User login
Very early ART may benefit infants with HIV
SEATTLE – Antiretroviral therapy (ART) in the earliest weeks of life is associated with reduced time to suppression, according to a new study. Each week that treatment was delayed, patients had a 35% reduction in odds of achieving earlier viral load (VL) suppression.
Previous research had already shown that patients treated in the first year of life have better outcomes, including shortened time to viral suppression, and a lower reservoir size. Those studies looked at median age of ART start by month, and a review of the literature revealed that no research had been done on the first month.
The research was presented at the Conference on Retroviruses & Opportunistic Infections by Sara Domínguez Rodríguez, biostatistician and data manager in the pediatric infectious disease service at Hospital 12 Octubre, Madrid.
The researchers retrospectively analyzed 44 patients who were treated in the first 28 days of life, who had uninterrupted ART for at least 2 years, and who had VL measured at least twice during follow-up. Among these, 25 patients received ART in the first week, 19 in weeks 2-4. Patients treated prophylactically with AZT + 3TC (lamivudine) + NVP (nevirapine) any time in the first 15 days of life were considered treated at day 1.
Five of the patients were from the United Kingdom, 23 from Spain, 3 from Italy, and 13 from Thailand. Fifty-seven percent were girls; 35% were preterm. Patients treated in the first week had a higher log10 HIV viral load at ART initiation (P = .02). There was no significant difference between the two groups with respect to CD4 count at ART initiation.
The time to suppression was not significantly different between the two groups, nor was the percentage of patients suppressed at various time points. Patients treated in the first week had reached suppression more often at 3 months and 6 months, but neither result reached statistical significance.
The small sample size of the study produced a challenge, and that led the team to consider suppression time and age as continuous variables. That revealed a curve that favored treatment in the first week of life: Each week of delay reduced the probability of achieving early viral suppression by 35% (hazard ratio, 0.65; 95% confidence interval, 0.46-0.92). “This means that if you delay the age at ART in terms of weeks, the probability of achieving suppression (over) time decreases, and this effect is particularly seen in the first year of follow-up,” Dr. Domínguez Rodríguez said in an interview.
Some might have concerns that treating children too early could have adverse effects. This study, though small, showed promising results. “You might think if you treat very early, maybe the child will not tolerate the medicine or keep on with the treatment, and we saw no difference. So that supports treating early,” senior author Pablo Rojo Conejo, PhD, an infectious disease specialist at Hospital 12 de Octubre, said in an interview.
Others in attendance found the results encouraging. “It’s very good news to see that early starting impacts the life of these children,” Filipe de Barros Perini, MD, head of care and treatment of the HIV program at the Brazilian Ministry of Health, said in an interview.
SOURCE: Domínguez Rodríguez S et al. CROI 2019, Abstract 44.
SEATTLE – Antiretroviral therapy (ART) in the earliest weeks of life is associated with reduced time to suppression, according to a new study. Each week that treatment was delayed, patients had a 35% reduction in odds of achieving earlier viral load (VL) suppression.
Previous research had already shown that patients treated in the first year of life have better outcomes, including shortened time to viral suppression, and a lower reservoir size. Those studies looked at median age of ART start by month, and a review of the literature revealed that no research had been done on the first month.
The research was presented at the Conference on Retroviruses & Opportunistic Infections by Sara Domínguez Rodríguez, biostatistician and data manager in the pediatric infectious disease service at Hospital 12 Octubre, Madrid.
The researchers retrospectively analyzed 44 patients who were treated in the first 28 days of life, who had uninterrupted ART for at least 2 years, and who had VL measured at least twice during follow-up. Among these, 25 patients received ART in the first week, 19 in weeks 2-4. Patients treated prophylactically with AZT + 3TC (lamivudine) + NVP (nevirapine) any time in the first 15 days of life were considered treated at day 1.
Five of the patients were from the United Kingdom, 23 from Spain, 3 from Italy, and 13 from Thailand. Fifty-seven percent were girls; 35% were preterm. Patients treated in the first week had a higher log10 HIV viral load at ART initiation (P = .02). There was no significant difference between the two groups with respect to CD4 count at ART initiation.
The time to suppression was not significantly different between the two groups, nor was the percentage of patients suppressed at various time points. Patients treated in the first week had reached suppression more often at 3 months and 6 months, but neither result reached statistical significance.
The small sample size of the study produced a challenge, and that led the team to consider suppression time and age as continuous variables. That revealed a curve that favored treatment in the first week of life: Each week of delay reduced the probability of achieving early viral suppression by 35% (hazard ratio, 0.65; 95% confidence interval, 0.46-0.92). “This means that if you delay the age at ART in terms of weeks, the probability of achieving suppression (over) time decreases, and this effect is particularly seen in the first year of follow-up,” Dr. Domínguez Rodríguez said in an interview.
Some might have concerns that treating children too early could have adverse effects. This study, though small, showed promising results. “You might think if you treat very early, maybe the child will not tolerate the medicine or keep on with the treatment, and we saw no difference. So that supports treating early,” senior author Pablo Rojo Conejo, PhD, an infectious disease specialist at Hospital 12 de Octubre, said in an interview.
Others in attendance found the results encouraging. “It’s very good news to see that early starting impacts the life of these children,” Filipe de Barros Perini, MD, head of care and treatment of the HIV program at the Brazilian Ministry of Health, said in an interview.
SOURCE: Domínguez Rodríguez S et al. CROI 2019, Abstract 44.
SEATTLE – Antiretroviral therapy (ART) in the earliest weeks of life is associated with reduced time to suppression, according to a new study. Each week that treatment was delayed, patients had a 35% reduction in odds of achieving earlier viral load (VL) suppression.
Previous research had already shown that patients treated in the first year of life have better outcomes, including shortened time to viral suppression, and a lower reservoir size. Those studies looked at median age of ART start by month, and a review of the literature revealed that no research had been done on the first month.
The research was presented at the Conference on Retroviruses & Opportunistic Infections by Sara Domínguez Rodríguez, biostatistician and data manager in the pediatric infectious disease service at Hospital 12 Octubre, Madrid.
The researchers retrospectively analyzed 44 patients who were treated in the first 28 days of life, who had uninterrupted ART for at least 2 years, and who had VL measured at least twice during follow-up. Among these, 25 patients received ART in the first week, 19 in weeks 2-4. Patients treated prophylactically with AZT + 3TC (lamivudine) + NVP (nevirapine) any time in the first 15 days of life were considered treated at day 1.
Five of the patients were from the United Kingdom, 23 from Spain, 3 from Italy, and 13 from Thailand. Fifty-seven percent were girls; 35% were preterm. Patients treated in the first week had a higher log10 HIV viral load at ART initiation (P = .02). There was no significant difference between the two groups with respect to CD4 count at ART initiation.
The time to suppression was not significantly different between the two groups, nor was the percentage of patients suppressed at various time points. Patients treated in the first week had reached suppression more often at 3 months and 6 months, but neither result reached statistical significance.
The small sample size of the study produced a challenge, and that led the team to consider suppression time and age as continuous variables. That revealed a curve that favored treatment in the first week of life: Each week of delay reduced the probability of achieving early viral suppression by 35% (hazard ratio, 0.65; 95% confidence interval, 0.46-0.92). “This means that if you delay the age at ART in terms of weeks, the probability of achieving suppression (over) time decreases, and this effect is particularly seen in the first year of follow-up,” Dr. Domínguez Rodríguez said in an interview.
Some might have concerns that treating children too early could have adverse effects. This study, though small, showed promising results. “You might think if you treat very early, maybe the child will not tolerate the medicine or keep on with the treatment, and we saw no difference. So that supports treating early,” senior author Pablo Rojo Conejo, PhD, an infectious disease specialist at Hospital 12 de Octubre, said in an interview.
Others in attendance found the results encouraging. “It’s very good news to see that early starting impacts the life of these children,” Filipe de Barros Perini, MD, head of care and treatment of the HIV program at the Brazilian Ministry of Health, said in an interview.
SOURCE: Domínguez Rodríguez S et al. CROI 2019, Abstract 44.
REPORTING FROM CROI 2019
HCC with no cirrhosis is more common in HIV patients
SEATTLE – Hepatocellular carcinoma (HCC) is on the rise in HIV-positive individuals, its incidence having quadrupled since 1996, and HIV-positive individuals have about a 300% increase risk of HCC, compared with the general population. However, more than 40% of patients with HIV who develop HCC have a Fibrosis-4 score (FIB-4) suggesting a lack of cirrhosis, according to a new retrospective analysis. By contrast, only about 13% of typical HCC patients have no cirrhosis.
The study also revealed some of the risk factors associated with HCC in this population, including longer duration of HIV viremia and lower CD4 cell counts, as well as markers of metabolic syndrome. “There was some signal that perhaps other markers of metabolic syndrome, obesity and diabetes, were more prevalent in those [who developed HCC] without advanced fibrosis or cirrhosis, suggesting that there may be other underlying etiologies of liver disease that we should be wary of when evaluating somebody for their risk of HCC,” Jessie Torgersen, MD, said in an interview.
Dr. Torgersen is an instructor of medicine at the University of Pennsylvania, Philadelphia. She presented the study at the Conference on Retroviruses & Opportunistic Infections.
The results of the study are tantalizing, but not yet practice changing. “I don’t think we have enough information from this study to recommend a dramatic overhaul of the current HCC screening guidelines, but with the anticipated elimination of hepatitis C, I think the emergence of [metabolic factors and their] contributions to our HIV-positive population’s risk of HCC needs to be better understood. Hopefully this will serve as a first step in further understanding those risks,” Dr. Torgersen said.
She also hopes to get a better handle on the biological mechanisms that might drive HCC in the absence of cirrhosis. “While the mechanisms are unclear as to why HCC would develop in HIV-positive patients without cirrhosis, there are a lot of biologically plausible mechanisms that seem to make [sense],” said Dr. Torgersen. The team hopes to get a better understanding of those mechanisms in order to information evaluation and screening for HCC.
The researchers analyzed data from the Veterans Affairs Cancer Registry as well as EMRs for HIV-positive veterans across the United States. The study included 2,497 participants with a FIB-4 score greater than 3.25, and 29,836 with an FIB-4 score less than or equal to 3.25. At baseline, subjects with FIB-4 greater than 3.25 were more likely to have an alcohol-related diagnosis (47% vs. 29%), be positive for hepatitis C virus RNA (59% vs. 30%), be positive for the hepatitis B surface antigen (10% versus 5%), have HIV RNA greater than or equal to 500 copies/mL (63% vs. 56%), and to have a CD4+ cell count less than 200 cells/m3 (39% vs. 26%).
A total of 278 subjects were diagnosed with HCC; 43% had an FIB-4 less than or equal to 3.25. Among those 43%, more patients had a body mass index of 30 or higher (16% vs. 12%), had diabetes (31% vs. 25%), and tested positive for the hepatitis B surface antigen (26% vs. 17%).
Among subjects with FIB-4 less than or equal to 3.25, factors associated with greater HCC risk included higher HIV RNA level (hazard ratio, 1.24 per 1.0 log10 copies/mL), CD4+ cell count less than 200 cells/m3 (HR, 1.78), hepatitis C virus infection (HR, 6.32), and positive hepatitis B surface antigen (HR, 4.93).
Among subjects with FIB-4 greater than 3.25, increased HCC risk was associated with HCV infection (HR, 6.18) and positive hepatitis B surface antigen (HR, 2.12).
The study was funded by the National Institutes of Health. Dr. Torgersen reported no financial disclosures.
SOURCE: Torgersen J et al. CROI 2019, Abstract 90.
SEATTLE – Hepatocellular carcinoma (HCC) is on the rise in HIV-positive individuals, its incidence having quadrupled since 1996, and HIV-positive individuals have about a 300% increase risk of HCC, compared with the general population. However, more than 40% of patients with HIV who develop HCC have a Fibrosis-4 score (FIB-4) suggesting a lack of cirrhosis, according to a new retrospective analysis. By contrast, only about 13% of typical HCC patients have no cirrhosis.
The study also revealed some of the risk factors associated with HCC in this population, including longer duration of HIV viremia and lower CD4 cell counts, as well as markers of metabolic syndrome. “There was some signal that perhaps other markers of metabolic syndrome, obesity and diabetes, were more prevalent in those [who developed HCC] without advanced fibrosis or cirrhosis, suggesting that there may be other underlying etiologies of liver disease that we should be wary of when evaluating somebody for their risk of HCC,” Jessie Torgersen, MD, said in an interview.
Dr. Torgersen is an instructor of medicine at the University of Pennsylvania, Philadelphia. She presented the study at the Conference on Retroviruses & Opportunistic Infections.
The results of the study are tantalizing, but not yet practice changing. “I don’t think we have enough information from this study to recommend a dramatic overhaul of the current HCC screening guidelines, but with the anticipated elimination of hepatitis C, I think the emergence of [metabolic factors and their] contributions to our HIV-positive population’s risk of HCC needs to be better understood. Hopefully this will serve as a first step in further understanding those risks,” Dr. Torgersen said.
