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Adenotonsillectomy doesn’t improve cognitive function in preschoolers with OSA
according to a prospective study.
The study showed no significant difference in global IQ at 12 months between children who underwent adenotonsillectomy and those who did not. However, as expected, the adenotonsillectomy group did experience improvements in sleep.
Karen A. Waters, MBBS, PhD, of the Children’s Hospital at Westmead and the University of Sydney, and her colleagues reported these results in Pediatrics. There also was a related commentary.
The study enrolled 190 children (ages 3-5 years) with mild obstructive sleep apnea. Roughly half of patients (n = 99) were randomized to early adenotonsillectomy (within 2 months), and the other half (n = 91) were randomized to no adenotonsillectomy (12-month routine wait). There were 121 patients who had global IQ assessments at 12 months, as measured by the Woodcock Johnson III Brief Intellectual Ability (BIA) test. Of these patients, 61 were in the adenotonsillectomy group, and 60 were in the control group.
Both groups had improvements in BIA scores from baseline to 12 months, and the 12-month BIA score was not significantly different between the groups.
At baseline, the mean W score (task proficiency) for BIA was 448.36 in the adenotonsillectomy group and 451.3 in the control group. At 12 months, the scores were 465.46 and 463.12, respectively (P = .29).
“Intellectual ability scores improved in both groups over time with no effect attributable to the intervention [adenotonsillectomy],” Dr. Waters and her colleagues wrote.
However, patients in the adenotonsillectomy group did have greater improvements in sleep than patients in the control group, as assessed by polysomnogram and parent reports.
In the adenotonsillectomy group, the mean total sleep time was 469.2 minutes at baseline and 481.8 minutes at 12 months. In the control group, the mean total sleep time was 463.8 minutes at baseline and 475.3 minutes at 12 months. The adjusted mean difference was –2.12 (P less than .001).
According to parent reports, children in the adenotonsillectomy group were significantly less likely than those in the control group to have trouble sleeping at night at 12 months: 8% and 74%, respectively (P less than .001).
“Children randomly assigned to adenotonsillectomy did show greater improvement in polysomnography obstructive indices and parent-reported behavior but did not demonstrate a treatment-attributable improvement in cognitive function,” David O. Francis, MD, of University of Wisconsin–Madison, and Derek J. Lam, MD, of Oregon Health & Science University in Portland, wrote in a related commentary.
The commentators noted that these results are similar to those of the CHAT study, which showed no significant differences in Developmental Neuropsychological Assessment results between children (ages 5-9 years) who underwent adenotonsillectomy and those who did not (N Engl J Med. 2013 Jun 20;368[25]:2366-76).
The current study was funded by the National Health and Medical Research Council, Sydney University, The Garnett Passe and Rodney Williams Memorial Foundation, and The Golden Casket, Brisbane. Dr. Waters, her coauthors, and the commentary authors said they have no relevant conflicts of interest. The commentators received no external funding.
SOURCE: Waters KA et al. Pediatrics. 2020;145(2):e20191450; Francis DO and Lam DJ. Pediatrics. 2020;145(2):e20192479.
according to a prospective study.
The study showed no significant difference in global IQ at 12 months between children who underwent adenotonsillectomy and those who did not. However, as expected, the adenotonsillectomy group did experience improvements in sleep.
Karen A. Waters, MBBS, PhD, of the Children’s Hospital at Westmead and the University of Sydney, and her colleagues reported these results in Pediatrics. There also was a related commentary.
The study enrolled 190 children (ages 3-5 years) with mild obstructive sleep apnea. Roughly half of patients (n = 99) were randomized to early adenotonsillectomy (within 2 months), and the other half (n = 91) were randomized to no adenotonsillectomy (12-month routine wait). There were 121 patients who had global IQ assessments at 12 months, as measured by the Woodcock Johnson III Brief Intellectual Ability (BIA) test. Of these patients, 61 were in the adenotonsillectomy group, and 60 were in the control group.
