumatol. 2000;12:71-76.
12. Valentonyte R, Hampe J, Huse K, et al. Sarcoidosis is associated with a truncating splice site mutation in BTNL2. Nat Genet. 2005;37:357-364.
13. Rybicki BA, Walewski JL, Maliarik MJ, et al. The BTNL2 gene and sarcoidosis susceptibility in African Americans and Whites. Am J Hum Genet. 2005;77:491-499.
14. Newman LS, Rose CS, Bresnitz EA, et al. A case control etiologic study of sarcoidosis: environmental and occupational risk factors. Am J Respir Crit Care Med. 2004;170:1324-1330.
15. Gorham ED, Garland CF, Garland FC, et al. Trends and occupational associations in incidence of hospitalized pulmonary sarcoidosis and other lung diseases in Navy personnel: a 27-year historical prospective study, 1975-2001. Chest. 2004;126:1431-1438.
16. Kucera GP, Rybicki BA, Kirkey KL, et al. Occupational risk factors for sarcoidosis in African-American siblings. Chest. 2003;123:1527-1535.
17. Prezant DJ, Dhala A, Goldstein A, et al. The incidence, prevalence, and severity of sarcoidosis in New York City firefighters. Chest. 1999;116:1183-1193.
18. Barnard J, Rose C, Newman L, et al. Job and industry classifications associated with sarcoidosis in A Case–Control Etiologic Study of Sarcoidosis (ACCESS). J Occup Environ Med. 2005;47:226-234.
19. Izbicki G, Chavko R, Banauch GI, et al. World Trade Center “sarcoid-like” granulomatous pulmonary disease in New York City Fire Department rescue workers. Chest. 2007;131:1414-1423.
20. Eishi Y, Suga M, Ishige I, et al. Quantitative analysis of mycobacterial and propionibacterial DNA in lymph nodes of Japanese and European patients with sarcoidosis. J Clin Microbiol. 2002;40:198-204.
21. Valeyre D, Prasse A, Nunes H, et al. Sarcoidosis. Lancet. 2014;383:1155-1167.
22. Crouser ED, Maier LA, Wilson KC, et al. Diagnosis and detection of sarcoidosis. An official American Thoracic Society clinical practice guideline. Am J Respir Crit Care Med. 2020;201:e26-51.
23. Judson MA, ed. Pulmonary Sarcoidosis: A Guide for the Practicing Clinician. Springer; 2014.
24. Govender P, Berman JS. The diagnosis of sarcoidosis. Clin Chest Med. 2015;36:585-602.
25. Valeyre D, Bernaudin J-F, Uzunhan Y, et al. Clinical presentation of sarcoidosis and diagnostic work-up. Semin Resp Crit Care Med. 2014;35:336-351.
26. Judson MA. The clinical features of sarcoidosis: a comprehensive review. Clin Rev Allergy Immunol. 2015;49:63-78.
27. Wanat KA, Rosenbach M. Cutaneous sarcoidosis. Clin Chest Med. 2015;36:685-702.
28. Culver DA, Neto ML, Moss BP, et al. Neurosarcoidosis. Semin Resp Crit Care Med. 2017;38:499-513.
29. Pasadhika S, Rosenbaum JT. Ocular sarcoidosis. Clin Chest Med. 2015;36:669-683.
30. Sayah DM, Bradfield JS, Moriarty JM, et al. Cardiac involvement in sarcoidosis: evolving concepts in diagnosis and treatment. Semin Resp Crit Care Med. 2017;38:477-498.
31. Baughman RP, Teirstein AS, Judson MA, et al. Clinical characteristics of patients in a case control study of sarcoidosis. Am J Resp Crit Care. 2012;164:1885-1889.
32. Keijsers RG, Veltkamp M, Grutters JC. Chest imaging. Clin Chest Med. 2015;36:603-619.
33. Scadding J. Prognosis of intrathoracic sarcoidosis in England. A review of 136 cases after five years’ observation. Brit Med J. 1961;2:1165-1172.
34. Miller B, Putman C. The chest radiograph and sarcoidosis. Reevaluation of the chest radiograph in assessing activity of sarcoidosis: a preliminary communication. Sarcoidosis. 1985;2:85-90.
35. Loddenkemper R, Kloppenborg A, Schoenfeld N, et al. Clinical findings in 715 patients with newly detected pulmonary sarcoidosis--results of a cooperative study in former West Germany and Switzerland. WATL Study Group. Wissenschaftliche Arbeitsgemeinschaft für die Therapie von Lungenkrankheitan. Sarcoidosis Vasc Diffuse Lung Dis. 1998;15:178-182.
36. Calandriello L, Walsh SLF. Imaging for sarcoidosis. Semin Resp Crit Care Med. 2017;38:417-436.
37. Gupta D, Dadhwal DS, Agarwal R, et al. Endobronchial ultrasound-guided transbronchial needle aspiration vs conventional transbronchial needle aspiration in the diagnosis of sarcoidosis. Chest. 2014;146:547-556.
38. Baydur A. Recent developments in the physiological assessment of sarcoidosis: clinical implications. Curr Opin Pulm Med. 2012;18:499-505.
39. Jamilloux Y, Maucort-Boulch D, Kerever S, et al. Sarcoidosis-related mortality in France: a multiple-cause-of-death analysis. Eur Respir J. 2016;48:1700-1709.
40. Gupta R, Baughman RP. Advanced pulmonary sarcoidosis. Semin Respir Crit Care Med. 2020;41:700-715.
41. Rossi G, Cavazza A, Colby TV. Pathology of sarcoidosis. Clin Rev Allergy Immunol. 2015;49:36-44.
42. Hansell D, Milne D, Wilsher M, et al. Pulmonary sarcoidosis: morphologic associations of airflow obstruction at thin-section CT. Radiology. 1998;209:697-704.
43. Judson MA, Thompson BW, Rabin DL, et al. The diagnostic pathway to sarcoidosis. Chest. 2003;123:406-412.
44. Müller NL, Mawson JB, Mathieson JR, et al. Sarcoidosis: correlation of extent of disease at CT with clinical, functional, and radiographic findings. Radiology. 1989;171:613-618.
45. Harrison BDW, Shaylor JM, Stokes TC, et al. Airflow limitation in sarcoidosis—a study of pulmonary function in 107 patients with newly diagnosed disease. Resp Med. 1991;85:59-64.
46. Polychronopoulos VS, Prakash UBS. Airway Involvement in sarcoidosis. Chest. 2009;136:1371-1380.
47. Chambellan A, Turbie P, Nunes H, et al. Endoluminal stenosis of proximal bronchi in sarcoidosis: bronchoscopy, function, and evolution. Chest. 2005;127:472-481.
48. Handa T, Nagai S, Fushimi Y, et al. Clinical and radiographic indices associated with airflow limitation in patients with sarcoidosis. Chest. 2006;130:1851-1856.
49. Nardi A, Brillet P-Y, Letoumelin P, et al. Stage IV sarcoidosis: comparison of survival with the general population and causes of death. Eur Respir J. 2011;38:1368-1373.
50. Zappala CJ, Desai SR, Copley SJ, et al. Accuracy of individual variables in the monitoring of long-term change in pulmonary sarcoidosis as judged by serial high-resolution CT scan data. Chest. 2014;145:101-107.
51. Gafà G, Sverzellati N, Bonati E, et al. Follow-up in pulmonary sarcoidosis: comparison between HRCT and pulmonary function tests. Radiol Med. 2012;117:968-978.
52. Gerke AK. Morbidity and mortality in sarcoidosis. Curr Opin Pulm Med. 2014;20:472-478.
53. Kearney GD, Obi ON, Maddipati V, et al. Sarcoidosis deaths in the United States: 1999–2016. Respir Med. 2019;149:30-35.
54. Baughman RP, Judson M, Wells A. The indications for the treatment of sarcoidosis: Wells Law. Sarcoidosis Vasc Diffuse Lung Dis. 2017;34:280-282.
55. Nagai S, Shigematsu M, Hamada K, et al. Clinical courses and prognoses of pulmonary sarcoidosis. Curr Opin Pulm Med. 1999;5:293-298.
56. Neville E, Walker AN, James DG. Prognostic factors predicting the outcome of sarcoidosis: an analysis of 818 patients. Q J Med. 1983;52:525-533.
57. Bradley B, Branley HM, Egan JJ, et al. Interstitial lung disease guideline: the British Thoracic Society in collaboration with the Thoracic Society of Australia and the Irish Thoracic Society. Thorax. 2008;63(suppl 5):v1-v58.
58. Pietinalho A, Tukiainen P, Haahtela T, et al. Oral prednisolone followed by inhaled budesonide in newly diagnosed pulmonary sarcoidosis: a double-blind, placebo-controlled multicenter study. Finnish Pulmonary Sarcoidosis Group. Chest. 1999;116:424-431.
59. Oberstein A, von Zitzewitz H, Schweden F, et al. Non invasive evaluation of the inflammatory activity in sarcoidosis with high-resolution computed tomography. Sarcoidosis Vasc Diffuse Lung Dis. 1997;14:65-72.
60. Gibson G, Prescott RJ, Muers MF, et al. British Thoracic Society Sarcoidosis study: effects of long term corticosteroid treatment. Thorax. 1996;51:238-247.
61. Baughman RP, Nunes H. Therapy for sarcoidosis: evidence-based recommendations. Expert Rev Clin Immunol. 2012;8:95-103.
62. Pietinalho A, Tukiainen P, Haahtela T, et al. Early treatment of stage II sarcoidosis improves 5-year pulmonary function. Chest. 2002;121:24-31.
63. Rahaghi FF, Baughman RP, Saketkoo LA, et al. Delphi consensus recommendations for a treatment algorithm in pulmonary sarcoidosis. Eur Respir Rev. 2020;29:190146.
64. Baughman RP, Iannuzzi MC, Lower EE, et al. Use of fluticasone in acute symptomatic pulmonary sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis. 2002;19:198-204.
65. du Bois RM, Greenhalgh PM, Southcott AM, et al. Randomized trial of inhaled fluticasone propionate in chronic stable pulmonary sarcoidosis: a pilot study. Eur Respir J. 1999;13:1345-1350.
66. Milman N, Graudal N, Grode G, Munch E. No effect of high‐dose inhaled steroids in pulmonary sarcoidosis: a double‐blind, placebo‐controlled study. J Intern Med. 1994;236:285-290.
67. Baughman RP, Winget DB, Lower EE. Methotrexate is steroid sparing in acute sarcoidosis: results of a double blind, randomized trial. Sarcoidosis Vasc Diffuse Lung Dis. 2000;17:60-66.
68. Vorselaars ADM, Wuyts WA, Vorselaars VMM, et al. Methotrexate vs azathioprine in second-line therapy of sarcoidosis. Chest. 2013;144:805-812.
69. Sahoo D, Bandyopadhyay D, Xu M, et al. Effectiveness and safety of leflunomide for pulmonary and extrapulmonary sarcoidosis. Eur Respir J. 2011;38:1145-1150.
70. Baughman RP, Drent M, Kavuru M, et al. Infliximab therapy in patients with chronic sarcoidosis and pulmonary involvement. Am J Resp Crit Care Med . 2006;174:795-802.
71. Rossman MD, Newman LS, Baughman RP, et al. A double-blinded, randomized, placebo-controlled trial of infliximab in subjects with active pulmonary sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis . 2006;23:201-208.
72. Selroos O, Sellergren T. Corticosteroid therapy of pulmonary sarcoidosis. A prospective evaluation of alternate day and daily dosage in stage II disease. Scand J Respir Dis . 1979;60:215-221.
73. Israel HL, Fouts DW, Beggs RA. A controlled trial of prednisone treatment of sarcoidosis. Am Rev Respir Dis . 1973;107:609-614.
74. Hamzeh N, Voelker A, Forssén A, et al. Efficacy of mycophenolate mofetil in sarcoidosis. Respir Med . 2014;108:1663-1669.
75. Brill A-K, Ott SR, Geiser T. Effect and safety of mycophenolate mofetil in chronic pulmonary sarcoidosis: a retrospective study. Respiration . 2013;86:376-383.
76. Baughman RP, Lower EE. Leflunomide for chronic sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis . 2004;21:43-48.
77. Sweiss NJ, Noth I, Mirsaeidi M, et al. Efficacy results of a 52-week trial of adalimumab in the treatment of refractory sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis . 2014;31:46-54.
78. Sweiss NJ, Lower EE, Mirsaeidi M, et al. Rituximab in the treatment of refractory pulmonary sarcoidosis. Eur Respir J . 2014;43:1525-1528.
79. Thatayatikom A, Thatayatikom S, White AJ. Infliximab treatment for severe granulomatous disease in common variable immunodeficiency: a case report and review of the literature. Ann Allergy Asthma Immunol . 2005;95:293-300.
80. Drake WP, Oswald-Richter K, Richmond BW, et al. Oral antimycobacterial therapy in chronic cutaneous sarcoidosis: a randomized, single-masked, placebo-controlled study. Jama Dermatol . 2013;149:1040-1049.
81. Drake WP, Richmond BW, Oswald-Richter K, et al. Effects of broad-spectrum antimycobacterial therapy on chronic pulmonary sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis . 2013;30:201-211.
82. Baughman RP, Culver DA, Cordova FC, et al. Bosentan for sarcoidosis-associated pulmonary hypertension: a double-blind placebo controlled randomized trial. Chest . 2014;145:810-817.
83. Baughman RP, Shlobin OA, Wells AU, et al. Clinical features of sarcoidosis associated pulmonary hypertension: results of a multi-national registry. Respir Med . 2018;139:72-78.
84. Fisher KA, Serlin DM, Wilson KC, et al. Sarcoidosis-associated pulmonary hypertension outcome with long-term epoprostenol treatment. Chest . 2006;130:1481-1488.
85. Baughman RP, Judson MA, Lower EE, et al. Inhaled iloprost for sarcoidosis associated pulmonary hypertension. Sarcoidosis Vasc Diffuse Lung Dis . 2009;26:110-120.
86. King TE, Bradford WZ, Castro-Bernardini S, et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med . 2014;370:2083-2092.
PRACTICE RECOMMENDATIONS
› Consider biopsy to aid in diagnosing sarcoidosis; it may be avoided with a high clinical suspicion for sarcoidosis (eg, Löfgren syndrome, lupus pernio, or Heerfordt syndrome). C
› Rule out alternative diagnoses such as infection, malignancy, collagen vascular disease, and vasculitis. C
› Identify extra-pulmonary organ involvement, as clinically indicated, by screening with a baseline eye examination; complete blood count; creatinine, alkaline phosphatase, and calcium levels; electrocardiogram, and other organ-specific studies. C
› Make a patient-centered decision whether to begin antiinflammatory treatment based on symptomatology and risk of organ failure or death. C
Strength of recommendation (SOR)
A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series
2020 Focused Updates to the Asthma Management Guidelines
National Asthma Education and Prevention Program (NAEPP) published its last Expert Panel Report in 2007. Since that time, substantial progress has been made in understanding the pathophysiology and treatment of asthma. A new report has provided a much-needed update in the evaluation and management of asthma. It focuses on several priority topics jointly decided upon by the National Heart, Lung, and Blood Institute (NHLBI) Advisory Council Asthma Expert Working Group, the National Asthma Education and Prevention Program (NAEPP) participant organizations, and the public in 2015. These topics include the role of fractional exhaled nitric oxide (FeNO), allergen mitigation, intermittent inhaled corticosteroids (ICS), long-acting muscarinic agents (LAMA), immunotherapy, and bronchial thermoplasty (BT) in asthma management. This document did not include the subsequent new developments in the role of biologics in asthma. The following is a summary of the recommendations made in the 2020 Focused Updates to the Asthma Management Guidelines.1
FeNO measurement is recommended to aid in asthma diagnosis and monitoring and to assist in ICS medication titration in individuals with asthma who are 5 years and older. The panel recommends that clinicians use FeNO levels, in conjunction with other relevant clinical data such as spirometry and asthma control questionnaires, for medical decision making. Similarly, when using FeNO to guide therapeutic changes in the ICS dose, the panel advises making changes based upon frequent measurements as a part of longitudinal assessment rather than one single measurement, as several factors can influence an FeNO measurement. Studies have demonstrated that a strategy that incorporates FeNO measurements into a treatment algorithm can reduce the risk of exacerbations; however, this has not been shown to reduce hospitalizations or quality of life.2
Allergen mitigation interventions, which can be used in individuals of all ages, are only recommended for those who have symptoms related to specific indoor aeroallergens exposure. This can be confirmed by skin testing or specific IgE in the appropriate clinical setting if specific allergen testing is not readily available. While most recommendations focus on using a multicomponent approach to allergen mitigation (ie, dust mite covers, HEPA filters, air purifiers, carpet removal, mold remediation, pest or pest removal, etc), pest removal was the only single-component approach that was deemed effective. Dust mite covers alone are unlikely to lead to significant improvement if not paired with additional mitigation strategies; however, note that there was low certainty about these recommendations. Ultimately, allergen mitigation should focus on addressing those identified triggers resulting in poor control of asthma. Simultaneously, the clinician should consider the resources and costs associated with some of these interventions.
The panel has recommended using ICS therapy for on-demand (prn) usage, even in those with mild persistent asthma, recognizing that earlier and more frequent on-demand ICS usage results in fewer exacerbations. While the recommendations slightly differ based upon the age group, in those >12 years with mild persistent asthma, recommendations are for either daily ICS + as-needed short-acting beta-agonist (SABA), or as-needed ICS and SABA use. As in the Global Initiative for Asthma (GINA) guidelines, the panel also recommends single maintenance and rescue therapy (SMART) using ICS-formoterol inhalers for moderate to severe asthma. SMART has also been shown to reduce the risk of exacerbation. The clinician needs to use ICS-LABA medications where formoterol is the LABA component due to its quick onset of action (within 5 minutes, hence allowing it to be used as a rescue). Shared decision-making must be utilized when considering cost, insurance formulary restrictions, and perhaps delayed insurer and pharmacy adoption of these guidelines, as patients are likely to use more than one canister in a month when utilizing SMART.3,4
LAMA is a pharmacologic class of long-acting inhaled bronchodilators. Guidelines addressed the role of LAMA in individuals aged 12 years and older. Three recommendations are made regarding the role of LAMA in this age group. In individuals with persistent, uncontrolled asthma while using ICS therapy, the guidelines recommend the addition of a LABA over LAMA therapy.5 LAMA can be added to ICS in individuals with uncontrolled asthma who cannot use LABA or are already on ICS-LABA maintenance therapy.
For those patients with mild to moderate allergic asthma, as defined by allergic sensitization via skin testing or in-vitro elevated serum IgE levels, the expert panel conditionally recommends subcutaneous immunotherapy (SCIT) as an adjunct treatment to standard pharmacotherapy. It is recommended only in those patients whose asthma remains controlled throughout initiation, build-up, and maintenance phases. SCIT should not be used for patients with severe asthma, and all attempts should be made to optimize asthma with standard therapy first. The risks and benefits of SCIT should be discussed with the specialist before starting therapy. Sublingual immunotherapy (SLIT) is not recommended for the treatment of asthma.
Regarding BT, the Expert Panel conditionally recommends against BT in individuals age 18 years and older with persistent asthma because of the small benefit to risk ratio and uncertain outcomes. Because there is a risk of worsening asthma control or inducing an exacerbation, it is advised that BT not be performed in individuals with an FEV <50%-60% or those with a history of life-threatening asthma. If BT is considered, it should be performed by an experienced specialist and should be done in conjunction with a clinical trial or registry to track its long-term safety and effectiveness.6 All efforts should be made to optimize asthma therapy and address comorbidities before pursuing BT.
This Expert Panel report provides a robust systematic review of the evidence that addresses key questions in the management of asthma. However, not providing any recommendations regarding the use of biologics was a significant gap. Further guidance regarding their role can be found in the GINA guidelines, and by the European Respiratory Society and American Thoracic Society, both of which were also published in 2020.7,8Dr. Adrish is Clinical Assistant Professor, Bronx Care Health System, New York; Dr. Patil is Assistant Professor, Department of Respiratory Sleep and Critical Care Medicine, Maharashtra University of Health Sciences (MUHS), India; Dr. Oberle is Assistant Professor of Medicine, Associate Medical Director, Duke Asthma, Allergy and Airway Center, Durham, NC.
References
1. Expert Panel Working Group of the National Heart, Lung, and Blood Institute (NHLBI) administered and coordinated National Asthma Education and Prevention Program Coordinating Committee (NAEPPCC), et al. 2020 Focused Updates to the Asthma Management Guidelines: A Report from the National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group. J Allergy Clin Immunol. 2020 Dec;146(6):1217-1270. doi: 10.1016/j.jaci.2020.10.003. PMID: 33280709; PMCID: PMC7924476.
2. Zeiger RS, Schatz M, Zhang F, et al. Association of exhaled nitric oxide to asthma burden in asthmatics on inhaled corticosteroids. J Asthma. 2011;48:8-17.
3. Bacharier LB, Phillips BR, Zeiger RS, et al. Episodic use of an inhaled corticosteroid or leukotriene receptor antagonist in preschool children with moderate-to-severe intermittent wheezing. J Allergy Clin Immunol. 2008;122:1127-35.e8.
4. Zeiger RS, Mauger D, Bacharier LB, et al. Daily or intermittent budesonide in preschool children with recurrent wheezing. N Engl J Med. 2011;365:1990-2001.
5. Wechsler ME, Yawn BP, Fuhlbrigge AL, et al. Anticholinergic vs long-acting beta-agonist in combination with inhaled corticosteroids in black adults with asthma: The BELT randomized clinical trial. JAMA. 2015;314:1720-30.
6. Thomson NC, Rubin AS, Niven RM, et al. Long-term (5 year) safety of bronchial thermoplasty: Asthma Intervention Research (AIR) trial. BMC Pulm Med. 2011;11:8.
7. Global strategy for asthma management and prevention. 2020.
8. Holguin F, Cardet JC, Chung KF, et al. Management of severe asthma: a European Respiratory Society/American Thoracic Society guideline. Eur Respir J. 2020;55:1900588.