She also hopes to get a better handle on the biological mechanisms that might drive HCC in the absence of cirrhosis. “While the mechanisms are unclear as to why HCC would develop in HIV-positive patients without cirrhosis, there are a lot of biologically plausible mechanisms that seem to make [sense],” said Dr. Torgersen. The team hopes to get a better understanding of those mechanisms in order to information evaluation and screening for HCC.
The researchers analyzed data from the Veterans Affairs Cancer Registry as well as EMRs for HIV-positive veterans across the United States. The study included 2,497 participants with a FIB-4 score greater than 3.25, and 29,836 with an FIB-4 score less than or equal to 3.25. At baseline, subjects with FIB-4 greater than 3.25 were more likely to have an alcohol-related diagnosis (47% vs. 29%), be positive for hepatitis C virus RNA (59% vs. 30%), be positive for the hepatitis B surface antigen (10% versus 5%), have HIV RNA greater than or equal to 500 copies/mL (63% vs. 56%), and to have a CD4+ cell count less than 200 cells/m3 (39% vs. 26%).
A total of 278 subjects were diagnosed with HCC; 43% had an FIB-4 less than or equal to 3.25. Among those 43%, more patients had a body mass index of 30 or higher (16% vs. 12%), had diabetes (31% vs. 25%), and tested positive for the hepatitis B surface antigen (26% vs. 17%).
Among subjects with FIB-4 less than or equal to 3.25, factors associated with greater HCC risk included higher HIV RNA level (hazard ratio, 1.24 per 1.0 log10 copies/mL), CD4+ cell count less than 200 cells/m3 (HR, 1.78), hepatitis C virus infection (HR, 6.32), and positive hepatitis B surface antigen (HR, 4.93).
Among subjects with FIB-4 greater than 3.25, increased HCC risk was associated with HCV infection (HR, 6.18) and positive hepatitis B surface antigen (HR, 2.12).
The study was funded by the National Institutes of Health. Dr. Torgersen reported no financial disclosures.
SOURCE: Torgersen J et al. CROI 2019, Abstract 90.
SEATTLE – Hepatocellular carcinoma (HCC) is on the rise in HIV-positive individuals, its incidence having quadrupled since 1996, and HIV-positive individuals have about a 300% increase risk of HCC, compared with the general population. However, more than 40% of patients with HIV who develop HCC have a Fibrosis-4 score (FIB-4) suggesting a lack of cirrhosis, according to a new retrospective analysis. By contrast, only about 13% of typical HCC patients have no cirrhosis.
The study also revealed some of the risk factors associated with HCC in this population, including longer duration of HIV viremia and lower CD4 cell counts, as well as markers of metabolic syndrome. “There was some signal that perhaps other markers of metabolic syndrome, obesity and diabetes, were more prevalent in those [who developed HCC] without advanced fibrosis or cirrhosis, suggesting that there may be other underlying etiologies of liver disease that we should be wary of when evaluating somebody for their risk of HCC,” Jessie Torgersen, MD, said in an interview.
Dr. Torgersen is an instructor of medicine at the University of Pennsylvania, Philadelphia. She presented the study at the Conference on Retroviruses & Opportunistic Infections.
The results of the study are tantalizing, but not yet practice changing. “I don’t think we have enough information from this study to recommend a dramatic overhaul of the current HCC screening guidelines, but with the anticipated elimination of hepatitis C, I think the emergence of [metabolic factors and their] contributions to our HIV-positive population’s risk of HCC needs to be better understood. Hopefully this will serve as a first step in further understanding those risks,” Dr. Torgersen said.
She also hopes to get a better handle on the biological mechanisms that might drive HCC in the absence of cirrhosis. “While the mechanisms are unclear as to why HCC would develop in HIV-positive patients without cirrhosis, there are a lot of biologically plausible mechanisms that seem to make [sense],” said Dr. Torgersen. The team hopes to get a better understanding of those mechanisms in order to information evaluation and screening for HCC.
The researchers analyzed data from the Veterans Affairs Cancer Registry as well as EMRs for HIV-positive veterans across the United States. The study included 2,497 participants with a FIB-4 score greater than 3.25, and 29,836 with an FIB-4 score less than or equal to 3.25. At baseline, subjects with FIB-4 greater than 3.25 were more likely to have an alcohol-related diagnosis (47% vs. 29%), be positive for hepatitis C virus RNA (59% vs. 30%), be positive for the hepatitis B surface antigen (10% versus 5%), have HIV RNA greater than or equal to 500 copies/mL (63% vs. 56%), and to have a CD4+ cell count less than 200 cells/m3 (39% vs. 26%).
A total of 278 subjects were diagnosed with HCC; 43% had an FIB-4 less than or equal to 3.25. Among those 43%, more patients had a body mass index of 30 or higher (16% vs. 12%), had diabetes (31% vs. 25%), and tested positive for the hepatitis B surface antigen (26% vs. 17%).
Among subjects with FIB-4 less than or equal to 3.25, factors associated with greater HCC risk included higher HIV RNA level (hazard ratio, 1.24 per 1.0 log10 copies/mL), CD4+ cell count less than 200 cells/m3 (HR, 1.78), hepatitis C virus infection (HR, 6.32), and positive hepatitis B surface antigen (HR, 4.93).
Among subjects with FIB-4 greater than 3.25, increased HCC risk was associated with HCV infection (HR, 6.18) and positive hepatitis B surface antigen (HR, 2.12).
The study was funded by the National Institutes of Health. Dr. Torgersen reported no financial disclosures.
SOURCE: Torgersen J et al. CROI 2019, Abstract 90.
REPORTING FROM CROI 2019
Raltegravir safe, effective in late pregnancy
SEATTLE – In HIV-positive pregnant women, an antiretroviral therapy (ART) regimen that included the integrase inhibitor raltegravir (RAL-ART) led to faster viral load (VL) reduction and a greater proportion of women with a VL of less than 200 copies/mL at delivery, compared with patients treated with an efavirenz-based ART (EFV-ART). There were no statistically significant differences between the two arms with respect to percentage of stillbirths, preterm delivery, or rates of HIV infection in the newborn.
“There are lots of advantages of these [integrase inhibitor] drugs, and we’d like to have pregnant women take advantage of them. The problem is, there’s no requirement of drug manufacturers to study the drugs in pregnancy. So these studies are put off until after the drug is licensed, and we’re playing catch-up,” Mark Mirochnick, MD, professor of pediatrics at Boston University, said in an interview. Dr. Mirochnick presented the results at the Conference on Retroviruses and Opportunistic Infections.
Another integrase inhibitor, dolutegravir, has a better resistance profile than that of raltegravir, but concerns over neural tube defects observed during a study in Botswana led both the Food and Drug Administration and the European Medicines Agency to issue safety warnings for that drug. The current study did not raise concern, since it began at 20 weeks’ gestation, well after the period when neural tube defects might occur. “I think it just demonstrates that [integrase inhibitors] are safe in mid- to late-pregnancy,” said Dr. Mirochnick.
It remains to be seen whether a potential link to neural tube defects, if it is a real effect, is due to a specific drug or the mechanism of action of integrase inhibitors more generally. “It’s a question we don’t have an answer to. So you have to balance the potential benefits and potential risks, and that’s probably a decision best made by an individual woman and her care provider. Some women do very well on a particular regimen and they don’t want to change, and you run the risk when you change that you’ll get a viral rebound. What do you tell women who are on dolutegravir and are thinking about becoming pregnant? That’s a controversial question. There are risks with both courses,” said Dr. Mirochnick.
The study comprised 408 patients recruited from centers in Brazil, Tanzania, South Africa, Thailand, Argentina, and the United States. The patients were between 20 and 37 weeks’ gestation and had not previously received ART. They were randomized to RAL-ART or EFV-ART. About 12% of patients were Asian, 36% were black, 52% were Hispanic, and 1% were white.
Overall, 94% of patients on RAL-ART had a VL less than 200 copies/mL at delivery, compared to 84% of EFV-ART patients (P = .001). The effect appeared to be driven by patients who enrolled later in pregnancy: There was no significant difference in those enrolled in weeks 20-28, but suppression occurred in 93% of the RAL-ART group versus 71% of the EFV-ART group among those enrolled in weeks 29-37 (P = .04).
Tolerability was slightly better in the RAL-ART group, with 99% versus 97% of patients staying on their assigned therapy (P = .05). In both groups, 30% of women experienced an adverse event of grade 3 or higher, as did 25% of live-born infants in both groups.
A total of 92% of women in the RAL-ART group had a sustained VL response through delivery, compared with 64% in the EFV-ART group (P less than .001). The median time to achieving a VL less than 200 copies/mL was 8 days in the RAL-ART group and 15 days in the EFV-ART group (generalized log-rank test P less than .001).
There was one stillbirth in the EFV-ART arm and three in the RAL-ART arm, with 11% in the EFV-ART group having preterm delivery compared with 12% in the RAL-ART group. In addition, the proportion of HIV-infected infants was lower in the RAL-ART arm (1% versus 3%). These differences were not significant.
The National Institutes of Health funded the study. Glaxo/ViiV, Merck, and Bristol-Myers Squibb supplied study drugs. Dr. Mirochnick has received research funding from those companies.
SOURCE: Mark Mirochnick et al. CROI 2019, Abstract 39 LB.
SEATTLE – In HIV-positive pregnant women, an antiretroviral therapy (ART) regimen that included the integrase inhibitor raltegravir (RAL-ART) led to faster viral load (VL) reduction and a greater proportion of women with a VL of less than 200 copies/mL at delivery, compared with patients treated with an efavirenz-based ART (EFV-ART). There were no statistically significant differences between the two arms with respect to percentage of stillbirths, preterm delivery, or rates of HIV infection in the newborn.
“There are lots of advantages of these [integrase inhibitor] drugs, and we’d like to have pregnant women take advantage of them. The problem is, there’s no requirement of drug manufacturers to study the drugs in pregnancy. So these studies are put off until after the drug is licensed, and we’re playing catch-up,” Mark Mirochnick, MD, professor of pediatrics at Boston University, said in an interview. Dr. Mirochnick presented the results at the Conference on Retroviruses and Opportunistic Infections.
Another integrase inhibitor, dolutegravir, has a better resistance profile than that of raltegravir, but concerns over neural tube defects observed during a study in Botswana led both the Food and Drug Administration and the European Medicines Agency to issue safety warnings for that drug. The current study did not raise concern, since it began at 20 weeks’ gestation, well after the period when neural tube defects might occur. “I think it just demonstrates that [integrase inhibitors] are safe in mid- to late-pregnancy,” said Dr. Mirochnick.
It remains to be seen whether a potential link to neural tube defects, if it is a real effect, is due to a specific drug or the mechanism of action of integrase inhibitors more generally. “It’s a question we don’t have an answer to. So you have to balance the potential benefits and potential risks, and that’s probably a decision best made by an individual woman and her care provider. Some women do very well on a particular regimen and they don’t want to change, and you run the risk when you change that you’ll get a viral rebound. What do you tell women who are on dolutegravir and are thinking about becoming pregnant? That’s a controversial question. There are risks with both courses,” said Dr. Mirochnick.
The study comprised 408 patients recruited from centers in Brazil, Tanzania, South Africa, Thailand, Argentina, and the United States. The patients were between 20 and 37 weeks’ gestation and had not previously received ART. They were randomized to RAL-ART or EFV-ART. About 12% of patients were Asian, 36% were black, 52% were Hispanic, and 1% were white.
Overall, 94% of patients on RAL-ART had a VL less than 200 copies/mL at delivery, compared to 84% of EFV-ART patients (P = .001). The effect appeared to be driven by patients who enrolled later in pregnancy: There was no significant difference in those enrolled in weeks 20-28, but suppression occurred in 93% of the RAL-ART group versus 71% of the EFV-ART group among those enrolled in weeks 29-37 (P = .04).
Tolerability was slightly better in the RAL-ART group, with 99% versus 97% of patients staying on their assigned therapy (P = .05). In both groups, 30% of women experienced an adverse event of grade 3 or higher, as did 25% of live-born infants in both groups.
A total of 92% of women in the RAL-ART group had a sustained VL response through delivery, compared with 64% in the EFV-ART group (P less than .001). The median time to achieving a VL less than 200 copies/mL was 8 days in the RAL-ART group and 15 days in the EFV-ART group (generalized log-rank test P less than .001).
There was one stillbirth in the EFV-ART arm and three in the RAL-ART arm, with 11% in the EFV-ART group having preterm delivery compared with 12% in the RAL-ART group. In addition, the proportion of HIV-infected infants was lower in the RAL-ART arm (1% versus 3%). These differences were not significant.
The National Institutes of Health funded the study. Glaxo/ViiV, Merck, and Bristol-Myers Squibb supplied study drugs. Dr. Mirochnick has received research funding from those companies.
SOURCE: Mark Mirochnick et al. CROI 2019, Abstract 39 LB.