Both groups had improvements in BIA scores from baseline to 12 months, and the 12-month BIA score was not significantly different between the groups.
At baseline, the mean W score (task proficiency) for BIA was 448.36 in the adenotonsillectomy group and 451.3 in the control group. At 12 months, the scores were 465.46 and 463.12, respectively (P = .29).
“Intellectual ability scores improved in both groups over time with no effect attributable to the intervention [adenotonsillectomy],” Dr. Waters and her colleagues wrote.
However, patients in the adenotonsillectomy group did have greater improvements in sleep than patients in the control group, as assessed by polysomnogram and parent reports.
In the adenotonsillectomy group, the mean total sleep time was 469.2 minutes at baseline and 481.8 minutes at 12 months. In the control group, the mean total sleep time was 463.8 minutes at baseline and 475.3 minutes at 12 months. The adjusted mean difference was –2.12 (P less than .001).
According to parent reports, children in the adenotonsillectomy group were significantly less likely than those in the control group to have trouble sleeping at night at 12 months: 8% and 74%, respectively (P less than .001).
“Children randomly assigned to adenotonsillectomy did show greater improvement in polysomnography obstructive indices and parent-reported behavior but did not demonstrate a treatment-attributable improvement in cognitive function,” David O. Francis, MD, of University of Wisconsin–Madison, and Derek J. Lam, MD, of Oregon Health & Science University in Portland, wrote in a related commentary.
The commentators noted that these results are similar to those of the CHAT study, which showed no significant differences in Developmental Neuropsychological Assessment results between children (ages 5-9 years) who underwent adenotonsillectomy and those who did not (N Engl J Med. 2013 Jun 20;368[25]:2366-76).
The current study was funded by the National Health and Medical Research Council, Sydney University, The Garnett Passe and Rodney Williams Memorial Foundation, and The Golden Casket, Brisbane. Dr. Waters, her coauthors, and the commentary authors said they have no relevant conflicts of interest. The commentators received no external funding.
SOURCE: Waters KA et al. Pediatrics. 2020;145(2):e20191450; Francis DO and Lam DJ. Pediatrics. 2020;145(2):e20192479.
according to a prospective study.
The study showed no significant difference in global IQ at 12 months between children who underwent adenotonsillectomy and those who did not. However, as expected, the adenotonsillectomy group did experience improvements in sleep.
Karen A. Waters, MBBS, PhD, of the Children’s Hospital at Westmead and the University of Sydney, and her colleagues reported these results in Pediatrics. There also was a related commentary.
The study enrolled 190 children (ages 3-5 years) with mild obstructive sleep apnea. Roughly half of patients (n = 99) were randomized to early adenotonsillectomy (within 2 months), and the other half (n = 91) were randomized to no adenotonsillectomy (12-month routine wait). There were 121 patients who had global IQ assessments at 12 months, as measured by the Woodcock Johnson III Brief Intellectual Ability (BIA) test. Of these patients, 61 were in the adenotonsillectomy group, and 60 were in the control group.
Both groups had improvements in BIA scores from baseline to 12 months, and the 12-month BIA score was not significantly different between the groups.
At baseline, the mean W score (task proficiency) for BIA was 448.36 in the adenotonsillectomy group and 451.3 in the control group. At 12 months, the scores were 465.46 and 463.12, respectively (P = .29).
“Intellectual ability scores improved in both groups over time with no effect attributable to the intervention [adenotonsillectomy],” Dr. Waters and her colleagues wrote.
However, patients in the adenotonsillectomy group did have greater improvements in sleep than patients in the control group, as assessed by polysomnogram and parent reports.
In the adenotonsillectomy group, the mean total sleep time was 469.2 minutes at baseline and 481.8 minutes at 12 months. In the control group, the mean total sleep time was 463.8 minutes at baseline and 475.3 minutes at 12 months. The adjusted mean difference was –2.12 (P less than .001).