National Asthma Education and Prevention Program (NAEPP) published its last Expert Panel Report in 2007. Since that time, substantial progress has been made in understanding the pathophysiology and treatment of asthma. A new report has provided a much-needed update in the evaluation and management of asthma. It focuses on several priority topics jointly decided upon by the National Heart, Lung, and Blood Institute (NHLBI) Advisory Council Asthma Expert Working Group, the National Asthma Education and Prevention Program (NAEPP) participant organizations, and the public in 2015. These topics include the role of fractional exhaled nitric oxide (FeNO), allergen mitigation, intermittent inhaled corticosteroids (ICS), long-acting muscarinic agents (LAMA), immunotherapy, and bronchial thermoplasty (BT) in asthma management. This document did not include the subsequent new developments in the role of biologics in asthma. The following is a summary of the recommendations made in the 2020 Focused Updates to the Asthma Management Guidelines.1
FeNO measurement is recommended to aid in asthma diagnosis and monitoring and to assist in ICS medication titration in individuals with asthma who are 5 years and older. The panel recommends that clinicians use FeNO levels, in conjunction with other relevant clinical data such as spirometry and asthma control questionnaires, for medical decision making. Similarly, when using FeNO to guide therapeutic changes in the ICS dose, the panel advises making changes based upon frequent measurements as a part of longitudinal assessment rather than one single measurement, as several factors can influence an FeNO measurement. Studies have demonstrated that a strategy that incorporates FeNO measurements into a treatment algorithm can reduce the risk of exacerbations; however, this has not been shown to reduce hospitalizations or quality of life.2
Allergen mitigation interventions, which can be used in individuals of all ages, are only recommended for those who have symptoms related to specific indoor aeroallergens exposure. This can be confirmed by skin testing or specific IgE in the appropriate clinical setting if specific allergen testing is not readily available. While most recommendations focus on using a multicomponent approach to allergen mitigation (ie, dust mite covers, HEPA filters, air purifiers, carpet removal, mold remediation, pest or pest removal, etc), pest removal was the only single-component approach that was deemed effective. Dust mite covers alone are unlikely to lead to significant improvement if not paired with additional mitigation strategies; however, note that there was low certainty about these recommendations. Ultimately, allergen mitigation should focus on addressing those identified triggers resulting in poor control of asthma. Simultaneously, the clinician should consider the resources and costs associated with some of these interventions.
The panel has recommended using ICS therapy for on-demand (prn) usage, even in those with mild persistent asthma, recognizing that earlier and more frequent on-demand ICS usage results in fewer exacerbations. While the recommendations slightly differ based upon the age group, in those >12 years with mild persistent asthma, recommendations are for either daily ICS + as-needed short-acting beta-agonist (SABA), or as-needed ICS and SABA use. As in the Global Initiative for Asthma (GINA) guidelines, the panel also recommends single maintenance and rescue therapy (SMART) using ICS-formoterol inhalers for moderate to severe asthma. SMART has also been shown to reduce the risk of exacerbation. The clinician needs to use ICS-LABA medications where formoterol is the LABA component due to its quick onset of action (within 5 minutes, hence allowing it to be used as a rescue). Shared decision-making must be utilized when considering cost, insurance formulary restrictions, and perhaps delayed insurer and pharmacy adoption of these guidelines, as patients are likely to use more than one canister in a month when utilizing SMART.3,4
LAMA is a pharmacologic class of long-acting inhaled bronchodilators. Guidelines addressed the role of LAMA in individuals aged 12 years and older. Three recommendations are made regarding the role of LAMA in this age group. In individuals with persistent, uncontrolled asthma while using ICS therapy, the guidelines recommend the addition of a LABA over LAMA therapy.5 LAMA can be added to ICS in individuals with uncontrolled asthma who cannot use LABA or are already on ICS-LABA maintenance therapy.
For those patients with mild to moderate allergic asthma, as defined by allergic sensitization via skin testing or in-vitro elevated serum IgE levels, the expert panel conditionally recommends subcutaneous immunotherapy (SCIT) as an adjunct treatment to standard pharmacotherapy. It is recommended only in those patients whose asthma remains controlled throughout initiation, build-up, and maintenance phases. SCIT should not be used for patients with severe asthma, and all attempts should be made to optimize asthma with standard therapy first. The risks and benefits of SCIT should be discussed with the specialist before starting therapy. Sublingual immunotherapy (SLIT) is not recommended for the treatment of asthma.
Regarding BT, the Expert Panel conditionally recommends against BT in individuals age 18 years and older with persistent asthma because of the small benefit to risk ratio and uncertain outcomes. Because there is a risk of worsening asthma control or inducing an exacerbation, it is advised that BT not be performed in individuals with an FEV <50%-60% or those with a history of life-threatening asthma. If BT is considered, it should be performed by an experienced specialist and should be done in conjunction with a clinical trial or registry to track its long-term safety and effectiveness.6 All efforts should be made to optimize asthma therapy and address comorbidities before pursuing BT.
This Expert Panel report provides a robust systematic review of the evidence that addresses key questions in the management of asthma. However, not providing any recommendations regarding the use of biologics was a significant gap. Further guidance regarding their role can be found in the GINA guidelines, and by the European Respiratory Society and American Thoracic Society, both of which were also published in 2020.7,8Dr. Adrish is Clinical Assistant Professor, Bronx Care Health System, New York; Dr. Patil is Assistant Professor, Department of Respiratory Sleep and Critical Care Medicine, Maharashtra University of Health Sciences (MUHS), India; Dr. Oberle is Assistant Professor of Medicine, Associate Medical Director, Duke Asthma, Allergy and Airway Center, Durham, NC.
References
1. Expert Panel Working Group of the National Heart, Lung, and Blood Institute (NHLBI) administered and coordinated National Asthma Education and Prevention Program Coordinating Committee (NAEPPCC), et al. 2020 Focused Updates to the Asthma Management Guidelines: A Report from the National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group. J Allergy Clin Immunol. 2020 Dec;146(6):1217-1270. doi: 10.1016/j.jaci.2020.10.003. PMID: 33280709; PMCID: PMC7924476.
2. Zeiger RS, Schatz M, Zhang F, et al. Association of exhaled nitric oxide to asthma burden in asthmatics on inhaled corticosteroids. J Asthma. 2011;48:8-17.
3. Bacharier LB, Phillips BR, Zeiger RS, et al. Episodic use of an inhaled corticosteroid or leukotriene receptor antagonist in preschool children with moderate-to-severe intermittent wheezing. J Allergy Clin Immunol. 2008;122:1127-35.e8.
4. Zeiger RS, Mauger D, Bacharier LB, et al. Daily or intermittent budesonide in preschool children with recurrent wheezing. N Engl J Med. 2011;365:1990-2001.
5. Wechsler ME, Yawn BP, Fuhlbrigge AL, et al. Anticholinergic vs long-acting beta-agonist in combination with inhaled corticosteroids in black adults with asthma: The BELT randomized clinical trial. JAMA. 2015;314:1720-30.
6. Thomson NC, Rubin AS, Niven RM, et al. Long-term (5 year) safety of bronchial thermoplasty: Asthma Intervention Research (AIR) trial. BMC Pulm Med. 2011;11:8.
7. Global strategy for asthma management and prevention. 2020.
8. Holguin F, Cardet JC, Chung KF, et al. Management of severe asthma: a European Respiratory Society/American Thoracic Society guideline. Eur Respir J. 2020;55:1900588.
National Asthma Education and Prevention Program (NAEPP) published its last Expert Panel Report in 2007. Since that time, substantial progress has been made in understanding the pathophysiology and treatment of asthma. A new report has provided a much-needed update in the evaluation and management of asthma. It focuses on several priority topics jointly decided upon by the National Heart, Lung, and Blood Institute (NHLBI) Advisory Council Asthma Expert Working Group, the National Asthma Education and Prevention Program (NAEPP) participant organizations, and the public in 2015. These topics include the role of fractional exhaled nitric oxide (FeNO), allergen mitigation, intermittent inhaled corticosteroids (ICS), long-acting muscarinic agents (LAMA), immunotherapy, and bronchial thermoplasty (BT) in asthma management. This document did not include the subsequent new developments in the role of biologics in asthma. The following is a summary of the recommendations made in the 2020 Focused Updates to the Asthma Management Guidelines.1
FeNO measurement is recommended to aid in asthma diagnosis and monitoring and to assist in ICS medication titration in individuals with asthma who are 5 years and older. The panel recommends that clinicians use FeNO levels, in conjunction with other relevant clinical data such as spirometry and asthma control questionnaires, for medical decision making. Similarly, when using FeNO to guide therapeutic changes in the ICS dose, the panel advises making changes based upon frequent measurements as a part of longitudinal assessment rather than one single measurement, as several factors can influence an FeNO measurement. Studies have demonstrated that a strategy that incorporates FeNO measurements into a treatment algorithm can reduce the risk of exacerbations; however, this has not been shown to reduce hospitalizations or quality of life.2
Allergen mitigation interventions, which can be used in individuals of all ages, are only recommended for those who have symptoms related to specific indoor aeroallergens exposure. This can be confirmed by skin testing or specific IgE in the appropriate clinical setting if specific allergen testing is not readily available. While most recommendations focus on using a multicomponent approach to allergen mitigation (ie, dust mite covers, HEPA filters, air purifiers, carpet removal, mold remediation, pest or pest removal, etc), pest removal was the only single-component approach that was deemed effective. Dust mite covers alone are unlikely to lead to significant improvement if not paired with additional mitigation strategies; however, note that there was low certainty about these recommendations. Ultimately, allergen mitigation should focus on addressing those identified triggers resulting in poor control of asthma. Simultaneously, the clinician should consider the resources and costs associated with some of these interventions.
The panel has recommended using ICS therapy for on-demand (prn) usage, even in those with mild persistent asthma, recognizing that earlier and more frequent on-demand ICS usage results in fewer exacerbations. While the recommendations slightly differ based upon the age group, in those >12 years with mild persistent asthma, recommendations are for either daily ICS + as-needed short-acting beta-agonist (SABA), or as-needed ICS and SABA use. As in the Global Initiative for Asthma (GINA) guidelines, the panel also recommends single maintenance and rescue therapy (SMART) using ICS-formoterol inhalers for moderate to severe asthma. SMART has also been shown to reduce the risk of exacerbation. The clinician needs to use ICS-LABA medications where formoterol is the LABA component due to its quick onset of action (within 5 minutes, hence allowing it to be used as a rescue). Shared decision-making must be utilized when considering cost, insurance formulary restrictions, and perhaps delayed insurer and pharmacy adoption of these guidelines, as patients are likely to use more than one canister in a month when utilizing SMART.3,4
LAMA is a pharmacologic class of long-acting inhaled bronchodilators. Guidelines addressed the role of LAMA in individuals aged 12 years and older. Three recommendations are made regarding the role of LAMA in this age group. In individuals with persistent, uncontrolled asthma while using ICS therapy, the guidelines recommend the addition of a LABA over LAMA therapy.5 LAMA can be added to ICS in individuals with uncontrolled asthma who cannot use LABA or are already on ICS-LABA maintenance therapy.
For those patients with mild to moderate allergic asthma, as defined by allergic sensitization via skin testing or in-vitro elevated serum IgE levels, the expert panel conditionally recommends subcutaneous immunotherapy (SCIT) as an adjunct treatment to standard pharmacotherapy. It is recommended only in those patients whose asthma remains controlled throughout initiation, build-up, and maintenance phases. SCIT should not be used for patients with severe asthma, and all attempts should be made to optimize asthma with standard therapy first. The risks and benefits of SCIT should be discussed with the specialist before starting therapy. Sublingual immunotherapy (SLIT) is not recommended for the treatment of asthma.
Regarding BT, the Expert Panel conditionally recommends against BT in individuals age 18 years and older with persistent asthma because of the small benefit to risk ratio and uncertain outcomes. Because there is a risk of worsening asthma control or inducing an exacerbation, it is advised that BT not be performed in individuals with an FEV <50%-60% or those with a history of life-threatening asthma. If BT is considered, it should be performed by an experienced specialist and should be done in conjunction with a clinical trial or registry to track its long-term safety and effectiveness.6 All efforts should be made to optimize asthma therapy and address comorbidities before pursuing BT.
This Expert Panel report provides a robust systematic review of the evidence that addresses key questions in the management of asthma. However, not providing any recommendations regarding the use of biologics was a significant gap. Further guidance regarding their role can be found in the GINA guidelines, and by the European Respiratory Society and American Thoracic Society, both of which were also published in 2020.7,8Dr. Adrish is Clinical Assistant Professor, Bronx Care Health System, New York; Dr. Patil is Assistant Professor, Department of Respiratory Sleep and Critical Care Medicine, Maharashtra University of Health Sciences (MUHS), India; Dr. Oberle is Assistant Professor of Medicine, Associate Medical Director, Duke Asthma, Allergy and Airway Center, Durham, NC.
References
1. Expert Panel Working Group of the National Heart, Lung, and Blood Institute (NHLBI) administered and coordinated National Asthma Education and Prevention Program Coordinating Committee (NAEPPCC), et al. 2020 Focused Updates to the Asthma Management Guidelines: A Report from the National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group. J Allergy Clin Immunol. 2020 Dec;146(6):1217-1270. doi: 10.1016/j.jaci.2020.10.003. PMID: 33280709; PMCID: PMC7924476.
2. Zeiger RS, Schatz M, Zhang F, et al. Association of exhaled nitric oxide to asthma burden in asthmatics on inhaled corticosteroids. J Asthma. 2011;48:8-17.
3. Bacharier LB, Phillips BR, Zeiger RS, et al. Episodic use of an inhaled corticosteroid or leukotriene receptor antagonist in preschool children with moderate-to-severe intermittent wheezing. J Allergy Clin Immunol. 2008;122:1127-35.e8.
4. Zeiger RS, Mauger D, Bacharier LB, et al. Daily or intermittent budesonide in preschool children with recurrent wheezing. N Engl J Med. 2011;365:1990-2001.
5. Wechsler ME, Yawn BP, Fuhlbrigge AL, et al. Anticholinergic vs long-acting beta-agonist in combination with inhaled corticosteroids in black adults with asthma: The BELT randomized clinical trial. JAMA. 2015;314:1720-30.
6. Thomson NC, Rubin AS, Niven RM, et al. Long-term (5 year) safety of bronchial thermoplasty: Asthma Intervention Research (AIR) trial. BMC Pulm Med. 2011;11:8.
7. Global strategy for asthma management and prevention. 2020.
8. Holguin F, Cardet JC, Chung KF, et al. Management of severe asthma: a European Respiratory Society/American Thoracic Society guideline. Eur Respir J. 2020;55:1900588.
The Natural History of a Patient With COVID-19 Pneumonia and Silent Hypoxemia
In less than a year, COVID-19 has infected nearly 100 million people worldwide and caused more than 2 million deaths and counting. Although the infection fatality rate is estimated to be 1% and the case fatality rate between 2% and 3%, COVID-19 has had a disproportionate effect on the older population and those with comorbidities. Some of these findings are mirrored in the US Department of Veterans Affairs (VA) population, which has seen a higher case fatality rate.1-4
As a respiratory tract infection, the most dreaded presentation is severe pneumonia with acute hypoxemia, which may rapidly deteriorate to acute respiratory distress syndrome (ARDS) and respiratory failure.5-7 This possibility has led to early intubation strategies aimed at preempting this rapid deterioration and minimizing viral exposure to health care workers. Intubation rates have varied widely with extremes of 6 to 88%.8,9
However, this early intubation strategy has waned as some of the rationale behind its endorsement has been called into question. Early intubation bypasses alternatives to intubation; high-flow nasal cannula oxygen, noninvasive ventilation, and awake proning are all effective maneuvers in the appropriate patient.10,11 The use of first-line high-flow nasal cannula oxygen and noninvasive ventilation has been widely reported. Reports of first-line use of high-flow nasal cannula oxygen has not demonstrated inferior outcomes, nor has the timing of intubation, suggesting a significant portion of patients could benefit from a trial of therapy and eventually avoid intubation.11-14 Other therapies, such as systemic corticosteroids, confer a mortality benefit in those patients with COVID-19 who require oxygen or mechanical ventilation, but their impact on the progression of respiratory failure and need for intubation are undetermined.
There also are reports of patients who report no signs of respiratory distress or dyspnea with their COVID-19 pneumonia despite profound hypoxemia or high oxygen requirements. Various terms, including silent hypoxemia or happy hypoxia, are descriptive of the demeanor of these patients, and treatment has invariably included oxygen.15,16 Nevertheless, low oxygen measurements have generally prompted higher levels of supplemental oxygen or more invasive therapies.
Treatment rendered may obscure the trajectory of response, which is important to understand to better position options for invasive therapies and other therapeutics. We recently encountered a patient with a course of illness that represented the natural history of COVID-19 pneumonia with low oxygen levels (referred to as hypoxemia for consistency) that highlighted several issues of management.
Case Presentation
A 62-year-old undomiciled woman with morbid obesity, prediabetes mellitus, long-standing schizophrenia, and bipolar disorder presented to our facility for evaluation of dry cough and need for tuberculosis clearance for admittance to a shelter. She appeared comfortable and was afebrile with blood pressure 111/74 mm Hg, heart rate 82 beats per minute. Her respiratory rate was 18 breaths per minute, but the pulse oximetry showed oxygen saturation of 70 to 75% on room air at rest. A chest X-ray showed bibasilar infiltrates (Figure 1), and a rapid COVID-19 nasopharyngeal polymerase chain reaction (PCR) test returned positive, confirmed by a second PCR test. Baseline inflammatory markers were elevated (Figure 2). In addition, the serum interleukin-6 also was elevated to 66.1 pg/mL (normal < 5.0), erythrocyte sedimentation rate elevated to 69 mm/h, but serum procalcitonin was essentially normal (0.22 ng/mL; normal < 20 ng/mL) as was the serum lactate (1.4 mmol/L).
The patient was admitted to the intensive care unit (ICU) for close monitoring in anticipation of the possibility of decompensation based on her age, hypoxia, and elevated inflammatory markers.17 Besides a subsequent low-grade fever (100.4 oF) and lymphopenia (manual count 550/uL), she remained clinically unchanged. Throughout her hospitalization, she maintained a persistent psychotic delusion that she did not have COVID-19, refusing all medical interventions, including a peripheral IV line and supplemental oxygen for the entire duration. Extensive efforts to identify family or a surrogate decision maker were unsuccessful. After consultation with Psychiatry, Bio-Ethics, and hospital leadership, the patient was deemed to lack decision-making capacity regarding treatment or disposition and was placed on a psychiatric hold. However, since any interventions against her will would require sedation, IV access, and potentially increase the risk of nosocomial COVID-19 transmission, she was allowed to remain untreated and was closely monitored for symptoms of worsening respiratory failure.
Over the next 2 weeks, her hypoxemia, inflammatory markers, and the infiltrates on imaging resolved (Figure 2). The lowest daily awake room air pulse oximetry readings are reported, initially with consistent readings in the low 80% range, but on day 12, readings were > 90% and remained > 90% for the remainder of her hospitalization. Therefore, shortly after hospital day 12, she was clinically stable for discharge from acute care to a subacute facility, but this required documentation of the clearance of her viral infection. She refused to undergo a subsequent nasopharyngeal swab but allowed an oropharyngeal COVID-19 PCR swab, which was negative. She remained stable and unchanged for the remainder of her hospitalization, awaiting identification of a receiving facility and was able to be discharged to transitional housing on day 38.
Discussion
The initial reports of COVID-19 pneumonia focused on ARDS and respiratory failure requiring mechanical ventilation with less emphasis on those with lower severity of illness. This was heightened by health care systems that were overwhelmed with large number of patients while faced with limited supplies and equipment. Given the risk to patients and providers of crash intubations, some recommended early intubation strategies.3 However, the natural history of COVID-19 pneumonia and the threshold for intubation of these patients remain poorly defined despite the creation of prognostic tools.17 This patient’s persistent hypoxemia and elevated inflammatory markers certainly met markers of disease associated with a high risk of progression.
The greatest concern would have been her level of hypoxemia. Acceptable thresholds of hypoxemia vary, but general consensus would classify pulse oximetry < 90% as hypoxemia and a threshold for administering supplemental oxygen. It is important to recognize how pulse oximetry readings translate to partial pressure of oxygen (PaO2) measurements (Table 1). Pulse oximetry readings of 90% corresponds to a PaO2 readings of 60 mm Hg in ideal conditions without the influence of acidosis, PaCO2, or temperature. While lower readings are of concern, these do not represent absolute indications for assisted ventilatory support as lower levels are well tolerated in a variety of conditions. A common example are patients with chronic obstructive pulmonary disease. Long-term mortality benefits of continuous supplemental oxygen are well established in specific populations, but the threshold for correction in the acute setting remains a case-by-case decision. This decision is complex and is based on more than an absolute number or the amount of oxygen required to achieve a threshold level of oxygenation.
The PaO2/FIO2 (fraction of inspired oxygen) is a common measure used to address severity of disease and oxygen requirements. It also has been used to define the severity of ARDS, but the ratio is based on intubated and mechanically ventilated patients and may not translate well to those not on assisted ventilation. Treatment with supplemental oxygen also involves entrained air with associated imprecision in oxygen delivery.18 For this discussion, the patient’s admission PaO2/FIO2 on room air would have been between 190 and 260. Coupled with the bilateral infiltrates on imaging, there was justified concern for progression to severe ARDS. Her presentation would have met most of the epidemiologic criteria used in initial case finding for severe COVID-19 cases, including a blood oxygen saturation ≤ 93%, PaO2/FIO2 < 300 with infiltrates involving close to if not exceeding 50% of the lung.
With COVID-19 pneumonia, the pathologic injury to the alveoli resembles that of any viral pneumonia with recruitment of predominantly lymphocytic inflammatory cells that fill the alveoli, derangements in ventilation/perfusion mismatch as the core mechanism of hypoxemia with interstitial edema and shuntlike physiology developing at the extremes of involvement. In later stages, the histologic appearance is similar to ARDS, including hyaline membrane formation and thickened alveolar septa with perivascular lymphocytic-plasmocytic infiltration. In addition, there also are findings of organizing pneumonia with fibroblastic proliferation, thrombosis, and diffuse alveolar damage, a constellation of findings similar to that seen in the latter stages of ARDS.2
Although these histologic findings resemble ARDS, many patients with respiratory failure due to COVID-19 have a different physiologic profile compared with those with typical ARDS, with the most striking finding of lungs with low elastance or high compliance. From the critical care standpoint, this meant that the lungs were relatively easy to ventilate with lower peak airway and plateau pressures and low driving pressures. This condition suggested that there was relatively less lung that could be recruited with positive end expiratory pressure; therefore, a somewhat different entity from that associated with ARDS.19 These findings were often noted early in the course of respiratory failure, and although there is debate about whether this represents a different phenotype or timepoint in the spectrum of disease, it clearly represents a subset that is distinct from that which had been previously encountered.