SEATTLE – In HIV-positive pregnant women, an antiretroviral therapy (ART) regimen that included the integrase inhibitor raltegravir (RAL-ART) led to faster viral load (VL) reduction and a greater proportion of women with a VL of less than 200 copies/mL at delivery, compared with patients treated with an efavirenz-based ART (EFV-ART). There were no statistically significant differences between the two arms with respect to percentage of stillbirths, preterm delivery, or rates of HIV infection in the newborn.
“There are lots of advantages of these [integrase inhibitor] drugs, and we’d like to have pregnant women take advantage of them. The problem is, there’s no requirement of drug manufacturers to study the drugs in pregnancy. So these studies are put off until after the drug is licensed, and we’re playing catch-up,” Mark Mirochnick, MD, professor of pediatrics at Boston University, said in an interview. Dr. Mirochnick presented the results at the Conference on Retroviruses and Opportunistic Infections.
Another integrase inhibitor, dolutegravir, has a better resistance profile than that of raltegravir, but concerns over neural tube defects observed during a study in Botswana led both the Food and Drug Administration and the European Medicines Agency to issue safety warnings for that drug. The current study did not raise concern, since it began at 20 weeks’ gestation, well after the period when neural tube defects might occur. “I think it just demonstrates that [integrase inhibitors] are safe in mid- to late-pregnancy,” said Dr. Mirochnick.
It remains to be seen whether a potential link to neural tube defects, if it is a real effect, is due to a specific drug or the mechanism of action of integrase inhibitors more generally. “It’s a question we don’t have an answer to. So you have to balance the potential benefits and potential risks, and that’s probably a decision best made by an individual woman and her care provider. Some women do very well on a particular regimen and they don’t want to change, and you run the risk when you change that you’ll get a viral rebound. What do you tell women who are on dolutegravir and are thinking about becoming pregnant? That’s a controversial question. There are risks with both courses,” said Dr. Mirochnick.
The study comprised 408 patients recruited from centers in Brazil, Tanzania, South Africa, Thailand, Argentina, and the United States. The patients were between 20 and 37 weeks’ gestation and had not previously received ART. They were randomized to RAL-ART or EFV-ART. About 12% of patients were Asian, 36% were black, 52% were Hispanic, and 1% were white.
Overall, 94% of patients on RAL-ART had a VL less than 200 copies/mL at delivery, compared to 84% of EFV-ART patients (P = .001). The effect appeared to be driven by patients who enrolled later in pregnancy: There was no significant difference in those enrolled in weeks 20-28, but suppression occurred in 93% of the RAL-ART group versus 71% of the EFV-ART group among those enrolled in weeks 29-37 (P = .04).
Tolerability was slightly better in the RAL-ART group, with 99% versus 97% of patients staying on their assigned therapy (P = .05). In both groups, 30% of women experienced an adverse event of grade 3 or higher, as did 25% of live-born infants in both groups.
A total of 92% of women in the RAL-ART group had a sustained VL response through delivery, compared with 64% in the EFV-ART group (P less than .001). The median time to achieving a VL less than 200 copies/mL was 8 days in the RAL-ART group and 15 days in the EFV-ART group (generalized log-rank test P less than .001).
There was one stillbirth in the EFV-ART arm and three in the RAL-ART arm, with 11% in the EFV-ART group having preterm delivery compared with 12% in the RAL-ART group. In addition, the proportion of HIV-infected infants was lower in the RAL-ART arm (1% versus 3%). These differences were not significant.
The National Institutes of Health funded the study. Glaxo/ViiV, Merck, and Bristol-Myers Squibb supplied study drugs. Dr. Mirochnick has received research funding from those companies.
SOURCE: Mark Mirochnick et al. CROI 2019, Abstract 39 LB.
REPORTING FROM CROI 2019
Sepsis survivors face ongoing immune system challenges
SAN DIEGO – Although it isn’t clear if such episodes result from incomplete resolution of the index infection, or they are due to lingering changes in immune function, they do suggest that physicians should engage sepsis patients in an effort to improve long-term outcomes.
It’s also an argument for biomarkers and precision immune modulation in these patients, Hallie Prescott, MD, a critical care physician at the VA Ann Arbor (Mich.) Healthcare System, said during a talk at the Critical Care Congress sponsored by the Society of Critical Care Medicine.
When sepsis was first defined in 1992, physicians tended to focus on the inflammatory component, but it’s now understood that multiple pathways become dysregulated, and inflammation is no longer part of the most current definition of sepsis. “We now recognize that there is early activation of both pro- and anti-inflammatory pathways, but over the course of sepsis the balance tips from this proinflammatory state in the first few days toward, for most patients, an anti-inflammatory or immune-suppressed state in the later days,” said Dr. Prescott.
As advances in care have increased initial survival rates, more patients go on to the later stages, leaving clinicians to address nosocomial and other secondary infections. An autopsy study showed that many patients who die of sepsis in the ICU have evidence of immune suppression. A study of patients at the end of a pneumonia hospitalization found that many patients had elevated inflammatory markers even after hospital discharge, and that such elevation was associated with increased mortality as far out as 1 year. The relationship was significant even after adjustment for age, comorbidity, and acute illness. “It suggests that this isn’t just identification of patients who had a more severe septic episode,” said Dr. Prescott.
That study implies that some patients take a long time to return to homeostasis, and other work suggests that about two-thirds of sepsis deaths occur after day 5. A study by Dr. Prescott’s group showed about a 40% 2-year mortality after sepsis hospitalization. When they compared sepsis survivors to matched controls, they found about half the deaths could not be explained by presepsis health status. “Rather, it [seems to be] due to the last sequelae of sepsis, or perhaps this increased risk of secondary infections,” Dr. Prescott said.
Studies of the organisms causing secondary infections found increasing incidence of opportunistic infections, from 9% in the first 5 days of sepsis, to 18% in days 16 through 150. The frequency of Candida infection similarly increased, from 13% to 30%. “So in these later phases of sepsis, you’re more likely to see [pathogens] that are relatively rare as the initial cause of sepsis,” said Dr. Prescott.
Unfortunately, several studies showed that prophylaxis does not improve outcomes. “My suspicion is that it’s because these infections are one marker of a broader problem with immune dysfunction, and we probably need to boost or restore immune function more broadly as opposed to trying to prophylax against very specifically what the patient is at risk for,” said Dr. Prescott.
The problems appear to continue after hospital discharge. A study from Dr. Prescott’s group showed that about 40% of sepsis survivors were readmitted at least once within the next 90 days. The most common reason, at 6.4%, was another sepsis episode. Compared with matched controls, sepsis patients had about a 2.5-fold higher risk for sepsis, and about a 1.5-fold increased risk an infection. “So there seems to be this heightened risk among people surviving sepsis that’s not fully explained by the things that put them at risk for developing sepsis in the first place,” said Dr. Prescott.
Another study looking at the reason for recurring infections in sepsis survivors found that in about one in five cases, the readmission was due to the same infectious organism in the same site, suggesting incomplete resolution. In about half of patients, the infection was due to a different organism, or the same organism at a different site, and in about a third of patients, the results were ambiguous due to culture-negative infections.
“I think this suggests a complex picture. Some people perhaps fail to fully eradicate the initial infection, and a larger group of people come back with something else. There’s also a very high rate of infection in the same site – about 70% with a new bug have it in the same site as their initial sepsis. Some of this may be just be a reflection of the type of people who get sepsis the first time, but it still tells us that among the patients we care for who survive sepsis, that they are over the long haul at increased risk of recurrent infections and recurrent episodes of sepsis,” said Dr. Prescott.
The findings suggest a need for real-time assessment of immune function and the potential benefit of immune modulation in the later phases of sepsis. Such strategies are not likely to be implemented immediately, however. In the meantime, there are simple steps that clinicians can take, including screening of sepsis survivors and making sure they are up to date on vaccines, and then educating them about the risk of reinfection. “We know that the lay public awareness of sepsis is low. Even people who have sepsis are often unaware that they had it, and they are certainly unaware that they’re at risk for having another episode,” she said.
Dr. Prescott has no financial disclosures
SAN DIEGO – Although it isn’t clear if such episodes result from incomplete resolution of the index infection, or they are due to lingering changes in immune function, they do suggest that physicians should engage sepsis patients in an effort to improve long-term outcomes.
It’s also an argument for biomarkers and precision immune modulation in these patients, Hallie Prescott, MD, a critical care physician at the VA Ann Arbor (Mich.) Healthcare System, said during a talk at the Critical Care Congress sponsored by the Society of Critical Care Medicine.
When sepsis was first defined in 1992, physicians tended to focus on the inflammatory component, but it’s now understood that multiple pathways become dysregulated, and inflammation is no longer part of the most current definition of sepsis. “We now recognize that there is early activation of both pro- and anti-inflammatory pathways, but over the course of sepsis the balance tips from this proinflammatory state in the first few days toward, for most patients, an anti-inflammatory or immune-suppressed state in the later days,” said Dr. Prescott.
As advances in care have increased initial survival rates, more patients go on to the later stages, leaving clinicians to address nosocomial and other secondary infections. An autopsy study showed that many patients who die of sepsis in the ICU have evidence of immune suppression. A study of patients at the end of a pneumonia hospitalization found that many patients had elevated inflammatory markers even after hospital discharge, and that such elevation was associated with increased mortality as far out as 1 year. The relationship was significant even after adjustment for age, comorbidity, and acute illness. “It suggests that this isn’t just identification of patients who had a more severe septic episode,” said Dr. Prescott.
That study implies that some patients take a long time to return to homeostasis, and other work suggests that about two-thirds of sepsis deaths occur after day 5. A study by Dr. Prescott’s group showed about a 40% 2-year mortality after sepsis hospitalization. When they compared sepsis survivors to matched controls, they found about half the deaths could not be explained by presepsis health status. “Rather, it [seems to be] due to the last sequelae of sepsis, or perhaps this increased risk of secondary infections,” Dr. Prescott said.
Studies of the organisms causing secondary infections found increasing incidence of opportunistic infections, from 9% in the first 5 days of sepsis, to 18% in days 16 through 150. The frequency of Candida infection similarly increased, from 13% to 30%. “So in these later phases of sepsis, you’re more likely to see [pathogens] that are relatively rare as the initial cause of sepsis,” said Dr. Prescott.
Unfortunately, several studies showed that prophylaxis does not improve outcomes. “My suspicion is that it’s because these infections are one marker of a broader problem with immune dysfunction, and we probably need to boost or restore immune function more broadly as opposed to trying to prophylax against very specifically what the patient is at risk for,” said Dr. Prescott.
The problems appear to continue after hospital discharge. A study from Dr. Prescott’s group showed that about 40% of sepsis survivors were readmitted at least once within the next 90 days. The most common reason, at 6.4%, was another sepsis episode. Compared with matched controls, sepsis patients had about a 2.5-fold higher risk for sepsis, and about a 1.5-fold increased risk an infection. “So there seems to be this heightened risk among people surviving sepsis that’s not fully explained by the things that put them at risk for developing sepsis in the first place,” said Dr. Prescott.
Another study looking at the reason for recurring infections in sepsis survivors found that in about one in five cases, the readmission was due to the same infectious organism in the same site, suggesting incomplete resolution. In about half of patients, the infection was due to a different organism, or the same organism at a different site, and in about a third of patients, the results were ambiguous due to culture-negative infections.
“I think this suggests a complex picture. Some people perhaps fail to fully eradicate the initial infection, and a larger group of people come back with something else. There’s also a very high rate of infection in the same site – about 70% with a new bug have it in the same site as their initial sepsis. Some of this may be just be a reflection of the type of people who get sepsis the first time, but it still tells us that among the patients we care for who survive sepsis, that they are over the long haul at increased risk of recurrent infections and recurrent episodes of sepsis,” said Dr. Prescott.
The findings suggest a need for real-time assessment of immune function and the potential benefit of immune modulation in the later phases of sepsis. Such strategies are not likely to be implemented immediately, however. In the meantime, there are simple steps that clinicians can take, including screening of sepsis survivors and making sure they are up to date on vaccines, and then educating them about the risk of reinfection. “We know that the lay public awareness of sepsis is low. Even people who have sepsis are often unaware that they had it, and they are certainly unaware that they’re at risk for having another episode,” she said.
Dr. Prescott has no financial disclosures
SAN DIEGO – Although it isn’t clear if such episodes result from incomplete resolution of the index infection, or they are due to lingering changes in immune function, they do suggest that physicians should engage sepsis patients in an effort to improve long-term outcomes.
It’s also an argument for biomarkers and precision immune modulation in these patients, Hallie Prescott, MD, a critical care physician at the VA Ann Arbor (Mich.) Healthcare System, said during a talk at the Critical Care Congress sponsored by the Society of Critical Care Medicine.
When sepsis was first defined in 1992, physicians tended to focus on the inflammatory component, but it’s now understood that multiple pathways become dysregulated, and inflammation is no longer part of the most current definition of sepsis. “We now recognize that there is early activation of both pro- and anti-inflammatory pathways, but over the course of sepsis the balance tips from this proinflammatory state in the first few days toward, for most patients, an anti-inflammatory or immune-suppressed state in the later days,” said Dr. Prescott.