According to parent reports, children in the adenotonsillectomy group were significantly less likely than those in the control group to have trouble sleeping at night at 12 months: 8% and 74%, respectively (P less than .001).
“Children randomly assigned to adenotonsillectomy did show greater improvement in polysomnography obstructive indices and parent-reported behavior but did not demonstrate a treatment-attributable improvement in cognitive function,” David O. Francis, MD, of University of Wisconsin–Madison, and Derek J. Lam, MD, of Oregon Health & Science University in Portland, wrote in a related commentary.
The commentators noted that these results are similar to those of the CHAT study, which showed no significant differences in Developmental Neuropsychological Assessment results between children (ages 5-9 years) who underwent adenotonsillectomy and those who did not (N Engl J Med. 2013 Jun 20;368[25]:2366-76).
The current study was funded by the National Health and Medical Research Council, Sydney University, The Garnett Passe and Rodney Williams Memorial Foundation, and The Golden Casket, Brisbane. Dr. Waters, her coauthors, and the commentary authors said they have no relevant conflicts of interest. The commentators received no external funding.
SOURCE: Waters KA et al. Pediatrics. 2020;145(2):e20191450; Francis DO and Lam DJ. Pediatrics. 2020;145(2):e20192479.
FROM PEDIATRICS
Mystery pneumonia in China has health officials on alert
An according to a statement from the Centers for Disease Control and Prevention.
As of Jan. 5, 2020, 59 cases of the disease have been reported by the Wuhan Municipal Health Commission. The cluster of cases is linked to the Wuhan South China Seafood City market where – in addition to seafood – chickens, bats, marmots, and other animals were sold. That market has been closed since Jan. 1, 2020, for cleaning and disinfection.
Wuhan health authorities are closely monitoring over 150 contacts for symptoms. Laboratory results have been negative for influenza, avian influenza, adenovirus, and the viruses that caused SARS (severe acute respiratory syndrome) and MERS (Middle East respiratory syndrome). So far, there are no reports of person-to-person transmission or health care worker infection of this pneumonia.
The World Health Organization reported that, as of Dec. 31, 2019, about one-quarter of patients were severely ill with the pneumonia and the rest were stable. Symptoms reported include fever, difficulty breathing, and chest radiographs showing invasive lesions in both lungs. All patients are being treated in isolation and efforts to identify the pathogen are ongoing.
The WHO is monitoring the situation closely and is in close contact with Chinese health authorities.
The CDC has recommended that travelers to Wuhan, a city of over 19 million people, avoid animal and meat markets, avoid contact with sick people, and wash hands often with soap and water. Travelers who have been in Wuhan recently and who experience respiratory symptoms should notify the local health department immediately. In addition, the CDC has issued a Level 1 travel alert, which recommends travelers observe usual precautions against infectious disease.
In addition, the CDC recommends that, for symptomatic patients with a history of travel to Wuhan, caution should be exercised in the health care setting. “Ask such patients to don a surgical mask as soon as they are identified. Conduct their evaluation in a private room with the door closed. Personnel entering the room to evaluate the patient should use contact precautions and wear an N95 disposable facepiece respirator. For patients admitted for inpatient care, implement contact and airborne isolation precautions, in addition to standard precautions, until further information becomes available. For additional infection control guidance see: www.cdc.gov/infectioncontrol/guidelines/isolation/index.html.”
An according to a statement from the Centers for Disease Control and Prevention.
As of Jan. 5, 2020, 59 cases of the disease have been reported by the Wuhan Municipal Health Commission. The cluster of cases is linked to the Wuhan South China Seafood City market where – in addition to seafood – chickens, bats, marmots, and other animals were sold. That market has been closed since Jan. 1, 2020, for cleaning and disinfection.
Wuhan health authorities are closely monitoring over 150 contacts for symptoms. Laboratory results have been negative for influenza, avian influenza, adenovirus, and the viruses that caused SARS (severe acute respiratory syndrome) and MERS (Middle East respiratory syndrome). So far, there are no reports of person-to-person transmission or health care worker infection of this pneumonia.