On the other hand, the clinical features seen in those patients with COVID-19 pneumonia who progressed to advanced respiratory failure were essentially indistinguishable from those patients with traditional ARDS. Other explanations for this respiratory failure have included a disrupted vasoregulatory response to hypoxemia with failed hypoxic vasoconstriction, intravascular microthrombi, and impaired diffusion, all contributing to impaired gas exchange and hypoxemia.19-21 This can lead to shuntlike conditions that neither respond well to supplemental oxygen nor manifest the type of physiologic response seen with other causes of hypoxemia.
The severity of hypoxemia manifested by this patient may have elicited additional findings of respiratory distress, such as dyspnea and tachypnea. However, in patients with severe COVID-19 pneumonia, dyspnea was not a universal finding, reported in the 20 to 60% range of cohorts, higher in those with ARDS and mechanical ventilation, although some report near universal dyspnea in their series.1,4,8,22,23 Tachypnea is another symptom of interest. Using a threshold of > 24 breaths/min, tachypnea was noted in 16 to 29% of patients with a much greater proportion (63%) in nonsurvivors.6,24 Several explanations have been proposed for the discordance between the presence and severity of hypoxemia and lack of symptoms of dyspnea and tachypnea. It is important to recognize that misclassification of the severity of hypoxemia can occur due to technical issues and potential errors involving pulse oximetry measurement and shifts in the oxyhemoglobin dissociation curve. However, this is more pertinent for those with mild disease as the severity of hypoxemia in severe pneumonia is beyond what can be attributed to technical issues.
More important, the ventilatory response curve to hypoxemia may not be normal for some patients, blunted by as much as 50% in older patients, especially in those with diabetes mellitus.7,25,26 In addition, the ventilatory response varies widely even among normal individuals. This would translate to lower levels of minute ventilation (less tachypnea or respiratory effort) with hypoxemia. Hypocapnic hypoxemia also blunts the ventilatory response to hypoxemia. Subjects do not increase their minute ventilation if the PaCO2 remains low despite oxygen desaturation to < 70%, especially if PaCO2 < 30 mm Hg or alternatively, increases in minute ventilation are not seen until the PaCO2 exceeds 39 mm Hg.27 Both scenarios occur in those with COVID-19 pneumonia and provide another explanation for the absence of respiratory symptoms or signs of respiratory distress in some patients.
The observation of more compliant lungs may help in the understanding of the variable presentation of these patients. Compliant lungs do not require the increased pressure needed to achieve a specific tidal volume that, in turn, may increase the work of breathing. This may add to the explanation of seemingly paradoxical silent hypoxemia in those patients where the combination of a blunted ventilatory response, hypocapnia, shunt physiology, and normal respiratory system compliance is represented by the absence of increased breathing effort despite severe hypoxemia.
If not for the patient’s refusal of medical services, this patient quite possibly would have been intubated due to hypoxemia and health care providers’ concern for her risk of deterioration. Reported intubation and mechanical ventilation rates have varied widely from extremes of from < 5 to 88% in severely ill patients.9,22 About 75% will need oxygen, but many can be treated and recover without the need for intubation and mechanical ventilation.
As previously mentioned, options for treatment include standard and high-flow oxygen delivery, noninvasive ventilation, and awake prone ventilation. Their role in patient management has been recently outlined, and instead of an early intubation strategy, represents gradual escalation of support that may be sufficient to treat hypoxemia and avoid the need for intubation and mechanical ventilation (Table 2).
In addition, the patient’s hospital course was notable for the decline in known markers of active inflammation that mirrored the resolution of her hypoxemia and pneumonia. This included elevated lactate dehydrogenase, D-dimer, ferritin, and C-reactive protein with all but the latter rising and decreasing over 2 weeks. These findings provide additional information of the time for recovery and supports the use of these markers to monitor the course of pneumonia.
The patient declined all intervention, including oxygen, and recovered to her presumed prehospitalization condition. This experiment of nature due to unique circumstances may shed light on the natural time course of untreated hypoxemic COVID-19 pneumonia that has not previously been well appreciated. It is important to recognize that recovery occurred over 2 weeks. This is close to the observed and expected time for recovery that has been reported for those with severe COVID-19 pneumonia.
Conclusions
Since the emergence of the COVID-19, evidence has accumulated for the benefit of several adjunctive therapies in the treatment of this type of pneumonia, with corticosteroids providing a mortality benefit. Although unknown whether this patient’s experience can be generalized to others or whether it represents her unique response, this case provides another perspective for comparison of treatments and reinforces the need for prospective, randomized clinical trials to establish treatment efficacy. The exact nature of silent hypoxemia of COVID-19 remains incompletely understood; however, this case highlights the importance of treating the individual instead of clinical markers and provides a time course for recovery from pneumonia and severe hypoxemia that occurs without oxygen or any other treatment over about 2 weeks.
1. Ioannou GN, Locke E, Green P, et al. Risk factors for hospitalization, mechanical ventilation, or death among 10131 US veterans with SARS-CoV-2 infection. JAMA Netw Open. 2020;3(9):e2022310. doi:10.1001/jamanetworkopen.2020.22310
2. Wiersinga WJ, Rhodes A, Cheng AC, Peacock SJ, Prescott HC. Pathophysiology, transmission, diagnosis, and treatment of coronavirus disease 2019 (COVID-19): a review. JAMA. 2020;324(8):782-793. doi:10.1001/jama.2020.12839
3. Alhazzani W, Moller MH, Arabi YM, et al. Surviving sepsis campaign: guidelines on the management of critically ill adults with coronavirus disease 2019 (COVID-19). Crit Care Med. 2020;48(6):e440-e469. doi:10.1097/CCM.0000000000004363
4. Ziehr DR, Alladina J, Petri CR, et al. Respiratory pathophysiology of mechanically ventilated patients with COVID-19: a cohort study. Am J Respir Crit Care Med. 2020;201(12):1560-1564. doi:10.1164/rccm.202004-1163LE
5. Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72314 cases from the Chinese Center for Disease Control and Prevention. JAMA. 2020;323(13):1239-1242. doi:10.1001/jama.2020.2648
6. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054-1062. doi:10.1016/S01406736(20)30566-3
7. Tobin MJ, Laghi F, Jubran A. Why COVID-19 silent hypoxemia is baffling to physicians. Am J Respir Crit Care Med. 2020;202(3):356-360. doi:10.1164/rccm.202006-2157CP
8. Guan WJ, Ni ZY, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020;382(18):1708-1720. doi:10.1056/NEJMoa2002032
9. Grasselli G, Zangrillo A, Zanella A, et al. Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy Region, Italy. JAMA. 2020;323(16):1574-1581. doi:10.1001/jama.2020.5394
10. Raoof S, Nava S, Carpati C, Hill NS. High-flow, noninvasive ventilation and awake (nonintubation) proning in patients with coronavirus disease 2019 with respiratory failure. Chest. 2020;158(5):1992-2002. doi:10.1016/j.chest.2020.07.013
11. Ackermann M, Mentzer SJ, Jonigk D. Pulmonary vascular pathology in COVID-19. Reply. N Engl J Med. 2020;383(9):888-889. doi:10.1056/NEJMc2022068
12. McDonough G, Khaing P, Treacy T, McGrath C, Yoo EJ. The use of high-flow nasal oxygen in the ICU as a first-line therapy for acute hypoxemic respiratory failure secondary to coronavirus disease 2019. Crit Care Explor. 2020;2(10):e0257. doi:10.1097/CCE.0000000000000257
13. Hernandez-Romieu AC, Adelman MW, et al. Timing of intubation and mortality among critically ill coronavirus disease 2019 patients: a single-center cohort study. Crit Care Med. 2020;48(11):e1045-e1053. doi:10.1097/CCM.0000000000004600
14. Cummings MJ, Baldwin MR, Abrams D, et al. Epidemiology, clinical course, and outcomes of critically ill adults with COVID-19 in New York City: a prospective cohort study. Lancet. 2020;395(10239):1763-1770. doi:10.1016/S0140-6736(20)31189-2
15. Dhont S, Derom E, Van Braeckel E, Depuydt P, Lambrecht BN. The pathophysiology of ‘happy’ hypoxemia in COVID-19. Respir Res. 2020;21(1):198. doi:10.1186/s12931-020-01462-5
16. Wilkerson RG, Adler JD, Shah NG, Brown R. Silent hypoxia: a harbinger of clinical deterioration in patients with COVID-19. Am J Emerg Med. 2020;38(10):2243.e5-2243.e6. doi:10.1016/j.ajem.2020.05.044
17. Gong J, Ou J, Qiu X, et al. A tool for early prediction of severe coronavirus disease 2019 (COVID-19): a multicenter study using the risk nomogram in Wuhan and Guangdong, China. Clin Infect Dis. 2020;71(15):833-840. doi:10.1093/cid/ciaa443
18. Force ADT, Ranieri VM, Rubenfeld GD, et al. Acute respiratory distress syndrome: the Berlin Definition. JAMA. 2012;307(23):2526-2533. doi:10.1001/jama.2012.5669
19. Marini JJ, Gattinoni L. Management of COVID-19 respiratory distress. JAMA. 2020;323(22):2329-2330. doi:10.1001/jama.2020.6825
20. Schaller T, Hirschbuhl K, Burkhardt K, et al. Postmortem examination of patients with COVID-19. JAMA. 2020;323(24):2518-2520. doi:10.1001/jama.2020.8907
21. Ackermann M, Verleden SE, Kuehnel M, et al. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19. N Engl J Med. 2020;383(2):120-128. doi:10.1056/NEJMoa2015432
22. Wu C, Chen X, Cai Y, et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med. 2020;180(7):934-943. doi:10.1001/jamainternmed.2020.0994. Published correction appeared May 11, 2020. Errors in data and units of measure. doi:10.1001/jamainternmed.2020.1429
23. Yang J, Zheng Y, Gou X, et al. Prevalence of comorbidities and its effects in patients infected with SARS-CoV-2: a systematic review and meta-analysis. Int J Infect Dis. 2020;94:91-95. doi:10.1016/j.ijid.2020.03.017
24. Richardson S, Hirsch JS, Narasimhan M, et al. Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area. JAMA. 2020;323(20):2052-2059. doi:10.1001/jama.2020.6775
25. Tobin MJ, Jubran A, Laghi F. Misconceptions of pathophysiology of happy hypoxemia and implications for management of COVID-19. Respir Res. 2020;21(1):249. doi:10.1186/s12931-020-01520-y
26. Bickler PE, Feiner JR, Lipnick MS, McKleroy W. “Silent” presentation of hypoxemia and cardiorespiratory compensation in COVID-19. Anesthesiology. 2020;134(2):262-269. doi:10.1097/ALN.0000000000003578
27. Jounieaux V, Parreira VF, Aubert G, Dury M, Delguste P, Rodenstein DO. Effects of hypocapnic hyperventilation on the response to hypoxia in normal subjects receiving intermittent positive-pressure ventilation. Chest. 2002;121(4):1141-1148. doi:10.1378/chest.121.4.1141
In less than a year, COVID-19 has infected nearly 100 million people worldwide and caused more than 2 million deaths and counting. Although the infection fatality rate is estimated to be 1% and the case fatality rate between 2% and 3%, COVID-19 has had a disproportionate effect on the older population and those with comorbidities. Some of these findings are mirrored in the US Department of Veterans Affairs (VA) population, which has seen a higher case fatality rate.1-4
As a respiratory tract infection, the most dreaded presentation is severe pneumonia with acute hypoxemia, which may rapidly deteriorate to acute respiratory distress syndrome (ARDS) and respiratory failure.5-7 This possibility has led to early intubation strategies aimed at preempting this rapid deterioration and minimizing viral exposure to health care workers. Intubation rates have varied widely with extremes of 6 to 88%.8,9
However, this early intubation strategy has waned as some of the rationale behind its endorsement has been called into question. Early intubation bypasses alternatives to intubation; high-flow nasal cannula oxygen, noninvasive ventilation, and awake proning are all effective maneuvers in the appropriate patient.10,11 The use of first-line high-flow nasal cannula oxygen and noninvasive ventilation has been widely reported. Reports of first-line use of high-flow nasal cannula oxygen has not demonstrated inferior outcomes, nor has the timing of intubation, suggesting a significant portion of patients could benefit from a trial of therapy and eventually avoid intubation.11-14 Other therapies, such as systemic corticosteroids, confer a mortality benefit in those patients with COVID-19 who require oxygen or mechanical ventilation, but their impact on the progression of respiratory failure and need for intubation are undetermined.
There also are reports of patients who report no signs of respiratory distress or dyspnea with their COVID-19 pneumonia despite profound hypoxemia or high oxygen requirements. Various terms, including silent hypoxemia or happy hypoxia, are descriptive of the demeanor of these patients, and treatment has invariably included oxygen.15,16 Nevertheless, low oxygen measurements have generally prompted higher levels of supplemental oxygen or more invasive therapies.
Treatment rendered may obscure the trajectory of response, which is important to understand to better position options for invasive therapies and other therapeutics. We recently encountered a patient with a course of illness that represented the natural history of COVID-19 pneumonia with low oxygen levels (referred to as hypoxemia for consistency) that highlighted several issues of management.
Case Presentation
A 62-year-old undomiciled woman with morbid obesity, prediabetes mellitus, long-standing schizophrenia, and bipolar disorder presented to our facility for evaluation of dry cough and need for tuberculosis clearance for admittance to a shelter. She appeared comfortable and was afebrile with blood pressure 111/74 mm Hg, heart rate 82 beats per minute. Her respiratory rate was 18 breaths per minute, but the pulse oximetry showed oxygen saturation of 70 to 75% on room air at rest. A chest X-ray showed bibasilar infiltrates (Figure 1), and a rapid COVID-19 nasopharyngeal polymerase chain reaction (PCR) test returned positive, confirmed by a second PCR test. Baseline inflammatory markers were elevated (Figure 2). In addition, the serum interleukin-6 also was elevated to 66.1 pg/mL (normal < 5.0), erythrocyte sedimentation rate elevated to 69 mm/h, but serum procalcitonin was essentially normal (0.22 ng/mL; normal < 20 ng/mL) as was the serum lactate (1.4 mmol/L).
The patient was admitted to the intensive care unit (ICU) for close monitoring in anticipation of the possibility of decompensation based on her age, hypoxia, and elevated inflammatory markers.17 Besides a subsequent low-grade fever (100.4 oF) and lymphopenia (manual count 550/uL), she remained clinically unchanged. Throughout her hospitalization, she maintained a persistent psychotic delusion that she did not have COVID-19, refusing all medical interventions, including a peripheral IV line and supplemental oxygen for the entire duration. Extensive efforts to identify family or a surrogate decision maker were unsuccessful. After consultation with Psychiatry, Bio-Ethics, and hospital leadership, the patient was deemed to lack decision-making capacity regarding treatment or disposition and was placed on a psychiatric hold. However, since any interventions against her will would require sedation, IV access, and potentially increase the risk of nosocomial COVID-19 transmission, she was allowed to remain untreated and was closely monitored for symptoms of worsening respiratory failure.
Over the next 2 weeks, her hypoxemia, inflammatory markers, and the infiltrates on imaging resolved (Figure 2). The lowest daily awake room air pulse oximetry readings are reported, initially with consistent readings in the low 80% range, but on day 12, readings were > 90% and remained > 90% for the remainder of her hospitalization. Therefore, shortly after hospital day 12, she was clinically stable for discharge from acute care to a subacute facility, but this required documentation of the clearance of her viral infection. She refused to undergo a subsequent nasopharyngeal swab but allowed an oropharyngeal COVID-19 PCR swab, which was negative. She remained stable and unchanged for the remainder of her hospitalization, awaiting identification of a receiving facility and was able to be discharged to transitional housing on day 38.
Discussion
The initial reports of COVID-19 pneumonia focused on ARDS and respiratory failure requiring mechanical ventilation with less emphasis on those with lower severity of illness. This was heightened by health care systems that were overwhelmed with large number of patients while faced with limited supplies and equipment. Given the risk to patients and providers of crash intubations, some recommended early intubation strategies.3 However, the natural history of COVID-19 pneumonia and the threshold for intubation of these patients remain poorly defined despite the creation of prognostic tools.17 This patient’s persistent hypoxemia and elevated inflammatory markers certainly met markers of disease associated with a high risk of progression.
The greatest concern would have been her level of hypoxemia. Acceptable thresholds of hypoxemia vary, but general consensus would classify pulse oximetry < 90% as hypoxemia and a threshold for administering supplemental oxygen. It is important to recognize how pulse oximetry readings translate to partial pressure of oxygen (PaO2) measurements (Table 1). Pulse oximetry readings of 90% corresponds to a PaO2 readings of 60 mm Hg in ideal conditions without the influence of acidosis, PaCO2, or temperature. While lower readings are of concern, these do not represent absolute indications for assisted ventilatory support as lower levels are well tolerated in a variety of conditions. A common example are patients with chronic obstructive pulmonary disease. Long-term mortality benefits of continuous supplemental oxygen are well established in specific populations, but the threshold for correction in the acute setting remains a case-by-case decision. This decision is complex and is based on more than an absolute number or the amount of oxygen required to achieve a threshold level of oxygenation.
The PaO2/FIO2 (fraction of inspired oxygen) is a common measure used to address severity of disease and oxygen requirements. It also has been used to define the severity of ARDS, but the ratio is based on intubated and mechanically ventilated patients and may not translate well to those not on assisted ventilation. Treatment with supplemental oxygen also involves entrained air with associated imprecision in oxygen delivery.18 For this discussion, the patient’s admission PaO2/FIO2 on room air would have been between 190 and 260. Coupled with the bilateral infiltrates on imaging, there was justified concern for progression to severe ARDS. Her presentation would have met most of the epidemiologic criteria used in initial case finding for severe COVID-19 cases, including a blood oxygen saturation ≤ 93%, PaO2/FIO2 < 300 with infiltrates involving close to if not exceeding 50% of the lung.
With COVID-19 pneumonia, the pathologic injury to the alveoli resembles that of any viral pneumonia with recruitment of predominantly lymphocytic inflammatory cells that fill the alveoli, derangements in ventilation/perfusion mismatch as the core mechanism of hypoxemia with interstitial edema and shuntlike physiology developing at the extremes of involvement. In later stages, the histologic appearance is similar to ARDS, including hyaline membrane formation and thickened alveolar septa with perivascular lymphocytic-plasmocytic infiltration. In addition, there also are findings of organizing pneumonia with fibroblastic proliferation, thrombosis, and diffuse alveolar damage, a constellation of findings similar to that seen in the latter stages of ARDS.2
Although these histologic findings resemble ARDS, many patients with respiratory failure due to COVID-19 have a different physiologic profile compared with those with typical ARDS, with the most striking finding of lungs with low elastance or high compliance. From the critical care standpoint, this meant that the lungs were relatively easy to ventilate with lower peak airway and plateau pressures and low driving pressures. This condition suggested that there was relatively less lung that could be recruited with positive end expiratory pressure; therefore, a somewhat different entity from that associated with ARDS.19 These findings were often noted early in the course of respiratory failure, and although there is debate about whether this represents a different phenotype or timepoint in the spectrum of disease, it clearly represents a subset that is distinct from that which had been previously encountered.
On the other hand, the clinical features seen in those patients with COVID-19 pneumonia who progressed to advanced respiratory failure were essentially indistinguishable from those patients with traditional ARDS. Other explanations for this respiratory failure have included a disrupted vasoregulatory response to hypoxemia with failed hypoxic vasoconstriction, intravascular microthrombi, and impaired diffusion, all contributing to impaired gas exchange and hypoxemia.19-21 This can lead to shuntlike conditions that neither respond well to supplemental oxygen nor manifest the type of physiologic response seen with other causes of hypoxemia.
The severity of hypoxemia manifested by this patient may have elicited additional findings of respiratory distress, such as dyspnea and tachypnea. However, in patients with severe COVID-19 pneumonia, dyspnea was not a universal finding, reported in the 20 to 60% range of cohorts, higher in those with ARDS and mechanical ventilation, although some report near universal dyspnea in their series.1,4,8,22,23 Tachypnea is another symptom of interest. Using a threshold of > 24 breaths/min, tachypnea was noted in 16 to 29% of patients with a much greater proportion (63%) in nonsurvivors.6,24 Several explanations have been proposed for the discordance between the presence and severity of hypoxemia and lack of symptoms of dyspnea and tachypnea. It is important to recognize that misclassification of the severity of hypoxemia can occur due to technical issues and potential errors involving pulse oximetry measurement and shifts in the oxyhemoglobin dissociation curve. However, this is more pertinent for those with mild disease as the severity of hypoxemia in severe pneumonia is beyond what can be attributed to technical issues.
More important, the ventilatory response curve to hypoxemia may not be normal for some patients, blunted by as much as 50% in older patients, especially in those with diabetes mellitus.7,25,26 In addition, the ventilatory response varies widely even among normal individuals. This would translate to lower levels of minute ventilation (less tachypnea or respiratory effort) with hypoxemia. Hypocapnic hypoxemia also blunts the ventilatory response to hypoxemia. Subjects do not increase their minute ventilation if the PaCO2 remains low despite oxygen desaturation to < 70%, especially if PaCO2 < 30 mm Hg or alternatively, increases in minute ventilation are not seen until the PaCO2 exceeds 39 mm Hg.27 Both scenarios occur in those with COVID-19 pneumonia and provide another explanation for the absence of respiratory symptoms or signs of respiratory distress in some patients.
The observation of more compliant lungs may help in the understanding of the variable presentation of these patients. Compliant lungs do not require the increased pressure needed to achieve a specific tidal volume that, in turn, may increase the work of breathing. This may add to the explanation of seemingly paradoxical silent hypoxemia in those patients where the combination of a blunted ventilatory response, hypocapnia, shunt physiology, and normal respiratory system compliance is represented by the absence of increased breathing effort despite severe hypoxemia.
If not for the patient’s refusal of medical services, this patient quite possibly would have been intubated due to hypoxemia and health care providers’ concern for her risk of deterioration. Reported intubation and mechanical ventilation rates have varied widely from extremes of from < 5 to 88% in severely ill patients.9,22 About 75% will need oxygen, but many can be treated and recover without the need for intubation and mechanical ventilation.
As previously mentioned, options for treatment include standard and high-flow oxygen delivery, noninvasive ventilation, and awake prone ventilation. Their role in patient management has been recently outlined, and instead of an early intubation strategy, represents gradual escalation of support that may be sufficient to treat hypoxemia and avoid the need for intubation and mechanical ventilation (Table 2).
In addition, the patient’s hospital course was notable for the decline in known markers of active inflammation that mirrored the resolution of her hypoxemia and pneumonia. This included elevated lactate dehydrogenase, D-dimer, ferritin, and C-reactive protein with all but the latter rising and decreasing over 2 weeks. These findings provide additional information of the time for recovery and supports the use of these markers to monitor the course of pneumonia.