As advances in care have increased initial survival rates, more patients go on to the later stages, leaving clinicians to address nosocomial and other secondary infections. An autopsy study showed that many patients who die of sepsis in the ICU have evidence of immune suppression. A study of patients at the end of a pneumonia hospitalization found that many patients had elevated inflammatory markers even after hospital discharge, and that such elevation was associated with increased mortality as far out as 1 year. The relationship was significant even after adjustment for age, comorbidity, and acute illness. “It suggests that this isn’t just identification of patients who had a more severe septic episode,” said Dr. Prescott.
That study implies that some patients take a long time to return to homeostasis, and other work suggests that about two-thirds of sepsis deaths occur after day 5. A study by Dr. Prescott’s group showed about a 40% 2-year mortality after sepsis hospitalization. When they compared sepsis survivors to matched controls, they found about half the deaths could not be explained by presepsis health status. “Rather, it [seems to be] due to the last sequelae of sepsis, or perhaps this increased risk of secondary infections,” Dr. Prescott said.
Studies of the organisms causing secondary infections found increasing incidence of opportunistic infections, from 9% in the first 5 days of sepsis, to 18% in days 16 through 150. The frequency of Candida infection similarly increased, from 13% to 30%. “So in these later phases of sepsis, you’re more likely to see [pathogens] that are relatively rare as the initial cause of sepsis,” said Dr. Prescott.
Unfortunately, several studies showed that prophylaxis does not improve outcomes. “My suspicion is that it’s because these infections are one marker of a broader problem with immune dysfunction, and we probably need to boost or restore immune function more broadly as opposed to trying to prophylax against very specifically what the patient is at risk for,” said Dr. Prescott.
The problems appear to continue after hospital discharge. A study from Dr. Prescott’s group showed that about 40% of sepsis survivors were readmitted at least once within the next 90 days. The most common reason, at 6.4%, was another sepsis episode. Compared with matched controls, sepsis patients had about a 2.5-fold higher risk for sepsis, and about a 1.5-fold increased risk an infection. “So there seems to be this heightened risk among people surviving sepsis that’s not fully explained by the things that put them at risk for developing sepsis in the first place,” said Dr. Prescott.
Another study looking at the reason for recurring infections in sepsis survivors found that in about one in five cases, the readmission was due to the same infectious organism in the same site, suggesting incomplete resolution. In about half of patients, the infection was due to a different organism, or the same organism at a different site, and in about a third of patients, the results were ambiguous due to culture-negative infections.
“I think this suggests a complex picture. Some people perhaps fail to fully eradicate the initial infection, and a larger group of people come back with something else. There’s also a very high rate of infection in the same site – about 70% with a new bug have it in the same site as their initial sepsis. Some of this may be just be a reflection of the type of people who get sepsis the first time, but it still tells us that among the patients we care for who survive sepsis, that they are over the long haul at increased risk of recurrent infections and recurrent episodes of sepsis,” said Dr. Prescott.
The findings suggest a need for real-time assessment of immune function and the potential benefit of immune modulation in the later phases of sepsis. Such strategies are not likely to be implemented immediately, however. In the meantime, there are simple steps that clinicians can take, including screening of sepsis survivors and making sure they are up to date on vaccines, and then educating them about the risk of reinfection. “We know that the lay public awareness of sepsis is low. Even people who have sepsis are often unaware that they had it, and they are certainly unaware that they’re at risk for having another episode,” she said.
Dr. Prescott has no financial disclosures
REPORTING FROM CCC48
Rounding team boosts ICU liberation efforts
SAN DIEGO – A rounding team formed to oversee implementation of a bundle of ICU interventions reduced the incidence of ventilator-associated pneumonia (VAP) and the number of ventilation days, as well as the ICU and hospital length of stay, according to a new study conducted at a level 1 trauma center in California. The rounding team worked toward optimal implementation of the Society of Critical Care Medicine’s ABCDEF bundle, part of the society’s ICU liberation initiative.
ABCDEF stands for: Assessment, prevention, and management of pain; Both spontaneous awakening and breathing trials; Choice of analgesia and sedation; Delirium assessment, prevention, and management; Early mobility and exercise; and Family engagement and empowerment.
The Community Regional Medical Center in Fresno, Calif., where the study was conducted, was chosen in 2015 to participate in the ICU liberation initiative. The facility serves a population of 3.2 million and sees just under 4,000 trauma patients per year.
After a 6-month retrospective analysis, the team members at the medical center realized they needed to improve ABCDEF implementation with respect to evaluating sedation practices and improving delirium assessment.
Before the start of the 17-month collaborative period, they formed an ICU liberation team called SMART, short for Sedation, Mobilization, Assessment Rounding Team, which included representatives from ICU nursing, pharmacy, respiratory therapy, physical therapy, physicians, and administration. They developed a daily rounding tool to help the team implement procedures, with the goal of reducing the continuous infusion of benzodiazepines and increasing intermittent dosing, the use of short-acting medications, and conducting spontaneous awakening and breathing trials. The SMART team made daily rounds to ensure that the ABCDEF bundle was being implemented.
The researchers then continued the analysis for another 12 months after the end of the initiative. During this last phase, the benefits of the SMART team became evident.
“Stick with it. Don’t let up. Don’t quit,” Wade Veneman, a respiratory therapist at the medical center, said in an interview. He presented the study at the Critical Care Congress sponsored by the Society of Critical Care Medicine. “It can be particularly difficult in the face of critical care providers who may be skeptical of new initiatives. They think it’s something new, and they hope that it goes away. But this is something we feel we’re going to keep for a long time,” he added.
Mr. Veneman hopes to implement the SMART program in the neurological critical care ICU. The medical director of that unit did not participate in the initial collaborative, but Mr. Veneman hopes to change that. “The data is going to show that his VAP and ventilator days are going up, and everywhere else they’re going down,” he said.
The researchers analyzed data on 1,127 mechanically ventilated patients in the ICU. At total of 197 patients were treated 6 months before the implementation of the collaborative, 519 during 17 months of collaborative implementation, and 411 in the 12 months after implementation. There were some differences between the populations: The before group was slightly younger than the after-implementation group (mean 41 vs. 44, P = .04), and the mean Injury Severity Score score was 24 in the before group, 22 during, and 20 after (P = .002). The researchers noted that the differences were clinically significant.
Benzodiazepine use declined, but the effect was statistically significant only in the after population. Continuous use declined from 87% before implementation to 83% during (P = .21) and 53% after (P less than .001). Intermittent use was 57% before implementation, increased to 61% during (P = .44), and fell to 44% after (P less than .001). Delirium assessment performance improved throughout, from 9% before implementation to 42% during (P less than .001) to 73% after implementation (P less than .001).
The VAP rate increased from 3.4% before the SMART program to 4.5% during implementation (P = .53), and then dropped to 0.9% afterward (P = .001). Ventilation days started at a mean of 10.5, then dropped to 9.5 during implementation (P = .30), and 8.2 after implementation (P = .027).
ICU length of stay improved from 10.7 before implementation to 9.3 afterward (P = .021), and overall hospital length of stay went from 17.3 days to 16.3 (P = .005).
The study was not funded. Mr. Veneman has no relevant financial disclosures.
SOURCE: Veneman W et al. CCC48, Abstract 63.
SAN DIEGO – A rounding team formed to oversee implementation of a bundle of ICU interventions reduced the incidence of ventilator-associated pneumonia (VAP) and the number of ventilation days, as well as the ICU and hospital length of stay, according to a new study conducted at a level 1 trauma center in California. The rounding team worked toward optimal implementation of the Society of Critical Care Medicine’s ABCDEF bundle, part of the society’s ICU liberation initiative.
ABCDEF stands for: Assessment, prevention, and management of pain; Both spontaneous awakening and breathing trials; Choice of analgesia and sedation; Delirium assessment, prevention, and management; Early mobility and exercise; and Family engagement and empowerment.
The Community Regional Medical Center in Fresno, Calif., where the study was conducted, was chosen in 2015 to participate in the ICU liberation initiative. The facility serves a population of 3.2 million and sees just under 4,000 trauma patients per year.
After a 6-month retrospective analysis, the team members at the medical center realized they needed to improve ABCDEF implementation with respect to evaluating sedation practices and improving delirium assessment.
Before the start of the 17-month collaborative period, they formed an ICU liberation team called SMART, short for Sedation, Mobilization, Assessment Rounding Team, which included representatives from ICU nursing, pharmacy, respiratory therapy, physical therapy, physicians, and administration. They developed a daily rounding tool to help the team implement procedures, with the goal of reducing the continuous infusion of benzodiazepines and increasing intermittent dosing, the use of short-acting medications, and conducting spontaneous awakening and breathing trials. The SMART team made daily rounds to ensure that the ABCDEF bundle was being implemented.
The researchers then continued the analysis for another 12 months after the end of the initiative. During this last phase, the benefits of the SMART team became evident.
“Stick with it. Don’t let up. Don’t quit,” Wade Veneman, a respiratory therapist at the medical center, said in an interview. He presented the study at the Critical Care Congress sponsored by the Society of Critical Care Medicine. “It can be particularly difficult in the face of critical care providers who may be skeptical of new initiatives. They think it’s something new, and they hope that it goes away. But this is something we feel we’re going to keep for a long time,” he added.
Mr. Veneman hopes to implement the SMART program in the neurological critical care ICU. The medical director of that unit did not participate in the initial collaborative, but Mr. Veneman hopes to change that. “The data is going to show that his VAP and ventilator days are going up, and everywhere else they’re going down,” he said.
The researchers analyzed data on 1,127 mechanically ventilated patients in the ICU. At total of 197 patients were treated 6 months before the implementation of the collaborative, 519 during 17 months of collaborative implementation, and 411 in the 12 months after implementation. There were some differences between the populations: The before group was slightly younger than the after-implementation group (mean 41 vs. 44, P = .04), and the mean Injury Severity Score score was 24 in the before group, 22 during, and 20 after (P = .002). The researchers noted that the differences were clinically significant.
Benzodiazepine use declined, but the effect was statistically significant only in the after population. Continuous use declined from 87% before implementation to 83% during (P = .21) and 53% after (P less than .001). Intermittent use was 57% before implementation, increased to 61% during (P = .44), and fell to 44% after (P less than .001). Delirium assessment performance improved throughout, from 9% before implementation to 42% during (P less than .001) to 73% after implementation (P less than .001).
The VAP rate increased from 3.4% before the SMART program to 4.5% during implementation (P = .53), and then dropped to 0.9% afterward (P = .001). Ventilation days started at a mean of 10.5, then dropped to 9.5 during implementation (P = .30), and 8.2 after implementation (P = .027).
ICU length of stay improved from 10.7 before implementation to 9.3 afterward (P = .021), and overall hospital length of stay went from 17.3 days to 16.3 (P = .005).
The study was not funded. Mr. Veneman has no relevant financial disclosures.
SOURCE: Veneman W et al. CCC48, Abstract 63.
SAN DIEGO – A rounding team formed to oversee implementation of a bundle of ICU interventions reduced the incidence of ventilator-associated pneumonia (VAP) and the number of ventilation days, as well as the ICU and hospital length of stay, according to a new study conducted at a level 1 trauma center in California. The rounding team worked toward optimal implementation of the Society of Critical Care Medicine’s ABCDEF bundle, part of the society’s ICU liberation initiative.
ABCDEF stands for: Assessment, prevention, and management of pain; Both spontaneous awakening and breathing trials; Choice of analgesia and sedation; Delirium assessment, prevention, and management; Early mobility and exercise; and Family engagement and empowerment.
The Community Regional Medical Center in Fresno, Calif., where the study was conducted, was chosen in 2015 to participate in the ICU liberation initiative. The facility serves a population of 3.2 million and sees just under 4,000 trauma patients per year.
After a 6-month retrospective analysis, the team members at the medical center realized they needed to improve ABCDEF implementation with respect to evaluating sedation practices and improving delirium assessment.
Before the start of the 17-month collaborative period, they formed an ICU liberation team called SMART, short for Sedation, Mobilization, Assessment Rounding Team, which included representatives from ICU nursing, pharmacy, respiratory therapy, physical therapy, physicians, and administration. They developed a daily rounding tool to help the team implement procedures, with the goal of reducing the continuous infusion of benzodiazepines and increasing intermittent dosing, the use of short-acting medications, and conducting spontaneous awakening and breathing trials. The SMART team made daily rounds to ensure that the ABCDEF bundle was being implemented.
The researchers then continued the analysis for another 12 months after the end of the initiative. During this last phase, the benefits of the SMART team became evident.
“Stick with it. Don’t let up. Don’t quit,” Wade Veneman, a respiratory therapist at the medical center, said in an interview. He presented the study at the Critical Care Congress sponsored by the Society of Critical Care Medicine. “It can be particularly difficult in the face of critical care providers who may be skeptical of new initiatives. They think it’s something new, and they hope that it goes away. But this is something we feel we’re going to keep for a long time,” he added.