The World Health Organization reported that, as of Dec. 31, 2019, about one-quarter of patients were severely ill with the pneumonia and the rest were stable. Symptoms reported include fever, difficulty breathing, and chest radiographs showing invasive lesions in both lungs. All patients are being treated in isolation and efforts to identify the pathogen are ongoing.
The WHO is monitoring the situation closely and is in close contact with Chinese health authorities.
The CDC has recommended that travelers to Wuhan, a city of over 19 million people, avoid animal and meat markets, avoid contact with sick people, and wash hands often with soap and water. Travelers who have been in Wuhan recently and who experience respiratory symptoms should notify the local health department immediately. In addition, the CDC has issued a Level 1 travel alert, which recommends travelers observe usual precautions against infectious disease.
In addition, the CDC recommends that, for symptomatic patients with a history of travel to Wuhan, caution should be exercised in the health care setting. “Ask such patients to don a surgical mask as soon as they are identified. Conduct their evaluation in a private room with the door closed. Personnel entering the room to evaluate the patient should use contact precautions and wear an N95 disposable facepiece respirator. For patients admitted for inpatient care, implement contact and airborne isolation precautions, in addition to standard precautions, until further information becomes available. For additional infection control guidance see: www.cdc.gov/infectioncontrol/guidelines/isolation/index.html.”
An according to a statement from the Centers for Disease Control and Prevention.
As of Jan. 5, 2020, 59 cases of the disease have been reported by the Wuhan Municipal Health Commission. The cluster of cases is linked to the Wuhan South China Seafood City market where – in addition to seafood – chickens, bats, marmots, and other animals were sold. That market has been closed since Jan. 1, 2020, for cleaning and disinfection.
Wuhan health authorities are closely monitoring over 150 contacts for symptoms. Laboratory results have been negative for influenza, avian influenza, adenovirus, and the viruses that caused SARS (severe acute respiratory syndrome) and MERS (Middle East respiratory syndrome). So far, there are no reports of person-to-person transmission or health care worker infection of this pneumonia.
The World Health Organization reported that, as of Dec. 31, 2019, about one-quarter of patients were severely ill with the pneumonia and the rest were stable. Symptoms reported include fever, difficulty breathing, and chest radiographs showing invasive lesions in both lungs. All patients are being treated in isolation and efforts to identify the pathogen are ongoing.
The WHO is monitoring the situation closely and is in close contact with Chinese health authorities.
The CDC has recommended that travelers to Wuhan, a city of over 19 million people, avoid animal and meat markets, avoid contact with sick people, and wash hands often with soap and water. Travelers who have been in Wuhan recently and who experience respiratory symptoms should notify the local health department immediately. In addition, the CDC has issued a Level 1 travel alert, which recommends travelers observe usual precautions against infectious disease.
In addition, the CDC recommends that, for symptomatic patients with a history of travel to Wuhan, caution should be exercised in the health care setting. “Ask such patients to don a surgical mask as soon as they are identified. Conduct their evaluation in a private room with the door closed. Personnel entering the room to evaluate the patient should use contact precautions and wear an N95 disposable facepiece respirator. For patients admitted for inpatient care, implement contact and airborne isolation precautions, in addition to standard precautions, until further information becomes available. For additional infection control guidance see: www.cdc.gov/infectioncontrol/guidelines/isolation/index.html.”
A Veteran With a Solitary Pulmonary Nodule
Case Presentation. A 69-year-old veteran presented with an intermittent, waxing and waning cough. He had never smoked and had no family history of lung cancer. His primary care physician ordered a chest radiograph, which revealed a nodular opacity within the lingula concerning for a parenchymal nodule. Further characterization with a chest computed tomography (CT) demonstrated a 1.4-cm left upper lobe subpleural nodule with small satellite nodules (Figure 1). Given these imaging findings, the patient was referred to the pulmonary clinic.