The patient declined all intervention, including oxygen, and recovered to her presumed prehospitalization condition. This experiment of nature due to unique circumstances may shed light on the natural time course of untreated hypoxemic COVID-19 pneumonia that has not previously been well appreciated. It is important to recognize that recovery occurred over 2 weeks. This is close to the observed and expected time for recovery that has been reported for those with severe COVID-19 pneumonia.
Conclusions
Since the emergence of the COVID-19, evidence has accumulated for the benefit of several adjunctive therapies in the treatment of this type of pneumonia, with corticosteroids providing a mortality benefit. Although unknown whether this patient’s experience can be generalized to others or whether it represents her unique response, this case provides another perspective for comparison of treatments and reinforces the need for prospective, randomized clinical trials to establish treatment efficacy. The exact nature of silent hypoxemia of COVID-19 remains incompletely understood; however, this case highlights the importance of treating the individual instead of clinical markers and provides a time course for recovery from pneumonia and severe hypoxemia that occurs without oxygen or any other treatment over about 2 weeks.
In less than a year, COVID-19 has infected nearly 100 million people worldwide and caused more than 2 million deaths and counting. Although the infection fatality rate is estimated to be 1% and the case fatality rate between 2% and 3%, COVID-19 has had a disproportionate effect on the older population and those with comorbidities. Some of these findings are mirrored in the US Department of Veterans Affairs (VA) population, which has seen a higher case fatality rate.1-4
As a respiratory tract infection, the most dreaded presentation is severe pneumonia with acute hypoxemia, which may rapidly deteriorate to acute respiratory distress syndrome (ARDS) and respiratory failure.5-7 This possibility has led to early intubation strategies aimed at preempting this rapid deterioration and minimizing viral exposure to health care workers. Intubation rates have varied widely with extremes of 6 to 88%.8,9
However, this early intubation strategy has waned as some of the rationale behind its endorsement has been called into question. Early intubation bypasses alternatives to intubation; high-flow nasal cannula oxygen, noninvasive ventilation, and awake proning are all effective maneuvers in the appropriate patient.10,11 The use of first-line high-flow nasal cannula oxygen and noninvasive ventilation has been widely reported. Reports of first-line use of high-flow nasal cannula oxygen has not demonstrated inferior outcomes, nor has the timing of intubation, suggesting a significant portion of patients could benefit from a trial of therapy and eventually avoid intubation.11-14 Other therapies, such as systemic corticosteroids, confer a mortality benefit in those patients with COVID-19 who require oxygen or mechanical ventilation, but their impact on the progression of respiratory failure and need for intubation are undetermined.
There also are reports of patients who report no signs of respiratory distress or dyspnea with their COVID-19 pneumonia despite profound hypoxemia or high oxygen requirements. Various terms, including silent hypoxemia or happy hypoxia, are descriptive of the demeanor of these patients, and treatment has invariably included oxygen.15,16 Nevertheless, low oxygen measurements have generally prompted higher levels of supplemental oxygen or more invasive therapies.
Treatment rendered may obscure the trajectory of response, which is important to understand to better position options for invasive therapies and other therapeutics. We recently encountered a patient with a course of illness that represented the natural history of COVID-19 pneumonia with low oxygen levels (referred to as hypoxemia for consistency) that highlighted several issues of management.
Case Presentation
A 62-year-old undomiciled woman with morbid obesity, prediabetes mellitus, long-standing schizophrenia, and bipolar disorder presented to our facility for evaluation of dry cough and need for tuberculosis clearance for admittance to a shelter. She appeared comfortable and was afebrile with blood pressure 111/74 mm Hg, heart rate 82 beats per minute. Her respiratory rate was 18 breaths per minute, but the pulse oximetry showed oxygen saturation of 70 to 75% on room air at rest. A chest X-ray showed bibasilar infiltrates (Figure 1), and a rapid COVID-19 nasopharyngeal polymerase chain reaction (PCR) test returned positive, confirmed by a second PCR test. Baseline inflammatory markers were elevated (Figure 2). In addition, the serum interleukin-6 also was elevated to 66.1 pg/mL (normal < 5.0), erythrocyte sedimentation rate elevated to 69 mm/h, but serum procalcitonin was essentially normal (0.22 ng/mL; normal < 20 ng/mL) as was the serum lactate (1.4 mmol/L).
The patient was admitted to the intensive care unit (ICU) for close monitoring in anticipation of the possibility of decompensation based on her age, hypoxia, and elevated inflammatory markers.17 Besides a subsequent low-grade fever (100.4 oF) and lymphopenia (manual count 550/uL), she remained clinically unchanged. Throughout her hospitalization, she maintained a persistent psychotic delusion that she did not have COVID-19, refusing all medical interventions, including a peripheral IV line and supplemental oxygen for the entire duration. Extensive efforts to identify family or a surrogate decision maker were unsuccessful. After consultation with Psychiatry, Bio-Ethics, and hospital leadership, the patient was deemed to lack decision-making capacity regarding treatment or disposition and was placed on a psychiatric hold. However, since any interventions against her will would require sedation, IV access, and potentially increase the risk of nosocomial COVID-19 transmission, she was allowed to remain untreated and was closely monitored for symptoms of worsening respiratory failure.
Over the next 2 weeks, her hypoxemia, inflammatory markers, and the infiltrates on imaging resolved (Figure 2). The lowest daily awake room air pulse oximetry readings are reported, initially with consistent readings in the low 80% range, but on day 12, readings were > 90% and remained > 90% for the remainder of her hospitalization. Therefore, shortly after hospital day 12, she was clinically stable for discharge from acute care to a subacute facility, but this required documentation of the clearance of her viral infection. She refused to undergo a subsequent nasopharyngeal swab but allowed an oropharyngeal COVID-19 PCR swab, which was negative. She remained stable and unchanged for the remainder of her hospitalization, awaiting identification of a receiving facility and was able to be discharged to transitional housing on day 38.
Discussion
The initial reports of COVID-19 pneumonia focused on ARDS and respiratory failure requiring mechanical ventilation with less emphasis on those with lower severity of illness. This was heightened by health care systems that were overwhelmed with large number of patients while faced with limited supplies and equipment. Given the risk to patients and providers of crash intubations, some recommended early intubation strategies.3 However, the natural history of COVID-19 pneumonia and the threshold for intubation of these patients remain poorly defined despite the creation of prognostic tools.17 This patient’s persistent hypoxemia and elevated inflammatory markers certainly met markers of disease associated with a high risk of progression.
The greatest concern would have been her level of hypoxemia. Acceptable thresholds of hypoxemia vary, but general consensus would classify pulse oximetry < 90% as hypoxemia and a threshold for administering supplemental oxygen. It is important to recognize how pulse oximetry readings translate to partial pressure of oxygen (PaO2) measurements (Table 1). Pulse oximetry readings of 90% corresponds to a PaO2 readings of 60 mm Hg in ideal conditions without the influence of acidosis, PaCO2, or temperature. While lower readings are of concern, these do not represent absolute indications for assisted ventilatory support as lower levels are well tolerated in a variety of conditions. A common example are patients with chronic obstructive pulmonary disease. Long-term mortality benefits of continuous supplemental oxygen are well established in specific populations, but the threshold for correction in the acute setting remains a case-by-case decision. This decision is complex and is based on more than an absolute number or the amount of oxygen required to achieve a threshold level of oxygenation.
The PaO2/FIO2 (fraction of inspired oxygen) is a common measure used to address severity of disease and oxygen requirements. It also has been used to define the severity of ARDS, but the ratio is based on intubated and mechanically ventilated patients and may not translate well to those not on assisted ventilation. Treatment with supplemental oxygen also involves entrained air with associated imprecision in oxygen delivery.18 For this discussion, the patient’s admission PaO2/FIO2 on room air would have been between 190 and 260. Coupled with the bilateral infiltrates on imaging, there was justified concern for progression to severe ARDS. Her presentation would have met most of the epidemiologic criteria used in initial case finding for severe COVID-19 cases, including a blood oxygen saturation ≤ 93%, PaO2/FIO2 < 300 with infiltrates involving close to if not exceeding 50% of the lung.
With COVID-19 pneumonia, the pathologic injury to the alveoli resembles that of any viral pneumonia with recruitment of predominantly lymphocytic inflammatory cells that fill the alveoli, derangements in ventilation/perfusion mismatch as the core mechanism of hypoxemia with interstitial edema and shuntlike physiology developing at the extremes of involvement. In later stages, the histologic appearance is similar to ARDS, including hyaline membrane formation and thickened alveolar septa with perivascular lymphocytic-plasmocytic infiltration. In addition, there also are findings of organizing pneumonia with fibroblastic proliferation, thrombosis, and diffuse alveolar damage, a constellation of findings similar to that seen in the latter stages of ARDS.2
Although these histologic findings resemble ARDS, many patients with respiratory failure due to COVID-19 have a different physiologic profile compared with those with typical ARDS, with the most striking finding of lungs with low elastance or high compliance. From the critical care standpoint, this meant that the lungs were relatively easy to ventilate with lower peak airway and plateau pressures and low driving pressures. This condition suggested that there was relatively less lung that could be recruited with positive end expiratory pressure; therefore, a somewhat different entity from that associated with ARDS.19 These findings were often noted early in the course of respiratory failure, and although there is debate about whether this represents a different phenotype or timepoint in the spectrum of disease, it clearly represents a subset that is distinct from that which had been previously encountered.
On the other hand, the clinical features seen in those patients with COVID-19 pneumonia who progressed to advanced respiratory failure were essentially indistinguishable from those patients with traditional ARDS. Other explanations for this respiratory failure have included a disrupted vasoregulatory response to hypoxemia with failed hypoxic vasoconstriction, intravascular microthrombi, and impaired diffusion, all contributing to impaired gas exchange and hypoxemia.19-21 This can lead to shuntlike conditions that neither respond well to supplemental oxygen nor manifest the type of physiologic response seen with other causes of hypoxemia.
The severity of hypoxemia manifested by this patient may have elicited additional findings of respiratory distress, such as dyspnea and tachypnea. However, in patients with severe COVID-19 pneumonia, dyspnea was not a universal finding, reported in the 20 to 60% range of cohorts, higher in those with ARDS and mechanical ventilation, although some report near universal dyspnea in their series.1,4,8,22,23 Tachypnea is another symptom of interest. Using a threshold of > 24 breaths/min, tachypnea was noted in 16 to 29% of patients with a much greater proportion (63%) in nonsurvivors.6,24 Several explanations have been proposed for the discordance between the presence and severity of hypoxemia and lack of symptoms of dyspnea and tachypnea. It is important to recognize that misclassification of the severity of hypoxemia can occur due to technical issues and potential errors involving pulse oximetry measurement and shifts in the oxyhemoglobin dissociation curve. However, this is more pertinent for those with mild disease as the severity of hypoxemia in severe pneumonia is beyond what can be attributed to technical issues.
More important, the ventilatory response curve to hypoxemia may not be normal for some patients, blunted by as much as 50% in older patients, especially in those with diabetes mellitus.7,25,26 In addition, the ventilatory response varies widely even among normal individuals. This would translate to lower levels of minute ventilation (less tachypnea or respiratory effort) with hypoxemia. Hypocapnic hypoxemia also blunts the ventilatory response to hypoxemia. Subjects do not increase their minute ventilation if the PaCO2 remains low despite oxygen desaturation to < 70%, especially if PaCO2 < 30 mm Hg or alternatively, increases in minute ventilation are not seen until the PaCO2 exceeds 39 mm Hg.27 Both scenarios occur in those with COVID-19 pneumonia and provide another explanation for the absence of respiratory symptoms or signs of respiratory distress in some patients.
The observation of more compliant lungs may help in the understanding of the variable presentation of these patients. Compliant lungs do not require the increased pressure needed to achieve a specific tidal volume that, in turn, may increase the work of breathing. This may add to the explanation of seemingly paradoxical silent hypoxemia in those patients where the combination of a blunted ventilatory response, hypocapnia, shunt physiology, and normal respiratory system compliance is represented by the absence of increased breathing effort despite severe hypoxemia.
If not for the patient’s refusal of medical services, this patient quite possibly would have been intubated due to hypoxemia and health care providers’ concern for her risk of deterioration. Reported intubation and mechanical ventilation rates have varied widely from extremes of from < 5 to 88% in severely ill patients.9,22 About 75% will need oxygen, but many can be treated and recover without the need for intubation and mechanical ventilation.
As previously mentioned, options for treatment include standard and high-flow oxygen delivery, noninvasive ventilation, and awake prone ventilation. Their role in patient management has been recently outlined, and instead of an early intubation strategy, represents gradual escalation of support that may be sufficient to treat hypoxemia and avoid the need for intubation and mechanical ventilation (Table 2).
In addition, the patient’s hospital course was notable for the decline in known markers of active inflammation that mirrored the resolution of her hypoxemia and pneumonia. This included elevated lactate dehydrogenase, D-dimer, ferritin, and C-reactive protein with all but the latter rising and decreasing over 2 weeks. These findings provide additional information of the time for recovery and supports the use of these markers to monitor the course of pneumonia.
The patient declined all intervention, including oxygen, and recovered to her presumed prehospitalization condition. This experiment of nature due to unique circumstances may shed light on the natural time course of untreated hypoxemic COVID-19 pneumonia that has not previously been well appreciated. It is important to recognize that recovery occurred over 2 weeks. This is close to the observed and expected time for recovery that has been reported for those with severe COVID-19 pneumonia.
Conclusions
Since the emergence of the COVID-19, evidence has accumulated for the benefit of several adjunctive therapies in the treatment of this type of pneumonia, with corticosteroids providing a mortality benefit. Although unknown whether this patient’s experience can be generalized to others or whether it represents her unique response, this case provides another perspective for comparison of treatments and reinforces the need for prospective, randomized clinical trials to establish treatment efficacy. The exact nature of silent hypoxemia of COVID-19 remains incompletely understood; however, this case highlights the importance of treating the individual instead of clinical markers and provides a time course for recovery from pneumonia and severe hypoxemia that occurs without oxygen or any other treatment over about 2 weeks.
1. Ioannou GN, Locke E, Green P, et al. Risk factors for hospitalization, mechanical ventilation, or death among 10131 US veterans with SARS-CoV-2 infection. JAMA Netw Open. 2020;3(9):e2022310. doi:10.1001/jamanetworkopen.2020.22310
2. Wiersinga WJ, Rhodes A, Cheng AC, Peacock SJ, Prescott HC. Pathophysiology, transmission, diagnosis, and treatment of coronavirus disease 2019 (COVID-19): a review. JAMA. 2020;324(8):782-793. doi:10.1001/jama.2020.12839
3. Alhazzani W, Moller MH, Arabi YM, et al. Surviving sepsis campaign: guidelines on the management of critically ill adults with coronavirus disease 2019 (COVID-19). Crit Care Med. 2020;48(6):e440-e469. doi:10.1097/CCM.0000000000004363
4. Ziehr DR, Alladina J, Petri CR, et al. Respiratory pathophysiology of mechanically ventilated patients with COVID-19: a cohort study. Am J Respir Crit Care Med. 2020;201(12):1560-1564. doi:10.1164/rccm.202004-1163LE
5. Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72314 cases from the Chinese Center for Disease Control and Prevention. JAMA. 2020;323(13):1239-1242. doi:10.1001/jama.2020.2648
6. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054-1062. doi:10.1016/S01406736(20)30566-3
7. Tobin MJ, Laghi F, Jubran A. Why COVID-19 silent hypoxemia is baffling to physicians. Am J Respir Crit Care Med. 2020;202(3):356-360. doi:10.1164/rccm.202006-2157CP
8. Guan WJ, Ni ZY, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020;382(18):1708-1720. doi:10.1056/NEJMoa2002032
9. Grasselli G, Zangrillo A, Zanella A, et al. Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy Region, Italy. JAMA. 2020;323(16):1574-1581. doi:10.1001/jama.2020.5394
10. Raoof S, Nava S, Carpati C, Hill NS. High-flow, noninvasive ventilation and awake (nonintubation) proning in patients with coronavirus disease 2019 with respiratory failure. Chest. 2020;158(5):1992-2002. doi:10.1016/j.chest.2020.07.013
11. Ackermann M, Mentzer SJ, Jonigk D. Pulmonary vascular pathology in COVID-19. Reply. N Engl J Med. 2020;383(9):888-889. doi:10.1056/NEJMc2022068
12. McDonough G, Khaing P, Treacy T, McGrath C, Yoo EJ. The use of high-flow nasal oxygen in the ICU as a first-line therapy for acute hypoxemic respiratory failure secondary to coronavirus disease 2019. Crit Care Explor. 2020;2(10):e0257. doi:10.1097/CCE.0000000000000257
13. Hernandez-Romieu AC, Adelman MW, et al. Timing of intubation and mortality among critically ill coronavirus disease 2019 patients: a single-center cohort study. Crit Care Med. 2020;48(11):e1045-e1053. doi:10.1097/CCM.0000000000004600
14. Cummings MJ, Baldwin MR, Abrams D, et al. Epidemiology, clinical course, and outcomes of critically ill adults with COVID-19 in New York City: a prospective cohort study. Lancet. 2020;395(10239):1763-1770. doi:10.1016/S0140-6736(20)31189-2
15. Dhont S, Derom E, Van Braeckel E, Depuydt P, Lambrecht BN. The pathophysiology of ‘happy’ hypoxemia in COVID-19. Respir Res. 2020;21(1):198. doi:10.1186/s12931-020-01462-5
16. Wilkerson RG, Adler JD, Shah NG, Brown R. Silent hypoxia: a harbinger of clinical deterioration in patients with COVID-19. Am J Emerg Med. 2020;38(10):2243.e5-2243.e6. doi:10.1016/j.ajem.2020.05.044
17. Gong J, Ou J, Qiu X, et al. A tool for early prediction of severe coronavirus disease 2019 (COVID-19): a multicenter study using the risk nomogram in Wuhan and Guangdong, China. Clin Infect Dis. 2020;71(15):833-840. doi:10.1093/cid/ciaa443
18. Force ADT, Ranieri VM, Rubenfeld GD, et al. Acute respiratory distress syndrome: the Berlin Definition. JAMA. 2012;307(23):2526-2533. doi:10.1001/jama.2012.5669
19. Marini JJ, Gattinoni L. Management of COVID-19 respiratory distress. JAMA. 2020;323(22):2329-2330. doi:10.1001/jama.2020.6825
20. Schaller T, Hirschbuhl K, Burkhardt K, et al. Postmortem examination of patients with COVID-19. JAMA. 2020;323(24):2518-2520. doi:10.1001/jama.2020.8907
21. Ackermann M, Verleden SE, Kuehnel M, et al. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19. N Engl J Med. 2020;383(2):120-128. doi:10.1056/NEJMoa2015432
22. Wu C, Chen X, Cai Y, et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med. 2020;180(7):934-943. doi:10.1001/jamainternmed.2020.0994. Published correction appeared May 11, 2020. Errors in data and units of measure. doi:10.1001/jamainternmed.2020.1429
23. Yang J, Zheng Y, Gou X, et al. Prevalence of comorbidities and its effects in patients infected with SARS-CoV-2: a systematic review and meta-analysis. Int J Infect Dis. 2020;94:91-95. doi:10.1016/j.ijid.2020.03.017
24. Richardson S, Hirsch JS, Narasimhan M, et al. Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area. JAMA. 2020;323(20):2052-2059. doi:10.1001/jama.2020.6775
25. Tobin MJ, Jubran A, Laghi F. Misconceptions of pathophysiology of happy hypoxemia and implications for management of COVID-19. Respir Res. 2020;21(1):249. doi:10.1186/s12931-020-01520-y
26. Bickler PE, Feiner JR, Lipnick MS, McKleroy W. “Silent” presentation of hypoxemia and cardiorespiratory compensation in COVID-19. Anesthesiology. 2020;134(2):262-269. doi:10.1097/ALN.0000000000003578
27. Jounieaux V, Parreira VF, Aubert G, Dury M, Delguste P, Rodenstein DO. Effects of hypocapnic hyperventilation on the response to hypoxia in normal subjects receiving intermittent positive-pressure ventilation. Chest. 2002;121(4):1141-1148. doi:10.1378/chest.121.4.1141
1. Ioannou GN, Locke E, Green P, et al. Risk factors for hospitalization, mechanical ventilation, or death among 10131 US veterans with SARS-CoV-2 infection. JAMA Netw Open. 2020;3(9):e2022310. doi:10.1001/jamanetworkopen.2020.22310
2. Wiersinga WJ, Rhodes A, Cheng AC, Peacock SJ, Prescott HC. Pathophysiology, transmission, diagnosis, and treatment of coronavirus disease 2019 (COVID-19): a review. JAMA. 2020;324(8):782-793. doi:10.1001/jama.2020.12839
3. Alhazzani W, Moller MH, Arabi YM, et al. Surviving sepsis campaign: guidelines on the management of critically ill adults with coronavirus disease 2019 (COVID-19). Crit Care Med. 2020;48(6):e440-e469. doi:10.1097/CCM.0000000000004363
4. Ziehr DR, Alladina J, Petri CR, et al. Respiratory pathophysiology of mechanically ventilated patients with COVID-19: a cohort study. Am J Respir Crit Care Med. 2020;201(12):1560-1564. doi:10.1164/rccm.202004-1163LE
5. Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72314 cases from the Chinese Center for Disease Control and Prevention. JAMA. 2020;323(13):1239-1242. doi:10.1001/jama.2020.2648
6. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054-1062. doi:10.1016/S01406736(20)30566-3
7. Tobin MJ, Laghi F, Jubran A. Why COVID-19 silent hypoxemia is baffling to physicians. Am J Respir Crit Care Med. 2020;202(3):356-360. doi:10.1164/rccm.202006-2157CP
8. Guan WJ, Ni ZY, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020;382(18):1708-1720. doi:10.1056/NEJMoa2002032
9. Grasselli G, Zangrillo A, Zanella A, et al. Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy Region, Italy. JAMA. 2020;323(16):1574-1581. doi:10.1001/jama.2020.5394
10. Raoof S, Nava S, Carpati C, Hill NS. High-flow, noninvasive ventilation and awake (nonintubation) proning in patients with coronavirus disease 2019 with respiratory failure. Chest. 2020;158(5):1992-2002. doi:10.1016/j.chest.2020.07.013
11. Ackermann M, Mentzer SJ, Jonigk D. Pulmonary vascular pathology in COVID-19. Reply. N Engl J Med. 2020;383(9):888-889. doi:10.1056/NEJMc2022068
12. McDonough G, Khaing P, Treacy T, McGrath C, Yoo EJ. The use of high-flow nasal oxygen in the ICU as a first-line therapy for acute hypoxemic respiratory failure secondary to coronavirus disease 2019. Crit Care Explor. 2020;2(10):e0257. doi:10.1097/CCE.0000000000000257
13. Hernandez-Romieu AC, Adelman MW, et al. Timing of intubation and mortality among critically ill coronavirus disease 2019 patients: a single-center cohort study. Crit Care Med. 2020;48(11):e1045-e1053. doi:10.1097/CCM.0000000000004600
14. Cummings MJ, Baldwin MR, Abrams D, et al. Epidemiology, clinical course, and outcomes of critically ill adults with COVID-19 in New York City: a prospective cohort study. Lancet. 2020;395(10239):1763-1770. doi:10.1016/S0140-6736(20)31189-2
15. Dhont S, Derom E, Van Braeckel E, Depuydt P, Lambrecht BN. The pathophysiology of ‘happy’ hypoxemia in COVID-19. Respir Res. 2020;21(1):198. doi:10.1186/s12931-020-01462-5
16. Wilkerson RG, Adler JD, Shah NG, Brown R. Silent hypoxia: a harbinger of clinical deterioration in patients with COVID-19. Am J Emerg Med. 2020;38(10):2243.e5-2243.e6. doi:10.1016/j.ajem.2020.05.044
17. Gong J, Ou J, Qiu X, et al. A tool for early prediction of severe coronavirus disease 2019 (COVID-19): a multicenter study using the risk nomogram in Wuhan and Guangdong, China. Clin Infect Dis. 2020;71(15):833-840. doi:10.1093/cid/ciaa443
18. Force ADT, Ranieri VM, Rubenfeld GD, et al. Acute respiratory distress syndrome: the Berlin Definition. JAMA. 2012;307(23):2526-2533. doi:10.1001/jama.2012.5669
19. Marini JJ, Gattinoni L. Management of COVID-19 respiratory distress. JAMA. 2020;323(22):2329-2330. doi:10.1001/jama.2020.6825
20. Schaller T, Hirschbuhl K, Burkhardt K, et al. Postmortem examination of patients with COVID-19. JAMA. 2020;323(24):2518-2520. doi:10.1001/jama.2020.8907
21. Ackermann M, Verleden SE, Kuehnel M, et al. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19. N Engl J Med. 2020;383(2):120-128. doi:10.1056/NEJMoa2015432
22. Wu C, Chen X, Cai Y, et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med. 2020;180(7):934-943. doi:10.1001/jamainternmed.2020.0994. Published correction appeared May 11, 2020. Errors in data and units of measure. doi:10.1001/jamainternmed.2020.1429
23. Yang J, Zheng Y, Gou X, et al. Prevalence of comorbidities and its effects in patients infected with SARS-CoV-2: a systematic review and meta-analysis. Int J Infect Dis. 2020;94:91-95. doi:10.1016/j.ijid.2020.03.017
24. Richardson S, Hirsch JS, Narasimhan M, et al. Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area. JAMA. 2020;323(20):2052-2059. doi:10.1001/jama.2020.6775
25. Tobin MJ, Jubran A, Laghi F. Misconceptions of pathophysiology of happy hypoxemia and implications for management of COVID-19. Respir Res. 2020;21(1):249. doi:10.1186/s12931-020-01520-y
26. Bickler PE, Feiner JR, Lipnick MS, McKleroy W. “Silent” presentation of hypoxemia and cardiorespiratory compensation in COVID-19. Anesthesiology. 2020;134(2):262-269. doi:10.1097/ALN.0000000000003578
27. Jounieaux V, Parreira VF, Aubert G, Dury M, Delguste P, Rodenstein DO. Effects of hypocapnic hyperventilation on the response to hypoxia in normal subjects receiving intermittent positive-pressure ventilation. Chest. 2002;121(4):1141-1148. doi:10.1378/chest.121.4.1141
37-year-old man • cough • increasing shortness of breath • pleuritic chest pain • Dx?