Mr. Veneman hopes to implement the SMART program in the neurological critical care ICU. The medical director of that unit did not participate in the initial collaborative, but Mr. Veneman hopes to change that. “The data is going to show that his VAP and ventilator days are going up, and everywhere else they’re going down,” he said.
The researchers analyzed data on 1,127 mechanically ventilated patients in the ICU. At total of 197 patients were treated 6 months before the implementation of the collaborative, 519 during 17 months of collaborative implementation, and 411 in the 12 months after implementation. There were some differences between the populations: The before group was slightly younger than the after-implementation group (mean 41 vs. 44, P = .04), and the mean Injury Severity Score score was 24 in the before group, 22 during, and 20 after (P = .002). The researchers noted that the differences were clinically significant.
Benzodiazepine use declined, but the effect was statistically significant only in the after population. Continuous use declined from 87% before implementation to 83% during (P = .21) and 53% after (P less than .001). Intermittent use was 57% before implementation, increased to 61% during (P = .44), and fell to 44% after (P less than .001). Delirium assessment performance improved throughout, from 9% before implementation to 42% during (P less than .001) to 73% after implementation (P less than .001).
The VAP rate increased from 3.4% before the SMART program to 4.5% during implementation (P = .53), and then dropped to 0.9% afterward (P = .001). Ventilation days started at a mean of 10.5, then dropped to 9.5 during implementation (P = .30), and 8.2 after implementation (P = .027).
ICU length of stay improved from 10.7 before implementation to 9.3 afterward (P = .021), and overall hospital length of stay went from 17.3 days to 16.3 (P = .005).
The study was not funded. Mr. Veneman has no relevant financial disclosures.
SOURCE: Veneman W et al. CCC48, Abstract 63.
REPORTING FROM CCC48
HCV treatment with DAA regimens linked to reduced diabetes risk
SEATTLE – Treatment of hepatitis C virus (HCV) with new direct-acting antiviral (DAA) regimens is associated with improved glucose control and reduced incidence of type 2 diabetes when compared to treatment with pegylated interferon/ribavirin (PEG/RBV ) and untreated controls, according to a new analysis of the Electronically Retrieved Cohort of HCV Infected Veterans.
“Previously, people who had diabetes were considered slightly more difficult to treat because their virologic response was a little lower, but now this is not the case, and we have the added benefit of reducing the incidence of diabetes,” said Adeel Butt, MD, professor of medicine and health care policy and research at Weill Cornell Medicine, New York and Qatar, in an interview. Dr. Butt presented the study at the Conference on Retroviruses & Opportunistic Infections.
The incidence of diabetes dropped in the overall treated cohort, compared with untreated patients, but this benefit was driven by the effect of DAAs, as there was no significant difference between PEG/RBV–treated patients and controls. “It’s another reason to argue with people who make it difficult to treat. Our biggest barriers to treating everyone with hepatitis C has to do with reimbursement and the capacity of the health care system, and this is another reason that we need to overcome those barriers. It’s an important insight that provides one more reason to try to continue to eradicate hepatitis C in our population,” said Robert Schooley, MD, professor of medicine at the University of California, San Diego, in an interview.
Patients may also need some reassurance, given concerns that have arisen over the potential for older regimens to cause diabetes. Dr. Butt cited an example of a patient who has an acute myocardial infarction, has a high body mass, and wants to know if DAAs will help or hurt them. “We see [such patients] frequently. This is pretty reassuring not only that DAAs don’t increase risk, but they actually decrease the risk of diabetes as opposed to older treatments. There is a growing body of evidence that non–liver [related conditions] significantly improve with treatment,” he said.
The results could also help prioritize patients for treatment. “It may be important to the patients who are at elevated risk of developing diabetes. They may need to be monitored more closely and offered treatment earlier, perhaps, but that requires more study,” said Dr. Butt.
The researchers excluded patients with HIV or hepatitis B virus, and those who had prevalent diabetes. The cohort included 26,043 treated patients and 26,043 propensity score–matched untreated control patients. Treated patients underwent at least 8 weeks of DAA or 24 weeks of PEG/RBV. Demographically, 54% of patients were white, 29% were black, 3% were Hispanic, and 96% of the patients were male. About one-third had a body mass index of 30 or above.
The incidence of diabetes was 20.6 per 1,000 person-years of follow-up among untreated patients, compared with 15.5 among treated patients (P less than .0001). The incidence was 19.8 in patients treated with PEG/RBV (P =.39) and 9.9 in those treated with DAAs (P less than. 001; hazard ratio, 0.48; P less than .0001). The incidence of diabetes in those with a sustained viral response (SVR) was 13.3 per 1,000 person-years, compared with 19.2 in patients with no SVR (P less than .0001). The incidence of diabetes was lower in treated patients regardless of baseline FIB-4 (Fibrosis-4, a liver fibrosis score) levels.
The study was funded by Gilead. Dr. Butt has had research grants from Gilead and Dr. Schooley is on Gilead’s scientific advisory board.
SOURCE: A Butt et al. CROI 2019. Abstract 88.
SEATTLE – Treatment of hepatitis C virus (HCV) with new direct-acting antiviral (DAA) regimens is associated with improved glucose control and reduced incidence of type 2 diabetes when compared to treatment with pegylated interferon/ribavirin (PEG/RBV ) and untreated controls, according to a new analysis of the Electronically Retrieved Cohort of HCV Infected Veterans.
“Previously, people who had diabetes were considered slightly more difficult to treat because their virologic response was a little lower, but now this is not the case, and we have the added benefit of reducing the incidence of diabetes,” said Adeel Butt, MD, professor of medicine and health care policy and research at Weill Cornell Medicine, New York and Qatar, in an interview. Dr. Butt presented the study at the Conference on Retroviruses & Opportunistic Infections.
The incidence of diabetes dropped in the overall treated cohort, compared with untreated patients, but this benefit was driven by the effect of DAAs, as there was no significant difference between PEG/RBV–treated patients and controls. “It’s another reason to argue with people who make it difficult to treat. Our biggest barriers to treating everyone with hepatitis C has to do with reimbursement and the capacity of the health care system, and this is another reason that we need to overcome those barriers. It’s an important insight that provides one more reason to try to continue to eradicate hepatitis C in our population,” said Robert Schooley, MD, professor of medicine at the University of California, San Diego, in an interview.
Patients may also need some reassurance, given concerns that have arisen over the potential for older regimens to cause diabetes. Dr. Butt cited an example of a patient who has an acute myocardial infarction, has a high body mass, and wants to know if DAAs will help or hurt them. “We see [such patients] frequently. This is pretty reassuring not only that DAAs don’t increase risk, but they actually decrease the risk of diabetes as opposed to older treatments. There is a growing body of evidence that non–liver [related conditions] significantly improve with treatment,” he said.
The results could also help prioritize patients for treatment. “It may be important to the patients who are at elevated risk of developing diabetes. They may need to be monitored more closely and offered treatment earlier, perhaps, but that requires more study,” said Dr. Butt.
The researchers excluded patients with HIV or hepatitis B virus, and those who had prevalent diabetes. The cohort included 26,043 treated patients and 26,043 propensity score–matched untreated control patients. Treated patients underwent at least 8 weeks of DAA or 24 weeks of PEG/RBV. Demographically, 54% of patients were white, 29% were black, 3% were Hispanic, and 96% of the patients were male. About one-third had a body mass index of 30 or above.
The incidence of diabetes was 20.6 per 1,000 person-years of follow-up among untreated patients, compared with 15.5 among treated patients (P less than .0001). The incidence was 19.8 in patients treated with PEG/RBV (P =.39) and 9.9 in those treated with DAAs (P less than. 001; hazard ratio, 0.48; P less than .0001). The incidence of diabetes in those with a sustained viral response (SVR) was 13.3 per 1,000 person-years, compared with 19.2 in patients with no SVR (P less than .0001). The incidence of diabetes was lower in treated patients regardless of baseline FIB-4 (Fibrosis-4, a liver fibrosis score) levels.
The study was funded by Gilead. Dr. Butt has had research grants from Gilead and Dr. Schooley is on Gilead’s scientific advisory board.
SOURCE: A Butt et al. CROI 2019. Abstract 88.
SEATTLE – Treatment of hepatitis C virus (HCV) with new direct-acting antiviral (DAA) regimens is associated with improved glucose control and reduced incidence of type 2 diabetes when compared to treatment with pegylated interferon/ribavirin (PEG/RBV ) and untreated controls, according to a new analysis of the Electronically Retrieved Cohort of HCV Infected Veterans.
“Previously, people who had diabetes were considered slightly more difficult to treat because their virologic response was a little lower, but now this is not the case, and we have the added benefit of reducing the incidence of diabetes,” said Adeel Butt, MD, professor of medicine and health care policy and research at Weill Cornell Medicine, New York and Qatar, in an interview. Dr. Butt presented the study at the Conference on Retroviruses & Opportunistic Infections.
The incidence of diabetes dropped in the overall treated cohort, compared with untreated patients, but this benefit was driven by the effect of DAAs, as there was no significant difference between PEG/RBV–treated patients and controls. “It’s another reason to argue with people who make it difficult to treat. Our biggest barriers to treating everyone with hepatitis C has to do with reimbursement and the capacity of the health care system, and this is another reason that we need to overcome those barriers. It’s an important insight that provides one more reason to try to continue to eradicate hepatitis C in our population,” said Robert Schooley, MD, professor of medicine at the University of California, San Diego, in an interview.
Patients may also need some reassurance, given concerns that have arisen over the potential for older regimens to cause diabetes. Dr. Butt cited an example of a patient who has an acute myocardial infarction, has a high body mass, and wants to know if DAAs will help or hurt them. “We see [such patients] frequently. This is pretty reassuring not only that DAAs don’t increase risk, but they actually decrease the risk of diabetes as opposed to older treatments. There is a growing body of evidence that non–liver [related conditions] significantly improve with treatment,” he said.
The results could also help prioritize patients for treatment. “It may be important to the patients who are at elevated risk of developing diabetes. They may need to be monitored more closely and offered treatment earlier, perhaps, but that requires more study,” said Dr. Butt.
The researchers excluded patients with HIV or hepatitis B virus, and those who had prevalent diabetes. The cohort included 26,043 treated patients and 26,043 propensity score–matched untreated control patients. Treated patients underwent at least 8 weeks of DAA or 24 weeks of PEG/RBV. Demographically, 54% of patients were white, 29% were black, 3% were Hispanic, and 96% of the patients were male. About one-third had a body mass index of 30 or above.
The incidence of diabetes was 20.6 per 1,000 person-years of follow-up among untreated patients, compared with 15.5 among treated patients (P less than .0001). The incidence was 19.8 in patients treated with PEG/RBV (P =.39) and 9.9 in those treated with DAAs (P less than. 001; hazard ratio, 0.48; P less than .0001). The incidence of diabetes in those with a sustained viral response (SVR) was 13.3 per 1,000 person-years, compared with 19.2 in patients with no SVR (P less than .0001). The incidence of diabetes was lower in treated patients regardless of baseline FIB-4 (Fibrosis-4, a liver fibrosis score) levels.
The study was funded by Gilead. Dr. Butt has had research grants from Gilead and Dr. Schooley is on Gilead’s scientific advisory board.
SOURCE: A Butt et al. CROI 2019. Abstract 88.
REPORTING FROM CROI 2019
Syphilis rates high in HIV-positive women
SEATTLE – The frequency of syphilis in HIV-infected women is unusually high, prompting concerns about congenital syphilis among newborns. The finding comes from a Centers for Disease Control analysis of the U.S. Center for Aids Research Clinical Network of Integrated Clinical Systems (CNICS) cohort.
“We found significant associations [between syphilis infection] and drug use and hepatitis C infection, which adds to some information from the CDC that what’s driving the epidemic in women is drug use – it’s a very different epidemic potentially in women with HIV than in men with HIV,” said Jodie Dionne-Odom, MD, chief of women’s health services at the University of Alabama, Birmingham’s 1917 Clinic. She described the results of her study at a press conference at the Conference on Retroviruses and Infectious Diseases.
“These predictors are important to understand so that we can come up with interventions to try to reduce the problem. Syphilis screening is relatively easy to do. USPSTF [U.S. Preventive Services Task Force] doesn’t even have a recommendation for that periodicity of screening frequency, so we have a ways to go to define how often we need to be looking, particularly in high-risk groups,” she said.
The likely force driving the increased incidence of syphilis is transactional sex. To explore that possibility, the researchers examined the number of sexual partners and found that more partners were linked to greater likelihood of having syphilis. “So I don’t think it’s the drug use itself – it’s the behavior that comes with the drug use,” Dr. Dionne-Odom said.
The findings shed more light on the interplay between drug use epidemics and disease epidemics. “As we have an increasing opioid epidemic and methamphetamine abuse that we’re all seeing in our clinics, it’s interesting to see this intersection between the drug use problem and the syphilis problem in this country. I think they’re not unrelated,” she said.