►Lauren Kearney, MD, Medical Resident, VA Boston Healthcare System (VABHS) and Boston Medical Center. What is the differential diagnosis of a solitary pulmonary nodule? What characteristics of the nodule do you consider to differentiate these diagnoses?
►Renda Wiener, MD, Pulmonary and Critical Care, VABHS, and Assistant Professor of Medicine, Boston University School of Medicine. Pulmonary nodules are well-defined lesions < 3 cm in diameter that are surrounded by lung parenchyma. Although cancer is a possibility (including primary lung cancers, metastatic cancers, or carcinoid tumors), most small nodules do not turn out to be malignant.1 Benign etiologies include infections, benign tumors, vascular malformations, and inflammatory conditions. Infectious causes of nodules are often granulomatous in nature, including fungi, Mycobacterium tuberculosis, and nontuberculous mycobacteria. Benign tumors are most commonly hamartomas, and these may be clearly distinguished based on imaging characteristics. Pulmonary arteriovenous malformations, hematomas, and infarcts may present as nodules as well. Inflammatory causes of nodules are important and relatively common, including granulomatosis with polyangiitis, rheumatoid arthritis, sarcoidosis, amyloidosis, and rounded atelectasis.
To distinguish benign from malignant etiologies, we look for several features of pulmonary nodules on imaging. Larger size, irregular borders, and upper lobe location all increase the likelihood of cancer, whereas solid attenuation and calcification make cancer less likely. One of the most reassuring findings that suggests a benign etiology is lack of growth over a period of surveillance; after 2 years without growth we typically consider a nodule benign.1 And of course, we also consider the patient’s symptoms and risk factors: weight loss, hemoptysis, a history of cigarette smoking or asbestos exposure, or family history of cancer all increase the likelihood of malignancy.
►Dr. Kearney. Given that the differential diagnosis is so broad, how do you think about the next step in evaluating a pulmonary nodule? How do you approach shared decision making with the patient?
►Dr. Wiener. The characteristics of the patient, the nodule, and the circumstances in which the nodule were discovered are all important to consider. Incidental pulmonary nodules are often found on chest imaging. The imaging characteristics of the nodule are important, as are the patient’s risk factors. A similarly appearing nodule can have very different implications if the patient is a never-smoker exposed to endemic fungi, or a long-time smoker enrolled in a lung cancer screening program. Consultation with a pulmonologist is often appropriate.
It’s important to note that we lack high-quality evidence on the optimal strategy to evaluate pulmonary nodules, and there is no single “right answer“ for all patients. For patients with a low risk of malignancy (< 5%-10%)—which comprises the majority of the incidental nodules discovered—we typically favor serial CT surveillance of the nodule over a period of a few years, whereas for patients at high risk of malignancy (> 65%), we favor early surgical resection if the patient is able to tolerate that. For patients with an intermediate risk of malignancy (~5%-65%), we might consider serial CT surveillance, positron emission tomography (PET) scan, or biopsy.1 The American College of Chest Physicians guidelines for pulmonary nodule evaluation recommend discussing with patients the different options and the trade-offs of these options in a shared decision-making process.1
►Dr. Kearney. The patient’s pulmonologist laid out options, including monitoring with serial CT scans, obtaining a PET scan, performing CT-guided needle biopsy, or referring for surgical excision. In this case, the patient elected to undergo CT-guided needle biopsy. Dr. Huang, can you discuss the pathology results?
►Qin Huang, MD, Pathology and Laboratory Medicine, VABHS, and Assistant Professor of Pathology, Harvard Medical School (HMS). The microscopic examination of the needle biopsy of the lung mass revealed rare clusters of atypical cells with crushed cells adjacent to an extensive area of necrosis with scarring. The atypical cells were suspicious for carcinoma. The Gomori methenamine silver (GMS) and periodic acid-Schiff (PAS) stains were negative for common bacterial and fungal microorganisms.
►Dr. Kearney. The tumor board, pulmonologist, and patient decide to move forward with video-assisted excisional biopsy with lymphadenectomy. Dr. Huang, can you interpret the pathology?