THE CASE
A 37-year-old man with a history of asthma, schizoaffective disorder, and tobacco use (36 packs per year) presented to the clinic after 5 days of worsening cough, reproducible left-sided chest pain, and increasing shortness of breath. He also experienced chills, fatigue, nausea, and vomiting but was afebrile. The patient had not travelled recently nor had direct contact with anyone sick. He also denied intravenous (IV) drug use, alcohol use, and bloody sputum. Recently, he had intentionally lost weight, as recommended by his psychiatrist.
Medication review revealed that he was taking many central-acting agents for schizoaffective disorder, including alprazolam, aripiprazole, desvenlafaxine, and quetiapine. Due to his intermittent asthma since childhood, he used an albuterol inhaler as needed, which currently offered only minimal relief. He denied any history of hospitalization or intubation for asthma.
During the clinic visit, his blood pressure was 90/60 mm Hg and his heart rate was normal. His pulse oximetry was 92% on room air. On physical examination, he had normal-appearing dentition. Auscultation revealed bilateral expiratory wheezes with decreased breath sounds at the left lower lobe.
A plain chest radiograph (CXR) performed in the clinic (FIGURE 1) showed a large, thick-walled cavitary lesion with an air-fluid level in the left lower lobe. The patient was directly admitted to the Family Medicine Inpatient Service. Computed tomography (CT) of the chest with contrast was ordered to rule out empyema or malignancy. The chest CT confirmed the previous findings while also revealing a surrounding satellite nodularity in the left lower lobe (FIGURE 2). QuantiFERON-TB Gold and HIV tests were both negative.
THE DIAGNOSIS
The patient was given a diagnosis of a lung abscess based on symptoms and imaging. An extensive smoking history, as well as multiple sedating medications, increased his likelihood of aspiration.
DISCUSSION
Lung abscess is the probable diagnosis in a patient with indolent infectious symptoms (cough, fever, night sweats) developing over days to weeks and a CXR finding of pulmonary opacity, often with an air-fluid level.1-4 A lung abscess is a circumscribed collection of pus in the lung parenchyma that develops as a result of microbial infection.4
Primary vs secondary abscess. Lung abscesses can be divided into 2 groups: primary and secondary abscesses. Primary abscesses (60%) occur without any other medical condition or in patients prone to aspiration.5 Secondary abscesses occur in the setting of a comorbid medical condition, such as lung disease, heart disease, bronchogenic neoplasm, or immunocompromised status.5
Continue to: With a primary lung abscess...
With a primary lung abscess, oropharyngeal contents are aspirated (generally while the patient is unconscious) and contain mixed flora.2 The aspirate typically migrates to the posterior segments of the upper lobes and to the superior segments of the lower lobes. These abscesses are usually singular and have an air-fluid level.1,2
Secondary lung abscesses occur in bronchial obstruction (by tumor, foreign body, or enlarged lymph nodes), with coexisting lung diseases (bronchiectasis, cystic fibrosis, infected pulmonary infarcts, lung contusion) or by direct spread (broncho-esophageal fistula, subphrenic abscess).6 Secondary abscesses are associated with a poorer prognosis, dependent on the patient’s general condition and underlying disease.7
What to rule out
The differential diagnosis of cavitary lung lesion includes tuberculosis, necrotizing pneumonia, bronchial carcinoma, pulmonary embolism, vasculitis (eg, Churg-Strauss syndrome), and localized pleural empyema.1,4 A CT scan is helpful to differentiate between a parenchymal lesion and pleural collection, which may not be as clear on CXR.1,4
Tuberculosis manifests with fatigue, weight loss, and night sweats; a chest CT will reveal a cavitating lesion (usually upper lobe) with a characteristic “rim sign” that includes caseous necrosis surrounded by a peripheral enhancing rim.8
Necrotizing pneumonia manifests as acute, fulminant infection. The most common causative organisms on sputum culture are Streptococcus pneumoniae, Staphylococcus aureus, Klebsiella pneumoniae, and Pseudomonas species. Plain radiography will reveal multiple cavities and often associated pleural effusion and empyema.9
Continue to: Excavating bronchogenic carcinomas
Excavating bronchogenic carcinomas differ from a lung abscess in that a patient with the latter is typically, but not always, febrile and has purulent sputum. On imaging, a bronchogenic carcinoma has a thicker and more irregular wall than a lung abscess.10
Treatment
When antibiotics first became available, penicillin was used to treat lung abscess.11 Then IV clindamycin became the drug of choice after 2 trials demonstrated its superiority to IV penicillin.12,13 More recently, clindamycin alone has fallen out of favor due to growing anaerobic resistance.14
Current therapy includes beta-lactam with beta-lactamase inhibitors.14 Lung abscesses are typically polymicrobial and thus carry different degrees of antibiotic resistance.15,16 If culture data are available, targeted therapy is preferred, especially for secondary abscesses.7 Antibiotic therapy is usually continued until a CXR reveals a small lesion or is clear, which may require several months of outpatient oral antibiotic therapy.4
Our patient was treated with IV clindamycin for 3 days in the hospital. Clindamycin was chosen due to his penicillin allergy and started empirically without any culture data. He was transitioned to oral clindamycin and completed a total 3-week course as his CXR continued to show improvement (FIGURE 3). He did not undergo bronchoscopy. A follow-up CXR showed resolution of lung abscess at 9 months. (FIGURE 4).
THE TAKEAWAY
All patients with lung abscesses should have sputum culture with gram stain done—ideally prior to starting antibiotics.3,4 Bronchoscopy should be considered for patients with atypical presentations or those who fail standard therapy, but may be used in other cases, as well.3
CORRESPONDENCE
Morteza Khodaee, MD, MPH, AFW Clinic, 3055 Roslyn Street, Denver, CO 80238; morteza.khodaee@cuanschutz.edu
1. Hassan M, Asciak R, Rizk R, et al. Lung abscess or empyema? Taking a closer look. Thorax. 2018;73:887-889. https://doi. org/10.1136/thoraxjnl-2018-211604
2. Moreira J da SM, Camargo J de JP, Felicetti JC, et al. Lung abscess: analysis of 252 consecutive cases diagnosed between 1968 and 2004. J Bras Pneumol. 2006;32:136-43. https://doi.org/10.1590/ s1806-37132006000200009
3. Schiza S, Siafakas NM. Clinical presentation and management of empyema, lung abscess and pleural effusion. Curr Opin Pulm Med. 2006;12:205-211. https://doi.org/10.1097/01. mcp.0000219270.73180.8b
4. Yazbeck MF, Dahdel M, Kalra A, et al. Lung abscess: update on microbiology and management. Am J Ther. 2014;21:217-221. https://doi.org/10.1097/MJT.0b013e3182383c9b
5. Nicolini A, Cilloniz C, Senarega R, et al. Lung abscess due to Streptococcus pneumoniae: a case series and brief review of the literature. Pneumonol Alergol Pol. 2014;82:276-285. https://doi. org/10.5603/PiAP.2014.0033
6. Puligandla PS, Laberge J-M. Respiratory infections: pneumonia, lung abscess, and empyema. Semin Pediatr Surg. 2008;17:42-52. https://doi.org/10.1053/j.sempedsurg.2007.10.007
7. Marra A, Hillejan L, Ukena D. [Management of Lung Abscess]. Zentralbl Chir. 2015;140 (suppl 1):S47-S53. https://doi. org/10.1055/s-0035-1557883
THE CASE
A 37-year-old man with a history of asthma, schizoaffective disorder, and tobacco use (36 packs per year) presented to the clinic after 5 days of worsening cough, reproducible left-sided chest pain, and increasing shortness of breath. He also experienced chills, fatigue, nausea, and vomiting but was afebrile. The patient had not travelled recently nor had direct contact with anyone sick. He also denied intravenous (IV) drug use, alcohol use, and bloody sputum. Recently, he had intentionally lost weight, as recommended by his psychiatrist.
Medication review revealed that he was taking many central-acting agents for schizoaffective disorder, including alprazolam, aripiprazole, desvenlafaxine, and quetiapine. Due to his intermittent asthma since childhood, he used an albuterol inhaler as needed, which currently offered only minimal relief. He denied any history of hospitalization or intubation for asthma.
During the clinic visit, his blood pressure was 90/60 mm Hg and his heart rate was normal. His pulse oximetry was 92% on room air. On physical examination, he had normal-appearing dentition. Auscultation revealed bilateral expiratory wheezes with decreased breath sounds at the left lower lobe.
A plain chest radiograph (CXR) performed in the clinic (FIGURE 1) showed a large, thick-walled cavitary lesion with an air-fluid level in the left lower lobe. The patient was directly admitted to the Family Medicine Inpatient Service. Computed tomography (CT) of the chest with contrast was ordered to rule out empyema or malignancy. The chest CT confirmed the previous findings while also revealing a surrounding satellite nodularity in the left lower lobe (FIGURE 2). QuantiFERON-TB Gold and HIV tests were both negative.
THE DIAGNOSIS
The patient was given a diagnosis of a lung abscess based on symptoms and imaging. An extensive smoking history, as well as multiple sedating medications, increased his likelihood of aspiration.
DISCUSSION
Lung abscess is the probable diagnosis in a patient with indolent infectious symptoms (cough, fever, night sweats) developing over days to weeks and a CXR finding of pulmonary opacity, often with an air-fluid level.1-4 A lung abscess is a circumscribed collection of pus in the lung parenchyma that develops as a result of microbial infection.4
Primary vs secondary abscess. Lung abscesses can be divided into 2 groups: primary and secondary abscesses. Primary abscesses (60%) occur without any other medical condition or in patients prone to aspiration.5 Secondary abscesses occur in the setting of a comorbid medical condition, such as lung disease, heart disease, bronchogenic neoplasm, or immunocompromised status.5
Continue to: With a primary lung abscess...
With a primary lung abscess, oropharyngeal contents are aspirated (generally while the patient is unconscious) and contain mixed flora.2 The aspirate typically migrates to the posterior segments of the upper lobes and to the superior segments of the lower lobes. These abscesses are usually singular and have an air-fluid level.1,2
Secondary lung abscesses occur in bronchial obstruction (by tumor, foreign body, or enlarged lymph nodes), with coexisting lung diseases (bronchiectasis, cystic fibrosis, infected pulmonary infarcts, lung contusion) or by direct spread (broncho-esophageal fistula, subphrenic abscess).6 Secondary abscesses are associated with a poorer prognosis, dependent on the patient’s general condition and underlying disease.7
What to rule out
The differential diagnosis of cavitary lung lesion includes tuberculosis, necrotizing pneumonia, bronchial carcinoma, pulmonary embolism, vasculitis (eg, Churg-Strauss syndrome), and localized pleural empyema.1,4 A CT scan is helpful to differentiate between a parenchymal lesion and pleural collection, which may not be as clear on CXR.1,4
Tuberculosis manifests with fatigue, weight loss, and night sweats; a chest CT will reveal a cavitating lesion (usually upper lobe) with a characteristic “rim sign” that includes caseous necrosis surrounded by a peripheral enhancing rim.8
Necrotizing pneumonia manifests as acute, fulminant infection. The most common causative organisms on sputum culture are Streptococcus pneumoniae, Staphylococcus aureus, Klebsiella pneumoniae, and Pseudomonas species. Plain radiography will reveal multiple cavities and often associated pleural effusion and empyema.9
Continue to: Excavating bronchogenic carcinomas
Excavating bronchogenic carcinomas differ from a lung abscess in that a patient with the latter is typically, but not always, febrile and has purulent sputum. On imaging, a bronchogenic carcinoma has a thicker and more irregular wall than a lung abscess.10
Treatment
When antibiotics first became available, penicillin was used to treat lung abscess.11 Then IV clindamycin became the drug of choice after 2 trials demonstrated its superiority to IV penicillin.12,13 More recently, clindamycin alone has fallen out of favor due to growing anaerobic resistance.14
Current therapy includes beta-lactam with beta-lactamase inhibitors.14 Lung abscesses are typically polymicrobial and thus carry different degrees of antibiotic resistance.15,16 If culture data are available, targeted therapy is preferred, especially for secondary abscesses.7 Antibiotic therapy is usually continued until a CXR reveals a small lesion or is clear, which may require several months of outpatient oral antibiotic therapy.4
Our patient was treated with IV clindamycin for 3 days in the hospital. Clindamycin was chosen due to his penicillin allergy and started empirically without any culture data. He was transitioned to oral clindamycin and completed a total 3-week course as his CXR continued to show improvement (FIGURE 3). He did not undergo bronchoscopy. A follow-up CXR showed resolution of lung abscess at 9 months. (FIGURE 4).
THE TAKEAWAY
All patients with lung abscesses should have sputum culture with gram stain done—ideally prior to starting antibiotics.3,4 Bronchoscopy should be considered for patients with atypical presentations or those who fail standard therapy, but may be used in other cases, as well.3
CORRESPONDENCE
Morteza Khodaee, MD, MPH, AFW Clinic, 3055 Roslyn Street, Denver, CO 80238; morteza.khodaee@cuanschutz.edu
THE CASE
A 37-year-old man with a history of asthma, schizoaffective disorder, and tobacco use (36 packs per year) presented to the clinic after 5 days of worsening cough, reproducible left-sided chest pain, and increasing shortness of breath. He also experienced chills, fatigue, nausea, and vomiting but was afebrile. The patient had not travelled recently nor had direct contact with anyone sick. He also denied intravenous (IV) drug use, alcohol use, and bloody sputum. Recently, he had intentionally lost weight, as recommended by his psychiatrist.
Medication review revealed that he was taking many central-acting agents for schizoaffective disorder, including alprazolam, aripiprazole, desvenlafaxine, and quetiapine. Due to his intermittent asthma since childhood, he used an albuterol inhaler as needed, which currently offered only minimal relief. He denied any history of hospitalization or intubation for asthma.
During the clinic visit, his blood pressure was 90/60 mm Hg and his heart rate was normal. His pulse oximetry was 92% on room air. On physical examination, he had normal-appearing dentition. Auscultation revealed bilateral expiratory wheezes with decreased breath sounds at the left lower lobe.
A plain chest radiograph (CXR) performed in the clinic (FIGURE 1) showed a large, thick-walled cavitary lesion with an air-fluid level in the left lower lobe. The patient was directly admitted to the Family Medicine Inpatient Service. Computed tomography (CT) of the chest with contrast was ordered to rule out empyema or malignancy. The chest CT confirmed the previous findings while also revealing a surrounding satellite nodularity in the left lower lobe (FIGURE 2). QuantiFERON-TB Gold and HIV tests were both negative.
THE DIAGNOSIS
The patient was given a diagnosis of a lung abscess based on symptoms and imaging. An extensive smoking history, as well as multiple sedating medications, increased his likelihood of aspiration.
DISCUSSION
Lung abscess is the probable diagnosis in a patient with indolent infectious symptoms (cough, fever, night sweats) developing over days to weeks and a CXR finding of pulmonary opacity, often with an air-fluid level.1-4 A lung abscess is a circumscribed collection of pus in the lung parenchyma that develops as a result of microbial infection.4
Primary vs secondary abscess. Lung abscesses can be divided into 2 groups: primary and secondary abscesses. Primary abscesses (60%) occur without any other medical condition or in patients prone to aspiration.5 Secondary abscesses occur in the setting of a comorbid medical condition, such as lung disease, heart disease, bronchogenic neoplasm, or immunocompromised status.5
Continue to: With a primary lung abscess...
With a primary lung abscess, oropharyngeal contents are aspirated (generally while the patient is unconscious) and contain mixed flora.2 The aspirate typically migrates to the posterior segments of the upper lobes and to the superior segments of the lower lobes. These abscesses are usually singular and have an air-fluid level.1,2
Secondary lung abscesses occur in bronchial obstruction (by tumor, foreign body, or enlarged lymph nodes), with coexisting lung diseases (bronchiectasis, cystic fibrosis, infected pulmonary infarcts, lung contusion) or by direct spread (broncho-esophageal fistula, subphrenic abscess).6 Secondary abscesses are associated with a poorer prognosis, dependent on the patient’s general condition and underlying disease.7
What to rule out
The differential diagnosis of cavitary lung lesion includes tuberculosis, necrotizing pneumonia, bronchial carcinoma, pulmonary embolism, vasculitis (eg, Churg-Strauss syndrome), and localized pleural empyema.1,4 A CT scan is helpful to differentiate between a parenchymal lesion and pleural collection, which may not be as clear on CXR.1,4
Tuberculosis manifests with fatigue, weight loss, and night sweats; a chest CT will reveal a cavitating lesion (usually upper lobe) with a characteristic “rim sign” that includes caseous necrosis surrounded by a peripheral enhancing rim.8
Necrotizing pneumonia manifests as acute, fulminant infection. The most common causative organisms on sputum culture are Streptococcus pneumoniae, Staphylococcus aureus, Klebsiella pneumoniae, and Pseudomonas species. Plain radiography will reveal multiple cavities and often associated pleural effusion and empyema.9
Continue to: Excavating bronchogenic carcinomas
Excavating bronchogenic carcinomas differ from a lung abscess in that a patient with the latter is typically, but not always, febrile and has purulent sputum. On imaging, a bronchogenic carcinoma has a thicker and more irregular wall than a lung abscess.10
Treatment
When antibiotics first became available, penicillin was used to treat lung abscess.11 Then IV clindamycin became the drug of choice after 2 trials demonstrated its superiority to IV penicillin.12,13 More recently, clindamycin alone has fallen out of favor due to growing anaerobic resistance.14
Current therapy includes beta-lactam with beta-lactamase inhibitors.14 Lung abscesses are typically polymicrobial and thus carry different degrees of antibiotic resistance.15,16 If culture data are available, targeted therapy is preferred, especially for secondary abscesses.7 Antibiotic therapy is usually continued until a CXR reveals a small lesion or is clear, which may require several months of outpatient oral antibiotic therapy.4
Our patient was treated with IV clindamycin for 3 days in the hospital. Clindamycin was chosen due to his penicillin allergy and started empirically without any culture data. He was transitioned to oral clindamycin and completed a total 3-week course as his CXR continued to show improvement (FIGURE 3). He did not undergo bronchoscopy. A follow-up CXR showed resolution of lung abscess at 9 months. (FIGURE 4).