She believes the results should have broad implications for screening programs. Women admitted to drug treatment programs should be tested for syphilis. And women who abuse drugs and are pregnant should be screened repeatedly – at entry to care, at their 20-week scan, and at delivery. “We know we have about 6,000 women with HIV who deliver each year, so this is potentially very impactful,” Dr. Dionne-Odom said.
The researchers extracted data from the CNICS cohort, including 4,795 women with records between 2005 and 2016. They defined incident syphilis as a newly positive nontreponemal serologic test or a 300% titer increase, followed by a confirmatory test.
After adjustment, factors associated with syphilis included prior intravenous drug abuse (adjusted odds ratio, 2.3; 95% confidence interval, 1.3-3.9), hepatitis C antibody positivity (aOR, 2.1; 95% CI, 1.3-3.7), as well as black race (aOR, 2.3; 95% CI, 1.4-3.9). There was no association between age and HIV viral load with respect to risk of syphilis.
The frequency appears to be rising, with later entry into the CNICS cohort assorted with a more than doubled risk of syphilis (aOR, 2.3; 95% CI, 1.4-3.9 for 2011-2016, compared with 1994-2004).
The study was funded by the National Institute of Child Health and Human Development. Dr. Dionne-Odom reported no relevant conflicts of interest.
SOURCE: J Dionne-Odom et al. CROI 2019, Abstract 47
SEATTLE – The frequency of syphilis in HIV-infected women is unusually high, prompting concerns about congenital syphilis among newborns. The finding comes from a Centers for Disease Control analysis of the U.S. Center for Aids Research Clinical Network of Integrated Clinical Systems (CNICS) cohort.
“We found significant associations [between syphilis infection] and drug use and hepatitis C infection, which adds to some information from the CDC that what’s driving the epidemic in women is drug use – it’s a very different epidemic potentially in women with HIV than in men with HIV,” said Jodie Dionne-Odom, MD, chief of women’s health services at the University of Alabama, Birmingham’s 1917 Clinic. She described the results of her study at a press conference at the Conference on Retroviruses and Infectious Diseases.
“These predictors are important to understand so that we can come up with interventions to try to reduce the problem. Syphilis screening is relatively easy to do. USPSTF [U.S. Preventive Services Task Force] doesn’t even have a recommendation for that periodicity of screening frequency, so we have a ways to go to define how often we need to be looking, particularly in high-risk groups,” she said.
The likely force driving the increased incidence of syphilis is transactional sex. To explore that possibility, the researchers examined the number of sexual partners and found that more partners were linked to greater likelihood of having syphilis. “So I don’t think it’s the drug use itself – it’s the behavior that comes with the drug use,” Dr. Dionne-Odom said.
The findings shed more light on the interplay between drug use epidemics and disease epidemics. “As we have an increasing opioid epidemic and methamphetamine abuse that we’re all seeing in our clinics, it’s interesting to see this intersection between the drug use problem and the syphilis problem in this country. I think they’re not unrelated,” she said.
She believes the results should have broad implications for screening programs. Women admitted to drug treatment programs should be tested for syphilis. And women who abuse drugs and are pregnant should be screened repeatedly – at entry to care, at their 20-week scan, and at delivery. “We know we have about 6,000 women with HIV who deliver each year, so this is potentially very impactful,” Dr. Dionne-Odom said.
The researchers extracted data from the CNICS cohort, including 4,795 women with records between 2005 and 2016. They defined incident syphilis as a newly positive nontreponemal serologic test or a 300% titer increase, followed by a confirmatory test.
After adjustment, factors associated with syphilis included prior intravenous drug abuse (adjusted odds ratio, 2.3; 95% confidence interval, 1.3-3.9), hepatitis C antibody positivity (aOR, 2.1; 95% CI, 1.3-3.7), as well as black race (aOR, 2.3; 95% CI, 1.4-3.9). There was no association between age and HIV viral load with respect to risk of syphilis.
The frequency appears to be rising, with later entry into the CNICS cohort assorted with a more than doubled risk of syphilis (aOR, 2.3; 95% CI, 1.4-3.9 for 2011-2016, compared with 1994-2004).
The study was funded by the National Institute of Child Health and Human Development. Dr. Dionne-Odom reported no relevant conflicts of interest.
SOURCE: J Dionne-Odom et al. CROI 2019, Abstract 47
SEATTLE – The frequency of syphilis in HIV-infected women is unusually high, prompting concerns about congenital syphilis among newborns. The finding comes from a Centers for Disease Control analysis of the U.S. Center for Aids Research Clinical Network of Integrated Clinical Systems (CNICS) cohort.
“We found significant associations [between syphilis infection] and drug use and hepatitis C infection, which adds to some information from the CDC that what’s driving the epidemic in women is drug use – it’s a very different epidemic potentially in women with HIV than in men with HIV,” said Jodie Dionne-Odom, MD, chief of women’s health services at the University of Alabama, Birmingham’s 1917 Clinic. She described the results of her study at a press conference at the Conference on Retroviruses and Infectious Diseases.
“These predictors are important to understand so that we can come up with interventions to try to reduce the problem. Syphilis screening is relatively easy to do. USPSTF [U.S. Preventive Services Task Force] doesn’t even have a recommendation for that periodicity of screening frequency, so we have a ways to go to define how often we need to be looking, particularly in high-risk groups,” she said.
The likely force driving the increased incidence of syphilis is transactional sex. To explore that possibility, the researchers examined the number of sexual partners and found that more partners were linked to greater likelihood of having syphilis. “So I don’t think it’s the drug use itself – it’s the behavior that comes with the drug use,” Dr. Dionne-Odom said.
The findings shed more light on the interplay between drug use epidemics and disease epidemics. “As we have an increasing opioid epidemic and methamphetamine abuse that we’re all seeing in our clinics, it’s interesting to see this intersection between the drug use problem and the syphilis problem in this country. I think they’re not unrelated,” she said.
She believes the results should have broad implications for screening programs. Women admitted to drug treatment programs should be tested for syphilis. And women who abuse drugs and are pregnant should be screened repeatedly – at entry to care, at their 20-week scan, and at delivery. “We know we have about 6,000 women with HIV who deliver each year, so this is potentially very impactful,” Dr. Dionne-Odom said.
The researchers extracted data from the CNICS cohort, including 4,795 women with records between 2005 and 2016. They defined incident syphilis as a newly positive nontreponemal serologic test or a 300% titer increase, followed by a confirmatory test.
After adjustment, factors associated with syphilis included prior intravenous drug abuse (adjusted odds ratio, 2.3; 95% confidence interval, 1.3-3.9), hepatitis C antibody positivity (aOR, 2.1; 95% CI, 1.3-3.7), as well as black race (aOR, 2.3; 95% CI, 1.4-3.9). There was no association between age and HIV viral load with respect to risk of syphilis.
The frequency appears to be rising, with later entry into the CNICS cohort assorted with a more than doubled risk of syphilis (aOR, 2.3; 95% CI, 1.4-3.9 for 2011-2016, compared with 1994-2004).
The study was funded by the National Institute of Child Health and Human Development. Dr. Dionne-Odom reported no relevant conflicts of interest.
SOURCE: J Dionne-Odom et al. CROI 2019, Abstract 47
REPORTING FROM CROI 2019
Positive FIT test should prompt new colonoscopy
Patients who test positive on a fecal immunochemical test (FIT), even after a recent colonoscopy, should be offered a repeat colonoscopy. That is the conclusion following a review of 2,228 subjects who were FIT positive, which revealed a greater risk of colorectal cancer (CRC) and advanced colo-rectal neoplasia (ACRN) the longer the gap since the last colonoscopy. The findings support the recommendations of the U.S. Multi-Society Task Force on CRC Screening to offer repeat colonoscopies to FIT-positive patients, even if they recently underwent a colonoscopy.
That recommendation was based on low-quality supporting evidence, and there is currently little agreement about whether annual FIT should be performed along with colonoscopy.
The researchers set out to detect the frequency of CRC and ACRN among patients with a positive FIT test. They analyzed data from the National Cancer Screening Program in Korea, which offers an annual FIT for adults aged 50 years and older as an initial screening, followed by a colonoscopy in case of a positive result.
The researchers analyzed data from 52,376 individuals who underwent FIT at a single center in Korea during January 2013–July 2017. They excluded patients with a history of CRC or colorectal surgery, inflammatory bowel disease, or poor bowel preparation.
FIT-positive and FIT-negative patients were divided into three groups based on the length of time since their last colonoscopy: less than 3 years, 3-10 years, or more than 10 years or no colonoscopy.
Compared with FIT-negative subjects, FIT-positive individuals were more likely to be diagnosed with any colorectal neoplasia (61.3% vs. 51.8%; P less than .001), ACRN (20.0% vs. 10.3%; P less than .001), and CRC (5.0% vs. 1.9%; P less than .001).
A total of 6% of subjects had a positive FIT result, and data from 2,228 were analyzed after exclusions. They were compared with 6,135 participants who had negative FIT results but underwent a colonoscopy.
Of patients with a positive FIT result, 23.1% had a colonoscopy less than 3 years before, 19.2% had one 3-10 years prior, and 57.8% had a colonoscopy more than 10 years earlier or had never had one.
The more-than-10-year group had a higher frequency of colorectal neoplasia, ACRN, or CRC (26.0%) than did the 3 to 10-year group (12.6%), and the less-than-3-year group (10.9%; P less than .001 for all). A similar trend was seen for CRC: 7.2%, 1.6%, and 2.1%, respectively (P less than .001).
Of the 6,135 FIT-negative participants, 22.2% were in the less-than-3-years group, 28.9%, 3-10 years; and 48.8%, more-than-10 years-or-never group. The more-than-10-years group had a higher frequency of ACRN (14.7%) than did the 3 to 10-year group (0.4%) and the 0 to 3-year group (0.7%, P less than .001).
Among FIT-positive patients, the more-than-10-year group was at higher risk of ACRN diagnosis during follow-up colonoscopy than was the less-than-3-year group (adjusted OR, 3.63; 95% confidence interval, 2.48-5.31), but not compared with the 3-10-year group (aOR, 1.17; 95% CI, 0.71-1.93). The more-than-10-year group also was at greater risk of a CRC diagnosis than was the less-than-3-year group (aOR, 3.66; 95% CI, 1.74-7.73). There was no significant difference in CRC risk between the less-than-3-year group and the 3 to 10-year group (aOR, 0.58; 95% CI, 0.17-1.93).The authors suggest that CRC and ACRN found in patients who had a colonoscopy in the past 3 years are likely to be lesions that were missed in the previous exam, rather than new, fast-growing lesions. That suggests that FIT may help catch lesions that were missed during earlier screenings, though just 2.1% of the less-than-3-year group and 1.6% of the 3 to 10-year group were diagnosed with CRC, and 10.9% and 12.6% with ACRN, respectively.
The authors conclude that it may not be appropriate to offer interval FIT to all patients, since it can lead to unnecessary colonoscopies. They call for more research to determine which categories of patients are most likely to benefit from interval FIT.
The study received no funding. The authors reported no conflicts of interest.
March is Colorectal Cancer Awareness Month. AGA is here to help with patient education materials and a new video series. Visit http://crcawareness.gastro.org/ to access all the resources and share on your practice website and social media channels.
SOURCE: Kim NH et al. Gastrointest Endosc. 2019 Jan 23. doi: 10.1016/j.gie.2019.01.012.
Patients who test positive on a fecal immunochemical test (FIT), even after a recent colonoscopy, should be offered a repeat colonoscopy. That is the conclusion following a review of 2,228 subjects who were FIT positive, which revealed a greater risk of colorectal cancer (CRC) and advanced colo-rectal neoplasia (ACRN) the longer the gap since the last colonoscopy. The findings support the recommendations of the U.S. Multi-Society Task Force on CRC Screening to offer repeat colonoscopies to FIT-positive patients, even if they recently underwent a colonoscopy.
That recommendation was based on low-quality supporting evidence, and there is currently little agreement about whether annual FIT should be performed along with colonoscopy.
The researchers set out to detect the frequency of CRC and ACRN among patients with a positive FIT test. They analyzed data from the National Cancer Screening Program in Korea, which offers an annual FIT for adults aged 50 years and older as an initial screening, followed by a colonoscopy in case of a positive result.
The researchers analyzed data from 52,376 individuals who underwent FIT at a single center in Korea during January 2013–July 2017. They excluded patients with a history of CRC or colorectal surgery, inflammatory bowel disease, or poor bowel preparation.
FIT-positive and FIT-negative patients were divided into three groups based on the length of time since their last colonoscopy: less than 3 years, 3-10 years, or more than 10 years or no colonoscopy.
Compared with FIT-negative subjects, FIT-positive individuals were more likely to be diagnosed with any colorectal neoplasia (61.3% vs. 51.8%; P less than .001), ACRN (20.0% vs. 10.3%; P less than .001), and CRC (5.0% vs. 1.9%; P less than .001).
A total of 6% of subjects had a positive FIT result, and data from 2,228 were analyzed after exclusions. They were compared with 6,135 participants who had negative FIT results but underwent a colonoscopy.