THE TAKEAWAY
All patients with lung abscesses should have sputum culture with gram stain done—ideally prior to starting antibiotics.3,4 Bronchoscopy should be considered for patients with atypical presentations or those who fail standard therapy, but may be used in other cases, as well.3
CORRESPONDENCE
Morteza Khodaee, MD, MPH, AFW Clinic, 3055 Roslyn Street, Denver, CO 80238; morteza.khodaee@cuanschutz.edu
1. Hassan M, Asciak R, Rizk R, et al. Lung abscess or empyema? Taking a closer look. Thorax. 2018;73:887-889. https://doi. org/10.1136/thoraxjnl-2018-211604
2. Moreira J da SM, Camargo J de JP, Felicetti JC, et al. Lung abscess: analysis of 252 consecutive cases diagnosed between 1968 and 2004. J Bras Pneumol. 2006;32:136-43. https://doi.org/10.1590/ s1806-37132006000200009
3. Schiza S, Siafakas NM. Clinical presentation and management of empyema, lung abscess and pleural effusion. Curr Opin Pulm Med. 2006;12:205-211. https://doi.org/10.1097/01. mcp.0000219270.73180.8b
4. Yazbeck MF, Dahdel M, Kalra A, et al. Lung abscess: update on microbiology and management. Am J Ther. 2014;21:217-221. https://doi.org/10.1097/MJT.0b013e3182383c9b
5. Nicolini A, Cilloniz C, Senarega R, et al. Lung abscess due to Streptococcus pneumoniae: a case series and brief review of the literature. Pneumonol Alergol Pol. 2014;82:276-285. https://doi. org/10.5603/PiAP.2014.0033
6. Puligandla PS, Laberge J-M. Respiratory infections: pneumonia, lung abscess, and empyema. Semin Pediatr Surg. 2008;17:42-52. https://doi.org/10.1053/j.sempedsurg.2007.10.007
7. Marra A, Hillejan L, Ukena D. [Management of Lung Abscess]. Zentralbl Chir. 2015;140 (suppl 1):S47-S53. https://doi. org/10.1055/s-0035-1557883
1. Hassan M, Asciak R, Rizk R, et al. Lung abscess or empyema? Taking a closer look. Thorax. 2018;73:887-889. https://doi. org/10.1136/thoraxjnl-2018-211604
2. Moreira J da SM, Camargo J de JP, Felicetti JC, et al. Lung abscess: analysis of 252 consecutive cases diagnosed between 1968 and 2004. J Bras Pneumol. 2006;32:136-43. https://doi.org/10.1590/ s1806-37132006000200009
3. Schiza S, Siafakas NM. Clinical presentation and management of empyema, lung abscess and pleural effusion. Curr Opin Pulm Med. 2006;12:205-211. https://doi.org/10.1097/01. mcp.0000219270.73180.8b
4. Yazbeck MF, Dahdel M, Kalra A, et al. Lung abscess: update on microbiology and management. Am J Ther. 2014;21:217-221. https://doi.org/10.1097/MJT.0b013e3182383c9b
5. Nicolini A, Cilloniz C, Senarega R, et al. Lung abscess due to Streptococcus pneumoniae: a case series and brief review of the literature. Pneumonol Alergol Pol. 2014;82:276-285. https://doi. org/10.5603/PiAP.2014.0033
6. Puligandla PS, Laberge J-M. Respiratory infections: pneumonia, lung abscess, and empyema. Semin Pediatr Surg. 2008;17:42-52. https://doi.org/10.1053/j.sempedsurg.2007.10.007
7. Marra A, Hillejan L, Ukena D. [Management of Lung Abscess]. Zentralbl Chir. 2015;140 (suppl 1):S47-S53. https://doi. org/10.1055/s-0035-1557883
University taking aim at racial disparities in COVID vaccine trials
Although recent months have seen the arrival of several promising vaccines to combat COVID-19, many researchers have been concerned about the shortage of Black and Latinx volunteers in their pivotal trials.
Minority groups have long been underrepresented in clinical research. The pandemic’s inequitable fallout has heightened the need for more inclusive COVID-19 trials. By one estimate, Black Americans are three times more likely to become infected with SARS-Cov-2 and twice as likely to die from it, compared with their White counterparts.
It was therefore welcome news this past November when the Maryland-based biotech company Novavax unveiled their plans to boost participation among specific minority groups during the phase 3 trial of their COVID-19 vaccine candidate NVX-CoV2373. To help them in their efforts, the company tapped Howard University, in Washington, D.C., to be a clinical test site. The goal was to enroll 300 Black and Latinx volunteers through a recruitment registry at the Coronavirus Prevention Network.
“We have seen quite a good number of participants in the registry, and many are African American, who are the ones we are trying to reach in the trial,” explained Siham Mahgoub, MD, medical director of the Center of Infectious Diseases Management and Research and principal investigator for the Novavax trial at Howard University, Washington. “It’s very important for people of color to participate in the trial because we want to make sure these vaccines work in people of color,” Dr. Mahgoub said.
Over the years, Howard University has hosted several important clinical trials and studies, and its participation in the multi-institutional Georgetown–Howard Universities Center for Clinical and Translational Science consortium brings crucial infrastructural value. By bringing this vaccine trial to one of the most esteemed historically Black colleges or universities (HBCUs), researchers hoped to address a sense of hesitancy among possible participants that is prompted in part by the tragic history of medical testing in the Black community.
“The community trusts Howard,” said Dr. Mahgoub. “I think it’s great having Howard and an HBCU host this trial, because these are people who look like them.”
Lisa M. Dunkle, MD, vice president and global medical lead for coronavirus vaccine at Novavax, explained that, in addition to Howard being located close to the company’s headquarters, the university seemed like a great fit for the overall mission.
“As part of our goal to achieve a representative trial population that includes communities who are disproportionately impacted by the pandemic, we sought out some of the HBCUs to include in our trial sites. We hoped that this might encourage people of color to enroll and to increase their comfort level with vaccines in general,” Dr. Dunkle said.
Building more representative clinical trials
For decades, research on some of the most groundbreaking vaccines and treatments have been based on the results of studies conducted with predominately White participants, despite the fact that a much more demographically varied general population would ultimately receive them. This has led to calls to include people of different races and ethnic backgrounds in trials.
Homogeneity in clinical trials is discouraged, but trials are not heavily regulated in this regard. In 1993, Congress passed the Revitalization Act, which requires that trials that are conducted by the National Institutes of Health include women and members of minority groups among their cohorts. However, the number or proportion of such participants is not specified.
Underrepresentation in clinical trials also reflects a general unwillingness by members of ethnic minorities to volunteer because of the deeply unsettling history of such trials in minority communities. Among some Black persons, it is not uncommon for names like Tuskegee, Henrietta Lacks, and J. Marion Simms to be mentioned when giving reasons for not participating.
“There is certainly some dark history in how minorities have been treated by our health care system, and it’s not surprising that there is some fear and distrust,” said Dr. Dunkle. “By recruiting people of color into clinical trials that are governed with strict standards, we can begin to change perceptions and attitudes.”
Vaccine hesitancy is not only rooted in the past. The current state of medical care also has some potential trial participants worried. Misinformation, inequity in health care access, and low health literacy contribute to the current fears of scientific development.
A trial designed to engender trust
Having information about the vaccine come from trusted voices in the community is a key means of overcoming hesitancy. Howard University President Wayne Frederick, MD, reached out to a pastor of a local Black church to have more participants enroll in the trial. One who answered the call to action was Stephanie Williams, an elementary school teacher in Montgomery County, Maryland. When she saw that her pastor was participating in the Novavax trial and when she considered the devastation she had seen from COVID-19, she was on board.
“We had about three sessions where he shared his experiences. He also shared some links to read about it more,” Ms. Williams said. “When I saw that he took it, that gave me a lot of confidence. Since I’m going be going into the classroom, I wanted to be sure that I was well protected.”
Transparency is key to gaining more participation, explained Dr. Maghoub. Webinar-based information sessions have proven particularly important in achieving this.
“We do a lot of explaining in very simple language to make sure everyone understands about the vaccine. The participants have time to ask questions during the webinar, and at any time [during the trial], if a participant feels that it is not right for them, they can stop. They have time to learn about the trial and give consent. People often think they are like guinea pigs in trials, but they are not. They must give consent.”
There are signs that the approach has been successful. Over a period of 4-5 weeks, the Howard site enrolled 150 participants, of whom 30% were Black and 20% were Latinx.
Novavax has been in business for more than 3 decades but hasn’t seen the booming success that their competitors have. The company has noted progress in developing vaccines against Middle East respiratory syndrome and severe acute respiratory syndrome. However, they missed the mark in clinical trials, failing twice in 3 years to develop a respiratory syncytial virus vaccine administered through maternal immunizations.
From being on the verge of closing, Novavax has since made a dramatic turnaround after former President Trump awarded the company $1.6 billion dollars in July 2020 as part of Operation Warp Speed. If trial results are promising, the Novavax vaccine could enter the market in a few months, representing not only a new therapeutic option but perhaps a new model for building inclusivity in clinical trials.
A version of this article first appeared on Medscape.com.
Although recent months have seen the arrival of several promising vaccines to combat COVID-19, many researchers have been concerned about the shortage of Black and Latinx volunteers in their pivotal trials.
Minority groups have long been underrepresented in clinical research. The pandemic’s inequitable fallout has heightened the need for more inclusive COVID-19 trials. By one estimate, Black Americans are three times more likely to become infected with SARS-Cov-2 and twice as likely to die from it, compared with their White counterparts.
It was therefore welcome news this past November when the Maryland-based biotech company Novavax unveiled their plans to boost participation among specific minority groups during the phase 3 trial of their COVID-19 vaccine candidate NVX-CoV2373. To help them in their efforts, the company tapped Howard University, in Washington, D.C., to be a clinical test site. The goal was to enroll 300 Black and Latinx volunteers through a recruitment registry at the Coronavirus Prevention Network.
“We have seen quite a good number of participants in the registry, and many are African American, who are the ones we are trying to reach in the trial,” explained Siham Mahgoub, MD, medical director of the Center of Infectious Diseases Management and Research and principal investigator for the Novavax trial at Howard University, Washington. “It’s very important for people of color to participate in the trial because we want to make sure these vaccines work in people of color,” Dr. Mahgoub said.
Over the years, Howard University has hosted several important clinical trials and studies, and its participation in the multi-institutional Georgetown–Howard Universities Center for Clinical and Translational Science consortium brings crucial infrastructural value. By bringing this vaccine trial to one of the most esteemed historically Black colleges or universities (HBCUs), researchers hoped to address a sense of hesitancy among possible participants that is prompted in part by the tragic history of medical testing in the Black community.
“The community trusts Howard,” said Dr. Mahgoub. “I think it’s great having Howard and an HBCU host this trial, because these are people who look like them.”
Lisa M. Dunkle, MD, vice president and global medical lead for coronavirus vaccine at Novavax, explained that, in addition to Howard being located close to the company’s headquarters, the university seemed like a great fit for the overall mission.
“As part of our goal to achieve a representative trial population that includes communities who are disproportionately impacted by the pandemic, we sought out some of the HBCUs to include in our trial sites. We hoped that this might encourage people of color to enroll and to increase their comfort level with vaccines in general,” Dr. Dunkle said.
Building more representative clinical trials
For decades, research on some of the most groundbreaking vaccines and treatments have been based on the results of studies conducted with predominately White participants, despite the fact that a much more demographically varied general population would ultimately receive them. This has led to calls to include people of different races and ethnic backgrounds in trials.
Homogeneity in clinical trials is discouraged, but trials are not heavily regulated in this regard. In 1993, Congress passed the Revitalization Act, which requires that trials that are conducted by the National Institutes of Health include women and members of minority groups among their cohorts. However, the number or proportion of such participants is not specified.
Underrepresentation in clinical trials also reflects a general unwillingness by members of ethnic minorities to volunteer because of the deeply unsettling history of such trials in minority communities. Among some Black persons, it is not uncommon for names like Tuskegee, Henrietta Lacks, and J. Marion Simms to be mentioned when giving reasons for not participating.
“There is certainly some dark history in how minorities have been treated by our health care system, and it’s not surprising that there is some fear and distrust,” said Dr. Dunkle. “By recruiting people of color into clinical trials that are governed with strict standards, we can begin to change perceptions and attitudes.”
Vaccine hesitancy is not only rooted in the past. The current state of medical care also has some potential trial participants worried. Misinformation, inequity in health care access, and low health literacy contribute to the current fears of scientific development.
A trial designed to engender trust
Having information about the vaccine come from trusted voices in the community is a key means of overcoming hesitancy. Howard University President Wayne Frederick, MD, reached out to a pastor of a local Black church to have more participants enroll in the trial. One who answered the call to action was Stephanie Williams, an elementary school teacher in Montgomery County, Maryland. When she saw that her pastor was participating in the Novavax trial and when she considered the devastation she had seen from COVID-19, she was on board.
“We had about three sessions where he shared his experiences. He also shared some links to read about it more,” Ms. Williams said. “When I saw that he took it, that gave me a lot of confidence. Since I’m going be going into the classroom, I wanted to be sure that I was well protected.”
Transparency is key to gaining more participation, explained Dr. Maghoub. Webinar-based information sessions have proven particularly important in achieving this.
“We do a lot of explaining in very simple language to make sure everyone understands about the vaccine. The participants have time to ask questions during the webinar, and at any time [during the trial], if a participant feels that it is not right for them, they can stop. They have time to learn about the trial and give consent. People often think they are like guinea pigs in trials, but they are not. They must give consent.”
There are signs that the approach has been successful. Over a period of 4-5 weeks, the Howard site enrolled 150 participants, of whom 30% were Black and 20% were Latinx.
Novavax has been in business for more than 3 decades but hasn’t seen the booming success that their competitors have. The company has noted progress in developing vaccines against Middle East respiratory syndrome and severe acute respiratory syndrome. However, they missed the mark in clinical trials, failing twice in 3 years to develop a respiratory syncytial virus vaccine administered through maternal immunizations.
From being on the verge of closing, Novavax has since made a dramatic turnaround after former President Trump awarded the company $1.6 billion dollars in July 2020 as part of Operation Warp Speed. If trial results are promising, the Novavax vaccine could enter the market in a few months, representing not only a new therapeutic option but perhaps a new model for building inclusivity in clinical trials.
A version of this article first appeared on Medscape.com.
Although recent months have seen the arrival of several promising vaccines to combat COVID-19, many researchers have been concerned about the shortage of Black and Latinx volunteers in their pivotal trials.
Minority groups have long been underrepresented in clinical research. The pandemic’s inequitable fallout has heightened the need for more inclusive COVID-19 trials. By one estimate, Black Americans are three times more likely to become infected with SARS-Cov-2 and twice as likely to die from it, compared with their White counterparts.
It was therefore welcome news this past November when the Maryland-based biotech company Novavax unveiled their plans to boost participation among specific minority groups during the phase 3 trial of their COVID-19 vaccine candidate NVX-CoV2373. To help them in their efforts, the company tapped Howard University, in Washington, D.C., to be a clinical test site. The goal was to enroll 300 Black and Latinx volunteers through a recruitment registry at the Coronavirus Prevention Network.
“We have seen quite a good number of participants in the registry, and many are African American, who are the ones we are trying to reach in the trial,” explained Siham Mahgoub, MD, medical director of the Center of Infectious Diseases Management and Research and principal investigator for the Novavax trial at Howard University, Washington. “It’s very important for people of color to participate in the trial because we want to make sure these vaccines work in people of color,” Dr. Mahgoub said.
Over the years, Howard University has hosted several important clinical trials and studies, and its participation in the multi-institutional Georgetown–Howard Universities Center for Clinical and Translational Science consortium brings crucial infrastructural value. By bringing this vaccine trial to one of the most esteemed historically Black colleges or universities (HBCUs), researchers hoped to address a sense of hesitancy among possible participants that is prompted in part by the tragic history of medical testing in the Black community.
“The community trusts Howard,” said Dr. Mahgoub. “I think it’s great having Howard and an HBCU host this trial, because these are people who look like them.”
Lisa M. Dunkle, MD, vice president and global medical lead for coronavirus vaccine at Novavax, explained that, in addition to Howard being located close to the company’s headquarters, the university seemed like a great fit for the overall mission.
“As part of our goal to achieve a representative trial population that includes communities who are disproportionately impacted by the pandemic, we sought out some of the HBCUs to include in our trial sites. We hoped that this might encourage people of color to enroll and to increase their comfort level with vaccines in general,” Dr. Dunkle said.
Building more representative clinical trials
For decades, research on some of the most groundbreaking vaccines and treatments have been based on the results of studies conducted with predominately White participants, despite the fact that a much more demographically varied general population would ultimately receive them. This has led to calls to include people of different races and ethnic backgrounds in trials.
Homogeneity in clinical trials is discouraged, but trials are not heavily regulated in this regard. In 1993, Congress passed the Revitalization Act, which requires that trials that are conducted by the National Institutes of Health include women and members of minority groups among their cohorts. However, the number or proportion of such participants is not specified.
Underrepresentation in clinical trials also reflects a general unwillingness by members of ethnic minorities to volunteer because of the deeply unsettling history of such trials in minority communities. Among some Black persons, it is not uncommon for names like Tuskegee, Henrietta Lacks, and J. Marion Simms to be mentioned when giving reasons for not participating.
“There is certainly some dark history in how minorities have been treated by our health care system, and it’s not surprising that there is some fear and distrust,” said Dr. Dunkle. “By recruiting people of color into clinical trials that are governed with strict standards, we can begin to change perceptions and attitudes.”
Vaccine hesitancy is not only rooted in the past. The current state of medical care also has some potential trial participants worried. Misinformation, inequity in health care access, and low health literacy contribute to the current fears of scientific development.
A trial designed to engender trust
Having information about the vaccine come from trusted voices in the community is a key means of overcoming hesitancy. Howard University President Wayne Frederick, MD, reached out to a pastor of a local Black church to have more participants enroll in the trial. One who answered the call to action was Stephanie Williams, an elementary school teacher in Montgomery County, Maryland. When she saw that her pastor was participating in the Novavax trial and when she considered the devastation she had seen from COVID-19, she was on board.
“We had about three sessions where he shared his experiences. He also shared some links to read about it more,” Ms. Williams said. “When I saw that he took it, that gave me a lot of confidence. Since I’m going be going into the classroom, I wanted to be sure that I was well protected.”
Transparency is key to gaining more participation, explained Dr. Maghoub. Webinar-based information sessions have proven particularly important in achieving this.
“We do a lot of explaining in very simple language to make sure everyone understands about the vaccine. The participants have time to ask questions during the webinar, and at any time [during the trial], if a participant feels that it is not right for them, they can stop. They have time to learn about the trial and give consent. People often think they are like guinea pigs in trials, but they are not. They must give consent.”
There are signs that the approach has been successful. Over a period of 4-5 weeks, the Howard site enrolled 150 participants, of whom 30% were Black and 20% were Latinx.
Novavax has been in business for more than 3 decades but hasn’t seen the booming success that their competitors have. The company has noted progress in developing vaccines against Middle East respiratory syndrome and severe acute respiratory syndrome. However, they missed the mark in clinical trials, failing twice in 3 years to develop a respiratory syncytial virus vaccine administered through maternal immunizations.
From being on the verge of closing, Novavax has since made a dramatic turnaround after former President Trump awarded the company $1.6 billion dollars in July 2020 as part of Operation Warp Speed. If trial results are promising, the Novavax vaccine could enter the market in a few months, representing not only a new therapeutic option but perhaps a new model for building inclusivity in clinical trials.
A version of this article first appeared on Medscape.com.
Clinically important deterioration predicts poor future outcomes in COPD
Patients with COPD may benefit from stepped-up treatment of short-term disease progression with triple therapy to stave off longer-term exacerbations and all-cause mortality.
, a study based on data from more than 10,000 patients has shown.
For this study, clinically important deterioration (CID) as a measure of COPD is defined as a combination of change in lung function and/or health status, or a first acute moderate to severe COPD exacerbation, wrote MeiLan K. Han, MD, of the University of Michigan, Ann Arbor, and colleagues.
The study was published in ERJ Open Research The investigators analyzed data from the IMPACT trial, a phase III, double-blind, multicenter, 52-week study of symptomatic COPD patients aged 40 years and older.
In the intent-to-treat population, patients with symptomatic COPD and at least one moderate or severe exacerbation in the past year were randomized to a once-daily dose of fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25 mcg (4,151 patients); FF/VI 100/25 mcg (4,134 patients); or UMEC/VI 62.5/25 mcg using a single dry-power inhaler (2,070 patients).
The researchers explored both the prognostic value of a CID event on future clinical outcomes and the impact of single-inhaler triple versus dual therapy on reducing CID risk. CID was defined as any of the following: moderate/severe exacerbation; deterioration in lung function (defined as a decrease of 100 mL or more from baseline in trough forced expiratory volume per second); or deterioration in health status based on increases of 4.0 units or more on the St George’s Respiratory Questionnaire (SGRQ) total score or 2.0 units or more on the COPD Assessment Test (CAT) score.
Overall, patients with a CID by 28 weeks had significantly increased exacerbation rates after week 28, as well as smaller improvements in lung function and health status at week 52 (P < .001 for all). In addition, CID patients had an increased risk of all-cause mortality after 28 weeks, compared with patients without CID. However, FF/UMEC/VI significantly reduced CID risk, compared with dual therapies, the researchers noted.
Based on the CID SGRQ definition, patients with CID had a 75% increase in moderate to severe exacerbations by week 28 and a 96% in severe exacerbations over weeks 29-52. The increases were similar using the CID CAT definition (72% and 91%, respectively).
Patients with CID also showed significantly reduced improvements in both lung function and health status after 1 year, and a significantly increased risk of all-cause mortality compared to patients without CID.
In comparing triple vs. double therapies, FF/UMEC/VI patients showed significant reductions in CID risk by 52 weeks, compared with patients treated with FF/VI and UMEC/VI. This difference was true across all subgroups, except for the subgroup of patients who were on long-acting beta2-agonist (LABA) and long-acting muscarinic antagonist (LAMA) therapy prior to screening, the researchers said.
In addition, “treatment effect was greater at higher blood eosinophil counts for FF/UMEC/VI versus UMEC/VI,” the researchers noted.
The study findings were limited by several factors including the lack of CID as a primary endpoint, the relatively short 5-month follow-up period, and the use of a symptomatic patient population with an established risk of exacerbation, which could limit generalizability, the researchers noted. However, the findings support the value of preventing short-term CID and adding inhaled corticosteroids (ICS) or bronchodilation for patients in this study population, they said.