Of patients with a positive FIT result, 23.1% had a colonoscopy less than 3 years before, 19.2% had one 3-10 years prior, and 57.8% had a colonoscopy more than 10 years earlier or had never had one.
The more-than-10-year group had a higher frequency of colorectal neoplasia, ACRN, or CRC (26.0%) than did the 3 to 10-year group (12.6%), and the less-than-3-year group (10.9%; P less than .001 for all). A similar trend was seen for CRC: 7.2%, 1.6%, and 2.1%, respectively (P less than .001).
Of the 6,135 FIT-negative participants, 22.2% were in the less-than-3-years group, 28.9%, 3-10 years; and 48.8%, more-than-10 years-or-never group. The more-than-10-years group had a higher frequency of ACRN (14.7%) than did the 3 to 10-year group (0.4%) and the 0 to 3-year group (0.7%, P less than .001).
Among FIT-positive patients, the more-than-10-year group was at higher risk of ACRN diagnosis during follow-up colonoscopy than was the less-than-3-year group (adjusted OR, 3.63; 95% confidence interval, 2.48-5.31), but not compared with the 3-10-year group (aOR, 1.17; 95% CI, 0.71-1.93). The more-than-10-year group also was at greater risk of a CRC diagnosis than was the less-than-3-year group (aOR, 3.66; 95% CI, 1.74-7.73). There was no significant difference in CRC risk between the less-than-3-year group and the 3 to 10-year group (aOR, 0.58; 95% CI, 0.17-1.93).The authors suggest that CRC and ACRN found in patients who had a colonoscopy in the past 3 years are likely to be lesions that were missed in the previous exam, rather than new, fast-growing lesions. That suggests that FIT may help catch lesions that were missed during earlier screenings, though just 2.1% of the less-than-3-year group and 1.6% of the 3 to 10-year group were diagnosed with CRC, and 10.9% and 12.6% with ACRN, respectively.
The authors conclude that it may not be appropriate to offer interval FIT to all patients, since it can lead to unnecessary colonoscopies. They call for more research to determine which categories of patients are most likely to benefit from interval FIT.
The study received no funding. The authors reported no conflicts of interest.
March is Colorectal Cancer Awareness Month. AGA is here to help with patient education materials and a new video series. Visit http://crcawareness.gastro.org/ to access all the resources and share on your practice website and social media channels.
SOURCE: Kim NH et al. Gastrointest Endosc. 2019 Jan 23. doi: 10.1016/j.gie.2019.01.012.
Patients who test positive on a fecal immunochemical test (FIT), even after a recent colonoscopy, should be offered a repeat colonoscopy. That is the conclusion following a review of 2,228 subjects who were FIT positive, which revealed a greater risk of colorectal cancer (CRC) and advanced colo-rectal neoplasia (ACRN) the longer the gap since the last colonoscopy. The findings support the recommendations of the U.S. Multi-Society Task Force on CRC Screening to offer repeat colonoscopies to FIT-positive patients, even if they recently underwent a colonoscopy.
That recommendation was based on low-quality supporting evidence, and there is currently little agreement about whether annual FIT should be performed along with colonoscopy.
The researchers set out to detect the frequency of CRC and ACRN among patients with a positive FIT test. They analyzed data from the National Cancer Screening Program in Korea, which offers an annual FIT for adults aged 50 years and older as an initial screening, followed by a colonoscopy in case of a positive result.
The researchers analyzed data from 52,376 individuals who underwent FIT at a single center in Korea during January 2013–July 2017. They excluded patients with a history of CRC or colorectal surgery, inflammatory bowel disease, or poor bowel preparation.
FIT-positive and FIT-negative patients were divided into three groups based on the length of time since their last colonoscopy: less than 3 years, 3-10 years, or more than 10 years or no colonoscopy.
Compared with FIT-negative subjects, FIT-positive individuals were more likely to be diagnosed with any colorectal neoplasia (61.3% vs. 51.8%; P less than .001), ACRN (20.0% vs. 10.3%; P less than .001), and CRC (5.0% vs. 1.9%; P less than .001).
A total of 6% of subjects had a positive FIT result, and data from 2,228 were analyzed after exclusions. They were compared with 6,135 participants who had negative FIT results but underwent a colonoscopy.
Of patients with a positive FIT result, 23.1% had a colonoscopy less than 3 years before, 19.2% had one 3-10 years prior, and 57.8% had a colonoscopy more than 10 years earlier or had never had one.
The more-than-10-year group had a higher frequency of colorectal neoplasia, ACRN, or CRC (26.0%) than did the 3 to 10-year group (12.6%), and the less-than-3-year group (10.9%; P less than .001 for all). A similar trend was seen for CRC: 7.2%, 1.6%, and 2.1%, respectively (P less than .001).
Of the 6,135 FIT-negative participants, 22.2% were in the less-than-3-years group, 28.9%, 3-10 years; and 48.8%, more-than-10 years-or-never group. The more-than-10-years group had a higher frequency of ACRN (14.7%) than did the 3 to 10-year group (0.4%) and the 0 to 3-year group (0.7%, P less than .001).
Among FIT-positive patients, the more-than-10-year group was at higher risk of ACRN diagnosis during follow-up colonoscopy than was the less-than-3-year group (adjusted OR, 3.63; 95% confidence interval, 2.48-5.31), but not compared with the 3-10-year group (aOR, 1.17; 95% CI, 0.71-1.93). The more-than-10-year group also was at greater risk of a CRC diagnosis than was the less-than-3-year group (aOR, 3.66; 95% CI, 1.74-7.73). There was no significant difference in CRC risk between the less-than-3-year group and the 3 to 10-year group (aOR, 0.58; 95% CI, 0.17-1.93).The authors suggest that CRC and ACRN found in patients who had a colonoscopy in the past 3 years are likely to be lesions that were missed in the previous exam, rather than new, fast-growing lesions. That suggests that FIT may help catch lesions that were missed during earlier screenings, though just 2.1% of the less-than-3-year group and 1.6% of the 3 to 10-year group were diagnosed with CRC, and 10.9% and 12.6% with ACRN, respectively.
The authors conclude that it may not be appropriate to offer interval FIT to all patients, since it can lead to unnecessary colonoscopies. They call for more research to determine which categories of patients are most likely to benefit from interval FIT.
The study received no funding. The authors reported no conflicts of interest.
March is Colorectal Cancer Awareness Month. AGA is here to help with patient education materials and a new video series. Visit http://crcawareness.gastro.org/ to access all the resources and share on your practice website and social media channels.
SOURCE: Kim NH et al. Gastrointest Endosc. 2019 Jan 23. doi: 10.1016/j.gie.2019.01.012.
Whole genome sequencing benefits pediatric ICU patients
SAN DIEGO – In the pediatric intensive care unit (PICU), rapid whole genome sequencing (rWGS) with targeted phenotype analysis often leads to specific changes in patient management, similar to what is seen when rWGS is applied to neonatal ICUs. The findings come from the first study to look at outcomes of rWGS in the PICU outside of infancy.
In the NICU, previous studies have shown an rWGS diagnostic rate ranging from 36% to 57%, and an estimated 49%-72% of these diagnoses result in changes to patient management; 38%-45% of those diagnoses had not been previously considered.
The researchers found similar benefits when the age of patients was extended to 18 years in the PICU. “We were happy to see we were able to make specific changes in ICU management, with three of those being medication changes based on the diagnosis, and one being in the transition to palliative care while the patient was still in the PICU,” Erica Sanford, MD, said in an interview.
Dr. Sanford is a pediatric clinical care fellow at the University of California, San Diego. She presented the study at the Critical Care Congress sponsored by the Society of Critical Care Medicine.
Changes as a result of rWGS included factor replacement for a factor XIII deficiency, avoidance of renal biopsy because the diagnosis was made genetically, and use of serial MRI and other imaging methods to identify disorder-related sequela. “We’re hopeful as the turnaround for genome sequencing decreases that we’ll be able to offer this as a test when appropriate when a patient is presenting with an illness that doesn’t have a clear etiologic diagnosis,” said Dr. Sanford.
Certainly not every patient in the PICU should undergo rWGS, given its expense. Although the study was too small to identify candidate patients, there were some trends – patients in cardiac arrest were more likely to be receiving a genetic diagnosis. “We weren’t able to answer the question of which patients in the pediatric ICU should get whole genome sequencing – our next step is to have a larger group of patients so we can determine specifically which patients might benefit,” said Dr. Sanford. The team also plans to do a cost analysis of rWGS in the PICU setting.
The researchers examined data from a PICU at a tertiary children’s hospital, including records from 38 patients who underwent rWGS between July 2016 and May 2018. Based on the initial sequencing results, 18 underwent diagnostic rWGS. The average age of children was 5.7 years (median 3 years), with patients ranging from 4 months to 18 years old.
The most common reasons for PICU admission were shock (16% of all patients, 17% of patients who received diagnostic rWGS), respiratory failure (18% and 17%), cardiac arrest (13% and 22%), and altered mental status (13% and 11%).
Eleven of 18 patients (61%) who received an rWGS diagnosis experienced a subacute, non-ICU change in management. Four diagnoses (22%) led to a change in ICU management, and three led to no changes in patient management.
The National Institutes of Health funded the study. Dr. Sanford had no relevant financial disclosures.
SOURCE: Sanford E et al. CCC48, Abstract 373.
SAN DIEGO – In the pediatric intensive care unit (PICU), rapid whole genome sequencing (rWGS) with targeted phenotype analysis often leads to specific changes in patient management, similar to what is seen when rWGS is applied to neonatal ICUs. The findings come from the first study to look at outcomes of rWGS in the PICU outside of infancy.
In the NICU, previous studies have shown an rWGS diagnostic rate ranging from 36% to 57%, and an estimated 49%-72% of these diagnoses result in changes to patient management; 38%-45% of those diagnoses had not been previously considered.
The researchers found similar benefits when the age of patients was extended to 18 years in the PICU. “We were happy to see we were able to make specific changes in ICU management, with three of those being medication changes based on the diagnosis, and one being in the transition to palliative care while the patient was still in the PICU,” Erica Sanford, MD, said in an interview.
Dr. Sanford is a pediatric clinical care fellow at the University of California, San Diego. She presented the study at the Critical Care Congress sponsored by the Society of Critical Care Medicine.
Changes as a result of rWGS included factor replacement for a factor XIII deficiency, avoidance of renal biopsy because the diagnosis was made genetically, and use of serial MRI and other imaging methods to identify disorder-related sequela. “We’re hopeful as the turnaround for genome sequencing decreases that we’ll be able to offer this as a test when appropriate when a patient is presenting with an illness that doesn’t have a clear etiologic diagnosis,” said Dr. Sanford.
Certainly not every patient in the PICU should undergo rWGS, given its expense. Although the study was too small to identify candidate patients, there were some trends – patients in cardiac arrest were more likely to be receiving a genetic diagnosis. “We weren’t able to answer the question of which patients in the pediatric ICU should get whole genome sequencing – our next step is to have a larger group of patients so we can determine specifically which patients might benefit,” said Dr. Sanford. The team also plans to do a cost analysis of rWGS in the PICU setting.
The researchers examined data from a PICU at a tertiary children’s hospital, including records from 38 patients who underwent rWGS between July 2016 and May 2018. Based on the initial sequencing results, 18 underwent diagnostic rWGS. The average age of children was 5.7 years (median 3 years), with patients ranging from 4 months to 18 years old.
The most common reasons for PICU admission were shock (16% of all patients, 17% of patients who received diagnostic rWGS), respiratory failure (18% and 17%), cardiac arrest (13% and 22%), and altered mental status (13% and 11%).
Eleven of 18 patients (61%) who received an rWGS diagnosis experienced a subacute, non-ICU change in management. Four diagnoses (22%) led to a change in ICU management, and three led to no changes in patient management.
The National Institutes of Health funded the study. Dr. Sanford had no relevant financial disclosures.
SOURCE: Sanford E et al. CCC48, Abstract 373.
SAN DIEGO – In the pediatric intensive care unit (PICU), rapid whole genome sequencing (rWGS) with targeted phenotype analysis often leads to specific changes in patient management, similar to what is seen when rWGS is applied to neonatal ICUs. The findings come from the first study to look at outcomes of rWGS in the PICU outside of infancy.
In the NICU, previous studies have shown an rWGS diagnostic rate ranging from 36% to 57%, and an estimated 49%-72% of these diagnoses result in changes to patient management; 38%-45% of those diagnoses had not been previously considered.
The researchers found similar benefits when the age of patients was extended to 18 years in the PICU. “We were happy to see we were able to make specific changes in ICU management, with three of those being medication changes based on the diagnosis, and one being in the transition to palliative care while the patient was still in the PICU,” Erica Sanford, MD, said in an interview.
Dr. Sanford is a pediatric clinical care fellow at the University of California, San Diego. She presented the study at the Critical Care Congress sponsored by the Society of Critical Care Medicine.