Data may help drive tailored treatments
“This study is a post hoc analysis of data from the IMPACT trial, an RCT examining triple therapy vs ICS/LABA vs LABA/LAMA,” Dr. Han, lead and corresponding author, said in an interview. “In this particular paper, we conducted a treatment independent analysis examining individuals who experienced clinically important deteriorations at week 28 and then compared outcomes at week 52 based on CID status at week 28. Patients with a CID by week 28 had significantly increased exacerbation rates after week 28, smaller improvements in lung function and health status at week 52, and increased risk of all-cause mortality after week 28 versus patients who were CID free,” she emphasized. “We also saw that FF/UMEC/VI significantly reduced CID risk versus dual therapies.” These data suggest that shorter-term changes are associated with longer term outcomes, and provide important information both for the purposes of clinical trials design as well as patient clinical assessments, she added.
Dr. Han said she was not surprised by the findings. “I think these results are consistent with prior analyses but suggest that short-term outcomes relate to longer-term ones,” she said. However, she stressed the need for individualized treatment.
“While there are relationships between symptoms, lung function, and exacerbations as demonstrated by these analyses, in any individual patient sometimes these three disease axes do not perfectly align,” she explained. Dr. Han’s main message for clinicians in practice is that optimization of triple therapy in patients with severe disease and high risk for exacerbations was associated not only with short-term improvements in symptoms and lung function, but also with longer-term reductions in exacerbations and mortality.
As for additional research, prospective studies using CID as a primary or secondary outcome would help validate the composite outcome in this study, as regulatory agencies have been slow to adopt composite outcomes, Dr. Han said.
Dr. Han disclosed relationships with GlaxoSmithKline, which funded the study, as well as AstraZeneca, Boehringer Ingelheim, Novartis, Sunovion, Mylan, Merck, and Verona.
Patients with COPD may benefit from stepped-up treatment of short-term disease progression with triple therapy to stave off longer-term exacerbations and all-cause mortality.
, a study based on data from more than 10,000 patients has shown.
For this study, clinically important deterioration (CID) as a measure of COPD is defined as a combination of change in lung function and/or health status, or a first acute moderate to severe COPD exacerbation, wrote MeiLan K. Han, MD, of the University of Michigan, Ann Arbor, and colleagues.
The study was published in ERJ Open Research The investigators analyzed data from the IMPACT trial, a phase III, double-blind, multicenter, 52-week study of symptomatic COPD patients aged 40 years and older.
In the intent-to-treat population, patients with symptomatic COPD and at least one moderate or severe exacerbation in the past year were randomized to a once-daily dose of fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25 mcg (4,151 patients); FF/VI 100/25 mcg (4,134 patients); or UMEC/VI 62.5/25 mcg using a single dry-power inhaler (2,070 patients).
The researchers explored both the prognostic value of a CID event on future clinical outcomes and the impact of single-inhaler triple versus dual therapy on reducing CID risk. CID was defined as any of the following: moderate/severe exacerbation; deterioration in lung function (defined as a decrease of 100 mL or more from baseline in trough forced expiratory volume per second); or deterioration in health status based on increases of 4.0 units or more on the St George’s Respiratory Questionnaire (SGRQ) total score or 2.0 units or more on the COPD Assessment Test (CAT) score.
Overall, patients with a CID by 28 weeks had significantly increased exacerbation rates after week 28, as well as smaller improvements in lung function and health status at week 52 (P < .001 for all). In addition, CID patients had an increased risk of all-cause mortality after 28 weeks, compared with patients without CID. However, FF/UMEC/VI significantly reduced CID risk, compared with dual therapies, the researchers noted.
Based on the CID SGRQ definition, patients with CID had a 75% increase in moderate to severe exacerbations by week 28 and a 96% in severe exacerbations over weeks 29-52. The increases were similar using the CID CAT definition (72% and 91%, respectively).
Patients with CID also showed significantly reduced improvements in both lung function and health status after 1 year, and a significantly increased risk of all-cause mortality compared to patients without CID.
In comparing triple vs. double therapies, FF/UMEC/VI patients showed significant reductions in CID risk by 52 weeks, compared with patients treated with FF/VI and UMEC/VI. This difference was true across all subgroups, except for the subgroup of patients who were on long-acting beta2-agonist (LABA) and long-acting muscarinic antagonist (LAMA) therapy prior to screening, the researchers said.
In addition, “treatment effect was greater at higher blood eosinophil counts for FF/UMEC/VI versus UMEC/VI,” the researchers noted.
The study findings were limited by several factors including the lack of CID as a primary endpoint, the relatively short 5-month follow-up period, and the use of a symptomatic patient population with an established risk of exacerbation, which could limit generalizability, the researchers noted. However, the findings support the value of preventing short-term CID and adding inhaled corticosteroids (ICS) or bronchodilation for patients in this study population, they said.
Data may help drive tailored treatments
“This study is a post hoc analysis of data from the IMPACT trial, an RCT examining triple therapy vs ICS/LABA vs LABA/LAMA,” Dr. Han, lead and corresponding author, said in an interview. “In this particular paper, we conducted a treatment independent analysis examining individuals who experienced clinically important deteriorations at week 28 and then compared outcomes at week 52 based on CID status at week 28. Patients with a CID by week 28 had significantly increased exacerbation rates after week 28, smaller improvements in lung function and health status at week 52, and increased risk of all-cause mortality after week 28 versus patients who were CID free,” she emphasized. “We also saw that FF/UMEC/VI significantly reduced CID risk versus dual therapies.” These data suggest that shorter-term changes are associated with longer term outcomes, and provide important information both for the purposes of clinical trials design as well as patient clinical assessments, she added.
Dr. Han said she was not surprised by the findings. “I think these results are consistent with prior analyses but suggest that short-term outcomes relate to longer-term ones,” she said. However, she stressed the need for individualized treatment.
“While there are relationships between symptoms, lung function, and exacerbations as demonstrated by these analyses, in any individual patient sometimes these three disease axes do not perfectly align,” she explained. Dr. Han’s main message for clinicians in practice is that optimization of triple therapy in patients with severe disease and high risk for exacerbations was associated not only with short-term improvements in symptoms and lung function, but also with longer-term reductions in exacerbations and mortality.
As for additional research, prospective studies using CID as a primary or secondary outcome would help validate the composite outcome in this study, as regulatory agencies have been slow to adopt composite outcomes, Dr. Han said.
Dr. Han disclosed relationships with GlaxoSmithKline, which funded the study, as well as AstraZeneca, Boehringer Ingelheim, Novartis, Sunovion, Mylan, Merck, and Verona.
Patients with COPD may benefit from stepped-up treatment of short-term disease progression with triple therapy to stave off longer-term exacerbations and all-cause mortality.
, a study based on data from more than 10,000 patients has shown.
For this study, clinically important deterioration (CID) as a measure of COPD is defined as a combination of change in lung function and/or health status, or a first acute moderate to severe COPD exacerbation, wrote MeiLan K. Han, MD, of the University of Michigan, Ann Arbor, and colleagues.
The study was published in ERJ Open Research The investigators analyzed data from the IMPACT trial, a phase III, double-blind, multicenter, 52-week study of symptomatic COPD patients aged 40 years and older.
In the intent-to-treat population, patients with symptomatic COPD and at least one moderate or severe exacerbation in the past year were randomized to a once-daily dose of fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25 mcg (4,151 patients); FF/VI 100/25 mcg (4,134 patients); or UMEC/VI 62.5/25 mcg using a single dry-power inhaler (2,070 patients).
The researchers explored both the prognostic value of a CID event on future clinical outcomes and the impact of single-inhaler triple versus dual therapy on reducing CID risk. CID was defined as any of the following: moderate/severe exacerbation; deterioration in lung function (defined as a decrease of 100 mL or more from baseline in trough forced expiratory volume per second); or deterioration in health status based on increases of 4.0 units or more on the St George’s Respiratory Questionnaire (SGRQ) total score or 2.0 units or more on the COPD Assessment Test (CAT) score.
Overall, patients with a CID by 28 weeks had significantly increased exacerbation rates after week 28, as well as smaller improvements in lung function and health status at week 52 (P < .001 for all). In addition, CID patients had an increased risk of all-cause mortality after 28 weeks, compared with patients without CID. However, FF/UMEC/VI significantly reduced CID risk, compared with dual therapies, the researchers noted.
Based on the CID SGRQ definition, patients with CID had a 75% increase in moderate to severe exacerbations by week 28 and a 96% in severe exacerbations over weeks 29-52. The increases were similar using the CID CAT definition (72% and 91%, respectively).
Patients with CID also showed significantly reduced improvements in both lung function and health status after 1 year, and a significantly increased risk of all-cause mortality compared to patients without CID.
In comparing triple vs. double therapies, FF/UMEC/VI patients showed significant reductions in CID risk by 52 weeks, compared with patients treated with FF/VI and UMEC/VI. This difference was true across all subgroups, except for the subgroup of patients who were on long-acting beta2-agonist (LABA) and long-acting muscarinic antagonist (LAMA) therapy prior to screening, the researchers said.
In addition, “treatment effect was greater at higher blood eosinophil counts for FF/UMEC/VI versus UMEC/VI,” the researchers noted.
The study findings were limited by several factors including the lack of CID as a primary endpoint, the relatively short 5-month follow-up period, and the use of a symptomatic patient population with an established risk of exacerbation, which could limit generalizability, the researchers noted. However, the findings support the value of preventing short-term CID and adding inhaled corticosteroids (ICS) or bronchodilation for patients in this study population, they said.
Data may help drive tailored treatments
“This study is a post hoc analysis of data from the IMPACT trial, an RCT examining triple therapy vs ICS/LABA vs LABA/LAMA,” Dr. Han, lead and corresponding author, said in an interview. “In this particular paper, we conducted a treatment independent analysis examining individuals who experienced clinically important deteriorations at week 28 and then compared outcomes at week 52 based on CID status at week 28. Patients with a CID by week 28 had significantly increased exacerbation rates after week 28, smaller improvements in lung function and health status at week 52, and increased risk of all-cause mortality after week 28 versus patients who were CID free,” she emphasized. “We also saw that FF/UMEC/VI significantly reduced CID risk versus dual therapies.” These data suggest that shorter-term changes are associated with longer term outcomes, and provide important information both for the purposes of clinical trials design as well as patient clinical assessments, she added.
Dr. Han said she was not surprised by the findings. “I think these results are consistent with prior analyses but suggest that short-term outcomes relate to longer-term ones,” she said. However, she stressed the need for individualized treatment.
“While there are relationships between symptoms, lung function, and exacerbations as demonstrated by these analyses, in any individual patient sometimes these three disease axes do not perfectly align,” she explained. Dr. Han’s main message for clinicians in practice is that optimization of triple therapy in patients with severe disease and high risk for exacerbations was associated not only with short-term improvements in symptoms and lung function, but also with longer-term reductions in exacerbations and mortality.
As for additional research, prospective studies using CID as a primary or secondary outcome would help validate the composite outcome in this study, as regulatory agencies have been slow to adopt composite outcomes, Dr. Han said.
Dr. Han disclosed relationships with GlaxoSmithKline, which funded the study, as well as AstraZeneca, Boehringer Ingelheim, Novartis, Sunovion, Mylan, Merck, and Verona.
FROM ERJ OPEN RESEARCH
AstraZeneca COVID vaccine: Clotting disorder mechanism revealed?
The European Medicines Agency continues to reassure the public about the safety of the AstraZeneca COVID-19 vaccine, although several countries have imposed new restrictions on the product, owing to its link to a rare clotting disorder.
Use of the vaccine has been suspended for individuals younger than 55 or 60 years in several European countries and in Canada after reports of a prothrombotic disorder and thrombocytopenia, mainly in younger individuals.
Now, more information on the prothrombotic disorder has become available. The vaccine appears to be linked to a condition that clinically resembles heparin-induced thrombocytopenia (HIT) and that occurs mainly in younger women.
Researchers have described clinical and laboratory details of nine patients from Germany and Austria who developed this condition 4-16 days after receiving the AstraZeneca vaccine in a preprint article published March 28, 2021, on Research Square.
They found that serum from four patients who were tested showed platelet-activating antibodies directed against platelet factor 4 (PF4), similar to what is seen in HIT.
They are proposing naming the condition “vaccine-induced prothrombotic immune thrombocytopenia (VIPIT)” to avoid confusion with HIT.
At a press conference March 31, the EMA said its ongoing review of the situation “has not identified any specific risk factors, such as age, gender, or a previous medical history of clotting disorders, for these very rare events. A causal link with the vaccine is not proven but is possible, and further analysis is continuing.”
A statement from the agency noted: “EMA is of the view that the benefits of the AstraZeneca vaccine in preventing COVID-19, with its associated risk of hospitalization and death, outweigh the risks of side effects.”
But it added: “Vaccinated people should be aware of the remote possibility of these very rare types of blood clots occurring. If they have symptoms suggestive of clotting problems as described in the product information, they should seek immediate medical attention and inform health care professionals of their recent vaccination.”
VIPIT study
In the Research Square preprint article, a group led by Andreas Greinacher, MD, professor of transfusion medicine at the Greifswald (Germany) University Clinic, reported on clinical and laboratory features of nine patients (eight of whom were women) in Germany and Austria who developed thrombosis and thrombocytopenia after they received the AstraZeneca vaccine.
The researchers explained that they investigated whether these patients could have a prothrombotic disorder caused by platelet-activating antibodies directed against PF4, which is known to be caused by heparin and sometimes environmental triggers.
The nine patients were aged 22-49 years and presented with thrombosis beginning 4-16 days post vaccination. Seven patients had cerebral venous thrombosis (CVT), one had pulmonary embolism, and one had splanchnic vein thrombosis and CVT. Four patients died. None had received heparin prior to symptom onset.
Serum from four patients was tested for anti-PF4/heparin antibodies, and all four tested strongly positive. All four also tested strongly positive on platelet activation assay for the presence of PF4 independently of heparin.
The authors noted that it has been recognized that triggers other than heparin, including some infections, can rarely cause a disorder that strongly resembles HIT. These cases have been referred to as spontaneous HIT syndrome.
They said that their current findings have several important clinical implications.
“Clinicians should be aware that onset of (venous or arterial) thrombosis particularly at unusual sites such as in the brain or abdomen and thrombocytopenia beginning approximately 5-14 days after vaccination can represent a rare adverse effect of preceding COVID-19 vaccination,” they wrote. To date, this has only been reported with the AstraZeneca vaccine.
They pointed out that enzyme immunoassays for HIT are widely available and can be used to investigate for potential postvaccination anti-PF4 antibody–associated thrombocytopenia/thrombosis. For such patients, referral should be made to a laboratory that performs platelet-activation assays.
Although this syndrome differs from typical HIT, the researchers noted that at least one patient showed strong platelet activation in the presence of heparin. They thus recommended therapy with nonheparin anticoagulants, such as the direct oral anticoagulants.
They also wrote that high-dose intravenous immunoglobulin has been shown to be effective for treating severe HIT and could also be an important treatment adjunct for patients who develop life-threatening thrombotic events, such as cerebral vein sinus thrombosis (CVST), after being vaccinated.
EMA data to date
Updated data, reported at the EMA press briefing on March 31, indicate that 62 cases of CVST have been reported worldwide (44 from the European Union). These data may not yet include all the German cases.
Peter Arlett, MD, head of pharmacovigilance and epidemiology at the EMA, said there were more cases than expected in the 2-week window after vaccination among patients younger than 60 and that health care professionals should be alert to features of this condition, including headache and blurred vision.
He suggested that the higher rate of the condition among younger women may reflect the population that received this vaccine, because initially, the vaccine was not recommended for older people in many countries and was targeted toward younger health care workers, who were mainly women.
The German regulatory agency, the Paul Ehrlich Institute, reported this week that it has now registered 31 cases of CVST among nearly 2.7 million people who had received the vaccine in Germany. Of these patients, 19 also were found to have a deficiency of blood platelets or thrombocytopenia. Nine of the affected patients died. All but two of the cases occurred in women aged 20-63 years. The two men were aged 36 and 57 years.
These data have prompted the German authorities to limit use of the AstraZeneca vaccine to those aged 60 years and older. Even before this decision, senior clinicians in Germany had been urging a change in the vaccination recommendations.
For example, Bernd Salzberger, MD, head of infectious diseases, University Hospital Regensburg (Germany), told the Science Media Center: “In women, a complicated course of COVID disease is less common from the start and is so rare in younger women that the chance of avoiding a fatal course through vaccination in women without comorbidities is of the same order of magnitude as the risk of this rare side effect.”
Sandra Ciesek, MD, a virologist at Goethe University, Frankfurt, Germany, told the journal Science: “The argument I keep hearing is that the risk-benefit ratio is still positive. But we do not have just one vaccine, we have several. So, restricting the AstraZeneca vaccine to older people makes sense to me, and it does not waste any doses.”
Concerns put in perspective
Commenting of the latest developments, thrombosis expert Saskia Middeldorp, MD, head of internal medicine at Radboud University Medical Center, Nijmegen, the Netherlands, said it was vitally important that these concerns be put in perspective and that the vaccination program with the AstraZeneca product continue.
“There are some concerning reports about very rare blood clotting disorders and low platelet counts possibly associated with the AstraZeneca vaccine. Groups from Germany and Norway have identified a syndrome similar to HIT, which seems to explain the cause of this very rare side effect,” Dr. Middeldorp noted.
“But with such a high pressure from the virus and many countries now going into a third wave of infection, anything that might slow down vaccination rates will cause much more harm than good,” she warned.
Dr. Middeldorp believes the incidence of this HIT-type syndrome linked to the vaccine is about 1-2 per million. “These are estimates based on the number of reports of this side effect and denominators from the U.K. and EU populations,” she explained. However, Germany has restricted the vaccine on the basis of German data, which appear to show higher rates of the condition. It is not known why the rates are higher in Germany.
“The European Medicines Agency is looking at this very closely. Their statement is quite clear. There is no foundation for changing policy on vaccination,” Dr. Middeldorp stated.
She cautioned that these reports were reducing confidence in the AstraZeneca vaccine, particularly among young people, which she said was causing “a major setback” for the vaccination program.
Noting that everything must be viewed in the context of this severe pandemic, Dr. Middeldorp emphasized that the benefit of the vaccine outweighed any risk, even among young people.
“To those who may be hesitating to have the vaccine as they don’t think they are at high risk of severe COVID infection, I would say there are a lot of young people in the ICU at present with COVID, and your chance of a severe COVID illness is far higher than the 1 or 2 in a million risk of a severe reaction to the vaccine,” she stated.
Dr. Greinacher has received grants and nonfinancial support from Aspen, Boehringer Ingelheim, Merck Sharp & Dohme, Bristol-Myers Squibb, Paringenix, Bayer Healthcare, Gore, Rovi, Sagent, and Biomarin/Prosensa; personal fees from Aspen, Boehringer Ingelheim, Merck Sharp & Dohme, Macopharma, Bristol-Myers Squibb, Chromatec, and Instrumentation Laboratory; and nonfinancial support from Boehringer Ingelheim, Portola, Ergomed, and GTH outside the submitted work.
A version of this article first appeared on Medscape.com.
The European Medicines Agency continues to reassure the public about the safety of the AstraZeneca COVID-19 vaccine, although several countries have imposed new restrictions on the product, owing to its link to a rare clotting disorder.
Use of the vaccine has been suspended for individuals younger than 55 or 60 years in several European countries and in Canada after reports of a prothrombotic disorder and thrombocytopenia, mainly in younger individuals.
Now, more information on the prothrombotic disorder has become available. The vaccine appears to be linked to a condition that clinically resembles heparin-induced thrombocytopenia (HIT) and that occurs mainly in younger women.
Researchers have described clinical and laboratory details of nine patients from Germany and Austria who developed this condition 4-16 days after receiving the AstraZeneca vaccine in a preprint article published March 28, 2021, on Research Square.
They found that serum from four patients who were tested showed platelet-activating antibodies directed against platelet factor 4 (PF4), similar to what is seen in HIT.
They are proposing naming the condition “vaccine-induced prothrombotic immune thrombocytopenia (VIPIT)” to avoid confusion with HIT.
At a press conference March 31, the EMA said its ongoing review of the situation “has not identified any specific risk factors, such as age, gender, or a previous medical history of clotting disorders, for these very rare events. A causal link with the vaccine is not proven but is possible, and further analysis is continuing.”
A statement from the agency noted: “EMA is of the view that the benefits of the AstraZeneca vaccine in preventing COVID-19, with its associated risk of hospitalization and death, outweigh the risks of side effects.”
But it added: “Vaccinated people should be aware of the remote possibility of these very rare types of blood clots occurring. If they have symptoms suggestive of clotting problems as described in the product information, they should seek immediate medical attention and inform health care professionals of their recent vaccination.”
VIPIT study
In the Research Square preprint article, a group led by Andreas Greinacher, MD, professor of transfusion medicine at the Greifswald (Germany) University Clinic, reported on clinical and laboratory features of nine patients (eight of whom were women) in Germany and Austria who developed thrombosis and thrombocytopenia after they received the AstraZeneca vaccine.
The researchers explained that they investigated whether these patients could have a prothrombotic disorder caused by platelet-activating antibodies directed against PF4, which is known to be caused by heparin and sometimes environmental triggers.
The nine patients were aged 22-49 years and presented with thrombosis beginning 4-16 days post vaccination. Seven patients had cerebral venous thrombosis (CVT), one had pulmonary embolism, and one had splanchnic vein thrombosis and CVT. Four patients died. None had received heparin prior to symptom onset.
Serum from four patients was tested for anti-PF4/heparin antibodies, and all four tested strongly positive. All four also tested strongly positive on platelet activation assay for the presence of PF4 independently of heparin.
The authors noted that it has been recognized that triggers other than heparin, including some infections, can rarely cause a disorder that strongly resembles HIT. These cases have been referred to as spontaneous HIT syndrome.
They said that their current findings have several important clinical implications.
“Clinicians should be aware that onset of (venous or arterial) thrombosis particularly at unusual sites such as in the brain or abdomen and thrombocytopenia beginning approximately 5-14 days after vaccination can represent a rare adverse effect of preceding COVID-19 vaccination,” they wrote. To date, this has only been reported with the AstraZeneca vaccine.
They pointed out that enzyme immunoassays for HIT are widely available and can be used to investigate for potential postvaccination anti-PF4 antibody–associated thrombocytopenia/thrombosis. For such patients, referral should be made to a laboratory that performs platelet-activation assays.
Although this syndrome differs from typical HIT, the researchers noted that at least one patient showed strong platelet activation in the presence of heparin. They thus recommended therapy with nonheparin anticoagulants, such as the direct oral anticoagulants.
They also wrote that high-dose intravenous immunoglobulin has been shown to be effective for treating severe HIT and could also be an important treatment adjunct for patients who develop life-threatening thrombotic events, such as cerebral vein sinus thrombosis (CVST), after being vaccinated.
EMA data to date
Updated data, reported at the EMA press briefing on March 31, indicate that 62 cases of CVST have been reported worldwide (44 from the European Union). These data may not yet include all the German cases.
Peter Arlett, MD, head of pharmacovigilance and epidemiology at the EMA, said there were more cases than expected in the 2-week window after vaccination among patients younger than 60 and that health care professionals should be alert to features of this condition, including headache and blurred vision.
He suggested that the higher rate of the condition among younger women may reflect the population that received this vaccine, because initially, the vaccine was not recommended for older people in many countries and was targeted toward younger health care workers, who were mainly women.
The German regulatory agency, the Paul Ehrlich Institute, reported this week that it has now registered 31 cases of CVST among nearly 2.7 million people who had received the vaccine in Germany. Of these patients, 19 also were found to have a deficiency of blood platelets or thrombocytopenia. Nine of the affected patients died. All but two of the cases occurred in women aged 20-63 years. The two men were aged 36 and 57 years.
These data have prompted the German authorities to limit use of the AstraZeneca vaccine to those aged 60 years and older. Even before this decision, senior clinicians in Germany had been urging a change in the vaccination recommendations.
For example, Bernd Salzberger, MD, head of infectious diseases, University Hospital Regensburg (Germany), told the Science Media Center: “In women, a complicated course of COVID disease is less common from the start and is so rare in younger women that the chance of avoiding a fatal course through vaccination in women without comorbidities is of the same order of magnitude as the risk of this rare side effect.”
Sandra Ciesek, MD, a virologist at Goethe University, Frankfurt, Germany, told the journal Science: “The argument I keep hearing is that the risk-benefit ratio is still positive. But we do not have just one vaccine, we have several. So, restricting the AstraZeneca vaccine to older people makes sense to me, and it does not waste any doses.”
Concerns put in perspective
Commenting of the latest developments, thrombosis expert Saskia Middeldorp, MD, head of internal medicine at Radboud University Medical Center, Nijmegen, the Netherlands, said it was vitally important that these concerns be put in perspective and that the vaccination program with the AstraZeneca product continue.
“There are some concerning reports about very rare blood clotting disorders and low platelet counts possibly associated with the AstraZeneca vaccine. Groups from Germany and Norway have identified a syndrome similar to HIT, which seems to explain the cause of this very rare side effect,” Dr. Middeldorp noted.
“But with such a high pressure from the virus and many countries now going into a third wave of infection, anything that might slow down vaccination rates will cause much more harm than good,” she warned.
Dr. Middeldorp believes the incidence of this HIT-type syndrome linked to the vaccine is about 1-2 per million. “These are estimates based on the number of reports of this side effect and denominators from the U.K. and EU populations,” she explained. However, Germany has restricted the vaccine on the basis of German data, which appear to show higher rates of the condition. It is not known why the rates are higher in Germany.
“The European Medicines Agency is looking at this very closely. Their statement is quite clear. There is no foundation for changing policy on vaccination,” Dr. Middeldorp stated.
She cautioned that these reports were reducing confidence in the AstraZeneca vaccine, particularly among young people, which she said was causing “a major setback” for the vaccination program.
Noting that everything must be viewed in the context of this severe pandemic, Dr. Middeldorp emphasized that the benefit of the vaccine outweighed any risk, even among young people.
“To those who may be hesitating to have the vaccine as they don’t think they are at high risk of severe COVID infection, I would say there are a lot of young people in the ICU at present with COVID, and your chance of a severe COVID illness is far higher than the 1 or 2 in a million risk of a severe reaction to the vaccine,” she stated.
Dr. Greinacher has received grants and nonfinancial support from Aspen, Boehringer Ingelheim, Merck Sharp & Dohme, Bristol-Myers Squibb, Paringenix, Bayer Healthcare, Gore, Rovi, Sagent, and Biomarin/Prosensa; personal fees from Aspen, Boehringer Ingelheim, Merck Sharp & Dohme, Macopharma, Bristol-Myers Squibb, Chromatec, and Instrumentation Laboratory; and nonfinancial support from Boehringer Ingelheim, Portola, Ergomed, and GTH outside the submitted work.
A version of this article first appeared on Medscape.com.
The European Medicines Agency continues to reassure the public about the safety of the AstraZeneca COVID-19 vaccine, although several countries have imposed new restrictions on the product, owing to its link to a rare clotting disorder.
Use of the vaccine has been suspended for individuals younger than 55 or 60 years in several European countries and in Canada after reports of a prothrombotic disorder and thrombocytopenia, mainly in younger individuals.
Now, more information on the prothrombotic disorder has become available. The vaccine appears to be linked to a condition that clinically resembles heparin-induced thrombocytopenia (HIT) and that occurs mainly in younger women.
Researchers have described clinical and laboratory details of nine patients from Germany and Austria who developed this condition 4-16 days after receiving the AstraZeneca vaccine in a preprint article published March 28, 2021, on Research Square.
They found that serum from four patients who were tested showed platelet-activating antibodies directed against platelet factor 4 (PF4), similar to what is seen in HIT.
They are proposing naming the condition “vaccine-induced prothrombotic immune thrombocytopenia (VIPIT)” to avoid confusion with HIT.
At a press conference March 31, the EMA said its ongoing review of the situation “has not identified any specific risk factors, such as age, gender, or a previous medical history of clotting disorders, for these very rare events. A causal link with the vaccine is not proven but is possible, and further analysis is continuing.”
A statement from the agency noted: “EMA is of the view that the benefits of the AstraZeneca vaccine in preventing COVID-19, with its associated risk of hospitalization and death, outweigh the risks of side effects.”
But it added: “Vaccinated people should be aware of the remote possibility of these very rare types of blood clots occurring. If they have symptoms suggestive of clotting problems as described in the product information, they should seek immediate medical attention and inform health care professionals of their recent vaccination.”
VIPIT study
In the Research Square preprint article, a group led by Andreas Greinacher, MD, professor of transfusion medicine at the Greifswald (Germany) University Clinic, reported on clinical and laboratory features of nine patients (eight of whom were women) in Germany and Austria who developed thrombosis and thrombocytopenia after they received the AstraZeneca vaccine.
The researchers explained that they investigated whether these patients could have a prothrombotic disorder caused by platelet-activating antibodies directed against PF4, which is known to be caused by heparin and sometimes environmental triggers.
The nine patients were aged 22-49 years and presented with thrombosis beginning 4-16 days post vaccination. Seven patients had cerebral venous thrombosis (CVT), one had pulmonary embolism, and one had splanchnic vein thrombosis and CVT. Four patients died. None had received heparin prior to symptom onset.
Serum from four patients was tested for anti-PF4/heparin antibodies, and all four tested strongly positive. All four also tested strongly positive on platelet activation assay for the presence of PF4 independently of heparin.
The authors noted that it has been recognized that triggers other than heparin, including some infections, can rarely cause a disorder that strongly resembles HIT. These cases have been referred to as spontaneous HIT syndrome.
They said that their current findings have several important clinical implications.
“Clinicians should be aware that onset of (venous or arterial) thrombosis particularly at unusual sites such as in the brain or abdomen and thrombocytopenia beginning approximately 5-14 days after vaccination can represent a rare adverse effect of preceding COVID-19 vaccination,” they wrote. To date, this has only been reported with the AstraZeneca vaccine.
They pointed out that enzyme immunoassays for HIT are widely available and can be used to investigate for potential postvaccination anti-PF4 antibody–associated thrombocytopenia/thrombosis. For such patients, referral should be made to a laboratory that performs platelet-activation assays.
Although this syndrome differs from typical HIT, the researchers noted that at least one patient showed strong platelet activation in the presence of heparin. They thus recommended therapy with nonheparin anticoagulants, such as the direct oral anticoagulants.
They also wrote that high-dose intravenous immunoglobulin has been shown to be effective for treating severe HIT and could also be an important treatment adjunct for patients who develop life-threatening thrombotic events, such as cerebral vein sinus thrombosis (CVST), after being vaccinated.
EMA data to date
Updated data, reported at the EMA press briefing on March 31, indicate that 62 cases of CVST have been reported worldwide (44 from the European Union). These data may not yet include all the German cases.
Peter Arlett, MD, head of pharmacovigilance and epidemiology at the EMA, said there were more cases than expected in the 2-week window after vaccination among patients younger than 60 and that health care professionals should be alert to features of this condition, including headache and blurred vision.
He suggested that the higher rate of the condition among younger women may reflect the population that received this vaccine, because initially, the vaccine was not recommended for older people in many countries and was targeted toward younger health care workers, who were mainly women.
The German regulatory agency, the Paul Ehrlich Institute, reported this week that it has now registered 31 cases of CVST among nearly 2.7 million people who had received the vaccine in Germany. Of these patients, 19 also were found to have a deficiency of blood platelets or thrombocytopenia. Nine of the affected patients died. All but two of the cases occurred in women aged 20-63 years. The two men were aged 36 and 57 years.
These data have prompted the German authorities to limit use of the AstraZeneca vaccine to those aged 60 years and older. Even before this decision, senior clinicians in Germany had been urging a change in the vaccination recommendations.
For example, Bernd Salzberger, MD, head of infectious diseases, University Hospital Regensburg (Germany), told the Science Media Center: “In women, a complicated course of COVID disease is less common from the start and is so rare in younger women that the chance of avoiding a fatal course through vaccination in women without comorbidities is of the same order of magnitude as the risk of this rare side effect.”
Sandra Ciesek, MD, a virologist at Goethe University, Frankfurt, Germany, told the journal Science: “The argument I keep hearing is that the risk-benefit ratio is still positive. But we do not have just one vaccine, we have several. So, restricting the AstraZeneca vaccine to older people makes sense to me, and it does not waste any doses.”
Concerns put in perspective
Commenting of the latest developments, thrombosis expert Saskia Middeldorp, MD, head of internal medicine at Radboud University Medical Center, Nijmegen, the Netherlands, said it was vitally important that these concerns be put in perspective and that the vaccination program with the AstraZeneca product continue.
“There are some concerning reports about very rare blood clotting disorders and low platelet counts possibly associated with the AstraZeneca vaccine. Groups from Germany and Norway have identified a syndrome similar to HIT, which seems to explain the cause of this very rare side effect,” Dr. Middeldorp noted.
“But with such a high pressure from the virus and many countries now going into a third wave of infection, anything that might slow down vaccination rates will cause much more harm than good,” she warned.
Dr. Middeldorp believes the incidence of this HIT-type syndrome linked to the vaccine is about 1-2 per million. “These are estimates based on the number of reports of this side effect and denominators from the U.K. and EU populations,” she explained. However, Germany has restricted the vaccine on the basis of German data, which appear to show higher rates of the condition. It is not known why the rates are higher in Germany.
“The European Medicines Agency is looking at this very closely. Their statement is quite clear. There is no foundation for changing policy on vaccination,” Dr. Middeldorp stated.
She cautioned that these reports were reducing confidence in the AstraZeneca vaccine, particularly among young people, which she said was causing “a major setback” for the vaccination program.
Noting that everything must be viewed in the context of this severe pandemic, Dr. Middeldorp emphasized that the benefit of the vaccine outweighed any risk, even among young people.
“To those who may be hesitating to have the vaccine as they don’t think they are at high risk of severe COVID infection, I would say there are a lot of young people in the ICU at present with COVID, and your chance of a severe COVID illness is far higher than the 1 or 2 in a million risk of a severe reaction to the vaccine,” she stated.
Dr. Greinacher has received grants and nonfinancial support from Aspen, Boehringer Ingelheim, Merck Sharp & Dohme, Bristol-Myers Squibb, Paringenix, Bayer Healthcare, Gore, Rovi, Sagent, and Biomarin/Prosensa; personal fees from Aspen, Boehringer Ingelheim, Merck Sharp & Dohme, Macopharma, Bristol-Myers Squibb, Chromatec, and Instrumentation Laboratory; and nonfinancial support from Boehringer Ingelheim, Portola, Ergomed, and GTH outside the submitted work.
A version of this article first appeared on Medscape.com.
New guidelines on the diagnosis and treatment of adults with CAP
Background: More than a decade has passed since the last CAP guidelines. Since then there have been new trials and epidemiological studies. There have also been changes to the process for guideline development. This guideline has moved away from the narrative style of guidelines to the GRADE format and PICO framework with hopes of answering specific questions by looking at the quality of evidence.
Study design: Multidisciplinary panel conducted pragmatic systemic reviews of high-quality studies.
Setting: The panel revised and built upon the 2007 guidelines, addressing 16 clinical questions to be used in immunocompetent patients with radiographic evidence of CAP in the United States with no recent foreign travel.
Synopsis: Changes from the 2007 guidelines are as follows: Sputum and blood cultures, previously recommended only in patients with severe CAP, are now also recommended for inpatients being empirically treated for Pseudomonas or methicillin-resistant Staphylococcus aureus (MRSA) and for those who have received IV antibiotics in the previous 90 days; use of procalcitonin is not recommended to decide whether to withhold antibiotics; steroids are not recommended unless being used for shock; HCAP categorization should be abandoned and need for empiric coverage of MRSA and Pseudomonas should be based on local epidemiology and local validated risk factors; B-lactam/macrolide is favored over fluoroquinolone for severe CAP therapy; and routine follow-up chest x-ray is not recommended.
Other recommendations include not routinely testing for urine pneumococcal or legionella antigens in nonsevere CAP; using PSI over CURB-65, in addition to clinical judgment, to determine need for inpatient care; using severe CAP criteria and clinical judgment for determining ICU need; not adding anaerobic coverage for aspiration pneumonia; and treating most cases of CAP that are clinically stable and uncomplicated for 5-7 days.
Bottom line: Given new data, updated recommendations have been made to help optimize CAP therapy.
Citation: Metlay JP et al. Diagnosis and treatment of adults with community-acquired pneumonia: An official clinical practice guideline of the American Thoracic Society and Infectious Diseases Society of America. Am J Respir Crit Care Med. 2019 Oct 1;200(7):e45-67.
Dr. Horton is a hospitalist and clinical instructor of medicine at the University of Utah, Salt Lake City.
Background: More than a decade has passed since the last CAP guidelines. Since then there have been new trials and epidemiological studies. There have also been changes to the process for guideline development. This guideline has moved away from the narrative style of guidelines to the GRADE format and PICO framework with hopes of answering specific questions by looking at the quality of evidence.
Study design: Multidisciplinary panel conducted pragmatic systemic reviews of high-quality studies.
Setting: The panel revised and built upon the 2007 guidelines, addressing 16 clinical questions to be used in immunocompetent patients with radiographic evidence of CAP in the United States with no recent foreign travel.
Synopsis: Changes from the 2007 guidelines are as follows: Sputum and blood cultures, previously recommended only in patients with severe CAP, are now also recommended for inpatients being empirically treated for Pseudomonas or methicillin-resistant Staphylococcus aureus (MRSA) and for those who have received IV antibiotics in the previous 90 days; use of procalcitonin is not recommended to decide whether to withhold antibiotics; steroids are not recommended unless being used for shock; HCAP categorization should be abandoned and need for empiric coverage of MRSA and Pseudomonas should be based on local epidemiology and local validated risk factors; B-lactam/macrolide is favored over fluoroquinolone for severe CAP therapy; and routine follow-up chest x-ray is not recommended.
Other recommendations include not routinely testing for urine pneumococcal or legionella antigens in nonsevere CAP; using PSI over CURB-65, in addition to clinical judgment, to determine need for inpatient care; using severe CAP criteria and clinical judgment for determining ICU need; not adding anaerobic coverage for aspiration pneumonia; and treating most cases of CAP that are clinically stable and uncomplicated for 5-7 days.
Bottom line: Given new data, updated recommendations have been made to help optimize CAP therapy.
Citation: Metlay JP et al. Diagnosis and treatment of adults with community-acquired pneumonia: An official clinical practice guideline of the American Thoracic Society and Infectious Diseases Society of America. Am J Respir Crit Care Med. 2019 Oct 1;200(7):e45-67.
Dr. Horton is a hospitalist and clinical instructor of medicine at the University of Utah, Salt Lake City.
Background: More than a decade has passed since the last CAP guidelines. Since then there have been new trials and epidemiological studies. There have also been changes to the process for guideline development. This guideline has moved away from the narrative style of guidelines to the GRADE format and PICO framework with hopes of answering specific questions by looking at the quality of evidence.
Study design: Multidisciplinary panel conducted pragmatic systemic reviews of high-quality studies.
Setting: The panel revised and built upon the 2007 guidelines, addressing 16 clinical questions to be used in immunocompetent patients with radiographic evidence of CAP in the United States with no recent foreign travel.
Synopsis: Changes from the 2007 guidelines are as follows: Sputum and blood cultures, previously recommended only in patients with severe CAP, are now also recommended for inpatients being empirically treated for Pseudomonas or methicillin-resistant Staphylococcus aureus (MRSA) and for those who have received IV antibiotics in the previous 90 days; use of procalcitonin is not recommended to decide whether to withhold antibiotics; steroids are not recommended unless being used for shock; HCAP categorization should be abandoned and need for empiric coverage of MRSA and Pseudomonas should be based on local epidemiology and local validated risk factors; B-lactam/macrolide is favored over fluoroquinolone for severe CAP therapy; and routine follow-up chest x-ray is not recommended.
Other recommendations include not routinely testing for urine pneumococcal or legionella antigens in nonsevere CAP; using PSI over CURB-65, in addition to clinical judgment, to determine need for inpatient care; using severe CAP criteria and clinical judgment for determining ICU need; not adding anaerobic coverage for aspiration pneumonia; and treating most cases of CAP that are clinically stable and uncomplicated for 5-7 days.
Bottom line: Given new data, updated recommendations have been made to help optimize CAP therapy.
Citation: Metlay JP et al. Diagnosis and treatment of adults with community-acquired pneumonia: An official clinical practice guideline of the American Thoracic Society and Infectious Diseases Society of America. Am J Respir Crit Care Med. 2019 Oct 1;200(7):e45-67.
Dr. Horton is a hospitalist and clinical instructor of medicine at the University of Utah, Salt Lake City.
Metoprolol increases severity, but not risk, of COPD exacerbations
Background: Beta-blockers are underutilized in patients with both COPD and established cardiovascular indications for beta-blocker therapy, despite evidence suggesting overall benefit. Prior observational studies have associated beta-blockers with improved outcomes in COPD in the absence of cardiovascular indications; however, this has not been previously evaluated in a randomized trial.
Study design: Placebo-controlled, double-blind, prospective, randomized trial.
Setting: A total of 26 centers in the United States.
Synopsis: The BLOCK COPD trial randomized more than 500 patients with moderate to severe COPD and no established indication for beta-blocker therapy to extended-release metoprolol or placebo. There was no significant difference in the primary endpoint of time until first exacerbation. While there was no difference in the overall risk of exacerbations of COPD, the trial was terminated early because of increased risk of severe or very severe exacerbations of COPD in the metoprolol group (hazard ratio, 1.91; 95% confidence interval, 1.20-2.83). These were defined as exacerbations requiring hospitalization and mechanical ventilation, respectively.
Importantly, this trial excluded patients with established indications for beta-blocker therapy, and study findings should not be applied to this population.
Bottom line: Metoprolol is not associated with increased risk of COPD exacerbations, but is associated with increased severity of COPD exacerbations in patients with moderate to severe COPD who have no established indications for beta-blockers.
Citation: Dransfield MT et al. Metoprolol for the prevention of acute exacerbations of COPD. N Engl J Med. 2019 Oct 20. doi: 10.1056/NEJMoa1908142.
Dr. Gerstenberger is a hospitalist and clinical assistant professor of medicine at the University of Utah, Salt Lake City.
Background: Beta-blockers are underutilized in patients with both COPD and established cardiovascular indications for beta-blocker therapy, despite evidence suggesting overall benefit. Prior observational studies have associated beta-blockers with improved outcomes in COPD in the absence of cardiovascular indications; however, this has not been previously evaluated in a randomized trial.
Study design: Placebo-controlled, double-blind, prospective, randomized trial.
Setting: A total of 26 centers in the United States.
Synopsis: The BLOCK COPD trial randomized more than 500 patients with moderate to severe COPD and no established indication for beta-blocker therapy to extended-release metoprolol or placebo. There was no significant difference in the primary endpoint of time until first exacerbation. While there was no difference in the overall risk of exacerbations of COPD, the trial was terminated early because of increased risk of severe or very severe exacerbations of COPD in the metoprolol group (hazard ratio, 1.91; 95% confidence interval, 1.20-2.83). These were defined as exacerbations requiring hospitalization and mechanical ventilation, respectively.
Importantly, this trial excluded patients with established indications for beta-blocker therapy, and study findings should not be applied to this population.
Bottom line: Metoprolol is not associated with increased risk of COPD exacerbations, but is associated with increased severity of COPD exacerbations in patients with moderate to severe COPD who have no established indications for beta-blockers.
Citation: Dransfield MT et al. Metoprolol for the prevention of acute exacerbations of COPD. N Engl J Med. 2019 Oct 20. doi: 10.1056/NEJMoa1908142.
Dr. Gerstenberger is a hospitalist and clinical assistant professor of medicine at the University of Utah, Salt Lake City.
Background: Beta-blockers are underutilized in patients with both COPD and established cardiovascular indications for beta-blocker therapy, despite evidence suggesting overall benefit. Prior observational studies have associated beta-blockers with improved outcomes in COPD in the absence of cardiovascular indications; however, this has not been previously evaluated in a randomized trial.
Study design: Placebo-controlled, double-blind, prospective, randomized trial.
Setting: A total of 26 centers in the United States.
Synopsis: The BLOCK COPD trial randomized more than 500 patients with moderate to severe COPD and no established indication for beta-blocker therapy to extended-release metoprolol or placebo. There was no significant difference in the primary endpoint of time until first exacerbation. While there was no difference in the overall risk of exacerbations of COPD, the trial was terminated early because of increased risk of severe or very severe exacerbations of COPD in the metoprolol group (hazard ratio, 1.91; 95% confidence interval, 1.20-2.83). These were defined as exacerbations requiring hospitalization and mechanical ventilation, respectively.
Importantly, this trial excluded patients with established indications for beta-blocker therapy, and study findings should not be applied to this population.
Bottom line: Metoprolol is not associated with increased risk of COPD exacerbations, but is associated with increased severity of COPD exacerbations in patients with moderate to severe COPD who have no established indications for beta-blockers.
Citation: Dransfield MT et al. Metoprolol for the prevention of acute exacerbations of COPD. N Engl J Med. 2019 Oct 20. doi: 10.1056/NEJMoa1908142.
Dr. Gerstenberger is a hospitalist and clinical assistant professor of medicine at the University of Utah, Salt Lake City.