Changes as a result of rWGS included factor replacement for a factor XIII deficiency, avoidance of renal biopsy because the diagnosis was made genetically, and use of serial MRI and other imaging methods to identify disorder-related sequela. “We’re hopeful as the turnaround for genome sequencing decreases that we’ll be able to offer this as a test when appropriate when a patient is presenting with an illness that doesn’t have a clear etiologic diagnosis,” said Dr. Sanford.
Certainly not every patient in the PICU should undergo rWGS, given its expense. Although the study was too small to identify candidate patients, there were some trends – patients in cardiac arrest were more likely to be receiving a genetic diagnosis. “We weren’t able to answer the question of which patients in the pediatric ICU should get whole genome sequencing – our next step is to have a larger group of patients so we can determine specifically which patients might benefit,” said Dr. Sanford. The team also plans to do a cost analysis of rWGS in the PICU setting.
The researchers examined data from a PICU at a tertiary children’s hospital, including records from 38 patients who underwent rWGS between July 2016 and May 2018. Based on the initial sequencing results, 18 underwent diagnostic rWGS. The average age of children was 5.7 years (median 3 years), with patients ranging from 4 months to 18 years old.
The most common reasons for PICU admission were shock (16% of all patients, 17% of patients who received diagnostic rWGS), respiratory failure (18% and 17%), cardiac arrest (13% and 22%), and altered mental status (13% and 11%).
Eleven of 18 patients (61%) who received an rWGS diagnosis experienced a subacute, non-ICU change in management. Four diagnoses (22%) led to a change in ICU management, and three led to no changes in patient management.
The National Institutes of Health funded the study. Dr. Sanford had no relevant financial disclosures.
SOURCE: Sanford E et al. CCC48, Abstract 373.
REPORTING FROM CCC48
Genomics have changed how researchers view trauma’s immunologic impact
SAN DIEGO – Severely injured patients often experience a massive inflammatory and immunomodulatory response that can lead to multiple organ failure, nosocomial infections, long ICU stays, and poor outcomes. But not all of them do. Some patients recover relatively rapidly, achieve earlier release, and have a faster immunologic recovery trajectory.
The longstanding theory, according to Ronald Maier, MD, a professor of surgery at the University of Washington, is that a trauma-related stimulus leads to an aggressive inflammatory response that can lead to multiple organ failure and death. In patients who recover from this early challenge, the theory goes, a counterregulatory response may overexuberantly down-regulate the inflammatory storm, which leaves the patient vulnerable to infections and poor wound healing. Then a later infection, sepsis, endotoxemia, or some other stimulus may ramp up the inflammatory system again, which leads to a crisis that can trigger mortality well after the initial trauma. Patients who recover from this challenge then return to homeostasis.
It’s a neat theory, but it’s wrong, said Dr. Maier in a talk at the Critical Care Congress sponsored by the Society of Critical Care Medicine. It has been undercut by genomic technology and high-throughput methods that have provided a new approach to investigating the underlying biology, as well as the ability to test circulating white blood cells to measure a patient’s immune response to traumatic injury.
“If you look at the underlying biology by looking at the genomic response, you can see that it’s not a sequential process. There is simultaneous up-regulation and down-regulation,” said Dr. Maier.
A study of 35 trauma patients using a gene chip found a measurable change in expression of over 17,000 genes; 5,136 genes had at least a twofold change in expression. “Eighty percent of the human genome changes measurably when you are hit by a cement truck,” said Dr. Maier.
To researchers’ surprise, more genes were found to be down-regulated in the immediate aftermath of the injury, and most of those down-regulated genes are involved in adaptive immunity. Up-regulated pathways were included in the innate and proinflammatory response. “The simultaneous down-regulation of the adaptive arm explains why the patients in the ICU with severe injuries are very susceptible to nosocomial infections, poor wound healing, and multiple complications,” said Dr. Maier.
Genomic studies also show down-regulation of genes associated with phagocytosis even out to 45 days. “Sometimes I wonder why every patient doesn’t evolve a nosocomial infection as a consequence of this impact on the immune system. In fact, I think it’s a great testimony to the countermeasures we’ve taken as far as sterility, hand washing – we’ve been able to prevent this dysfunction from being expressed as a nosocomial infection,” said Dr. Maier.
The genomic analysis can also be used to discriminate patients who regain homeostasis relatively quickly after severe trauma. There seems to be an inflection point between patients who resolve by 5 days and those who go on to experience prolonged ICU stays.
Perhaps surprisingly, the researchers found little difference between the two groups in terms of specific genes that were up- or down-regulated. Instead, the “uncomplicated” group saw their altered gene expression patterns return more quickly to baseline levels, whereas “complicated” patients lingered in the dysregulated state. “We’ve been chasing biomarkers for 35 years, and this explains why it’s very difficult. Those who do well return toward normal quickly. Those who have complications stay abnormal,” said Dr. Maier.
Instead, researchers identified a panel of 63 gene probes that can track the overall progress of the “genomic storm,” as he referred to the changes that occur in the wake of trauma. “This panel of 63 genes is the best predictor of the patient’s response to injury – better than injury severity score, better than multiple organ failure scores,” he said.
Dr. Maier is confident that such panels can alter patient management, even outside of trauma. “It may allow us to show which patients are going to have risk of early recurrence because of alterations in their adaptive immunity versus those who aren’t. We’re also going to predict those who are going to have infectious complications. Hopefully we’ll soon have a handle on which patients we need to be most aggressive with, and we can use monitoring to measure our therapeutic impact,” said Dr. Maier.
email address
SOURCE: Add the first author et al., journal citation/abstract number, and hyperlink it here.
SAN DIEGO – Severely injured patients often experience a massive inflammatory and immunomodulatory response that can lead to multiple organ failure, nosocomial infections, long ICU stays, and poor outcomes. But not all of them do. Some patients recover relatively rapidly, achieve earlier release, and have a faster immunologic recovery trajectory.
The longstanding theory, according to Ronald Maier, MD, a professor of surgery at the University of Washington, is that a trauma-related stimulus leads to an aggressive inflammatory response that can lead to multiple organ failure and death. In patients who recover from this early challenge, the theory goes, a counterregulatory response may overexuberantly down-regulate the inflammatory storm, which leaves the patient vulnerable to infections and poor wound healing. Then a later infection, sepsis, endotoxemia, or some other stimulus may ramp up the inflammatory system again, which leads to a crisis that can trigger mortality well after the initial trauma. Patients who recover from this challenge then return to homeostasis.
It’s a neat theory, but it’s wrong, said Dr. Maier in a talk at the Critical Care Congress sponsored by the Society of Critical Care Medicine. It has been undercut by genomic technology and high-throughput methods that have provided a new approach to investigating the underlying biology, as well as the ability to test circulating white blood cells to measure a patient’s immune response to traumatic injury.
“If you look at the underlying biology by looking at the genomic response, you can see that it’s not a sequential process. There is simultaneous up-regulation and down-regulation,” said Dr. Maier.
A study of 35 trauma patients using a gene chip found a measurable change in expression of over 17,000 genes; 5,136 genes had at least a twofold change in expression. “Eighty percent of the human genome changes measurably when you are hit by a cement truck,” said Dr. Maier.
To researchers’ surprise, more genes were found to be down-regulated in the immediate aftermath of the injury, and most of those down-regulated genes are involved in adaptive immunity. Up-regulated pathways were included in the innate and proinflammatory response. “The simultaneous down-regulation of the adaptive arm explains why the patients in the ICU with severe injuries are very susceptible to nosocomial infections, poor wound healing, and multiple complications,” said Dr. Maier.
Genomic studies also show down-regulation of genes associated with phagocytosis even out to 45 days. “Sometimes I wonder why every patient doesn’t evolve a nosocomial infection as a consequence of this impact on the immune system. In fact, I think it’s a great testimony to the countermeasures we’ve taken as far as sterility, hand washing – we’ve been able to prevent this dysfunction from being expressed as a nosocomial infection,” said Dr. Maier.
The genomic analysis can also be used to discriminate patients who regain homeostasis relatively quickly after severe trauma. There seems to be an inflection point between patients who resolve by 5 days and those who go on to experience prolonged ICU stays.
Perhaps surprisingly, the researchers found little difference between the two groups in terms of specific genes that were up- or down-regulated. Instead, the “uncomplicated” group saw their altered gene expression patterns return more quickly to baseline levels, whereas “complicated” patients lingered in the dysregulated state. “We’ve been chasing biomarkers for 35 years, and this explains why it’s very difficult. Those who do well return toward normal quickly. Those who have complications stay abnormal,” said Dr. Maier.
Instead, researchers identified a panel of 63 gene probes that can track the overall progress of the “genomic storm,” as he referred to the changes that occur in the wake of trauma. “This panel of 63 genes is the best predictor of the patient’s response to injury – better than injury severity score, better than multiple organ failure scores,” he said.
Dr. Maier is confident that such panels can alter patient management, even outside of trauma. “It may allow us to show which patients are going to have risk of early recurrence because of alterations in their adaptive immunity versus those who aren’t. We’re also going to predict those who are going to have infectious complications. Hopefully we’ll soon have a handle on which patients we need to be most aggressive with, and we can use monitoring to measure our therapeutic impact,” said Dr. Maier.
email address
SOURCE: Add the first author et al., journal citation/abstract number, and hyperlink it here.
SAN DIEGO – Severely injured patients often experience a massive inflammatory and immunomodulatory response that can lead to multiple organ failure, nosocomial infections, long ICU stays, and poor outcomes. But not all of them do. Some patients recover relatively rapidly, achieve earlier release, and have a faster immunologic recovery trajectory.
The longstanding theory, according to Ronald Maier, MD, a professor of surgery at the University of Washington, is that a trauma-related stimulus leads to an aggressive inflammatory response that can lead to multiple organ failure and death. In patients who recover from this early challenge, the theory goes, a counterregulatory response may overexuberantly down-regulate the inflammatory storm, which leaves the patient vulnerable to infections and poor wound healing. Then a later infection, sepsis, endotoxemia, or some other stimulus may ramp up the inflammatory system again, which leads to a crisis that can trigger mortality well after the initial trauma. Patients who recover from this challenge then return to homeostasis.
It’s a neat theory, but it’s wrong, said Dr. Maier in a talk at the Critical Care Congress sponsored by the Society of Critical Care Medicine. It has been undercut by genomic technology and high-throughput methods that have provided a new approach to investigating the underlying biology, as well as the ability to test circulating white blood cells to measure a patient’s immune response to traumatic injury.
“If you look at the underlying biology by looking at the genomic response, you can see that it’s not a sequential process. There is simultaneous up-regulation and down-regulation,” said Dr. Maier.
A study of 35 trauma patients using a gene chip found a measurable change in expression of over 17,000 genes; 5,136 genes had at least a twofold change in expression. “Eighty percent of the human genome changes measurably when you are hit by a cement truck,” said Dr. Maier.
To researchers’ surprise, more genes were found to be down-regulated in the immediate aftermath of the injury, and most of those down-regulated genes are involved in adaptive immunity. Up-regulated pathways were included in the innate and proinflammatory response. “The simultaneous down-regulation of the adaptive arm explains why the patients in the ICU with severe injuries are very susceptible to nosocomial infections, poor wound healing, and multiple complications,” said Dr. Maier.
Genomic studies also show down-regulation of genes associated with phagocytosis even out to 45 days. “Sometimes I wonder why every patient doesn’t evolve a nosocomial infection as a consequence of this impact on the immune system. In fact, I think it’s a great testimony to the countermeasures we’ve taken as far as sterility, hand washing – we’ve been able to prevent this dysfunction from being expressed as a nosocomial infection,” said Dr. Maier.
The genomic analysis can also be used to discriminate patients who regain homeostasis relatively quickly after severe trauma. There seems to be an inflection point between patients who resolve by 5 days and those who go on to experience prolonged ICU stays.
Perhaps surprisingly, the researchers found little difference between the two groups in terms of specific genes that were up- or down-regulated. Instead, the “uncomplicated” group saw their altered gene expression patterns return more quickly to baseline levels, whereas “complicated” patients lingered in the dysregulated state. “We’ve been chasing biomarkers for 35 years, and this explains why it’s very difficult. Those who do well return toward normal quickly. Those who have complications stay abnormal,” said Dr. Maier.
Instead, researchers identified a panel of 63 gene probes that can track the overall progress of the “genomic storm,” as he referred to the changes that occur in the wake of trauma. “This panel of 63 genes is the best predictor of the patient’s response to injury – better than injury severity score, better than multiple organ failure scores,” he said.
Dr. Maier is confident that such panels can alter patient management, even outside of trauma. “It may allow us to show which patients are going to have risk of early recurrence because of alterations in their adaptive immunity versus those who aren’t. We’re also going to predict those who are going to have infectious complications. Hopefully we’ll soon have a handle on which patients we need to be most aggressive with, and we can use monitoring to measure our therapeutic impact,” said Dr. Maier.
email address
SOURCE: Add the first author et al., journal citation/abstract number, and hyperlink it here.
EXPERT ANALYSIS FROM CCC48