►Dr. Huang. Figure 2 showed an hemotoxylin and eosin (H&E)-stained lung resection tissue section with multiple caseating necrotic granulomas. No foreign bodies were identified. There was no evidence of malignancy. The GMS stain revealed a fungal microorganism oval with morphology typical of histoplasma capsulatum (Figure 3).
►Dr. Kearney. What are some of the different ways histoplasmosis can present? Which of these diagnoses fits this patient’s presentation?
►Judy Strymish, MD, Infectious Disease, VABHS, and Assistant Professor of Medicine, HMS. Most patients who inhale histoplasmosis spores develop asymptomatic or self-limited infection that is usually not detected. Patients at risk of symptomatic and clinically relevant disease include those who are immunocompromised, at extremes of ages, or exposed to larger inoculums. Acute pulmonary histoplasmosis can present with cough, shortness of breath, fever, chills, and less commonly, rheumatologic complaints such as erythema nodosum or erythema multiforme. Imaging often shows patchy infiltrates and enlarged mediastinal and hilar lymphadenopathy. Patients can go on to develop subacute or chronic pulmonary disease with focal opacities and mediastinal and hilar lymphadenopathy. Those with chronic disease can have cavitary lesions similar to patients with tuberculosis. Progressive disseminated histoplasmosis can develop in immunocompromised patients and disseminate through the reticuloendothelial system to other organs with the gastrointestinal tract, central nervous system, and adrenal glands.2
Pulmonary nodules are common incidental finding on chest imaging of patients who reside in histoplasmosis endemic regions, and they are often hard to differentiate from malignancies. There are 3 mediastinal manifestations: adenitis, granuloma, and fibrosis. Usually the syndromes are subclinical, but occasionally the nodes cause symptoms by impinging on other structures.2
This patient had a solitary pulmonary nodule with none of the associated features mentioned above. Pathology showed caseating granuloma and confirmed histoplasmosis.
►Dr. Kearney. Given the diagnosis of solitary histoplasmoma, how should this patient be managed?
►Dr. Strymish. The optimal therapy for histoplasmosis depends on the patient’s clinical syndrome. Most infections are self-limited and require no therapy. However, patients who are immunocompromised, exposed to large inoculum, and have progressive disease require antifungal treatment, usually with itraconazole for mild-to-moderate disease and a combination of azole therapy and amphotericin B with extensive disease. Patients with few solitary pulmonary nodules do not benefit from antifungal therapy as the nodule could represent quiescent disease that is unlikely to have clinical impact; in this case, the treatment would be higher risk than the nodule.3
►Dr. Kearney. While the discussion of the diagnosis is interesting, it is also important to acknowledge what the patient went through to arrive at this, an essentially benign diagnosis: 8 months, multiple imaging studies, and 2 invasive diagnostic procedures. Further, the patient had to grapple with the possibility of a diagnosis of cancer. Dr. Wiener, can you talk about the challenges in communicating with patients about pulmonary nodules when cancer is on the differential? What are some of the harms patients face and how can clinicians work to mitigate these harms?
►Dr. Wiener. My colleague Dr. Christopher Slatore of the Portland VA Medical Center and I studied communication about pulmonary nodules in a series of surveys and qualitative studies of patients with pulmonary nodules and the clinicians who take care of them. We found that there seems to be a disconnect between patients’ perceptions of pulmonary nodules and their clinicians, often due to inadequate communication about the nodule. Many clinicians indicated that they do not tell patients about the chance that a nodule may be cancer, because the clinicians know that cancer is unlikely (< 5% of incidentally detected pulmonary nodules turn out to be malignant), and they do not want to alarm patients unnecessarily. However, we found that patients almost immediately wondered about cancer when they learned about their pulmonary nodule, and without hearing explicitly from their clinician that cancer was unlikely, patients tended to overestimate the likelihood of a malignant nodule. Moreover, patients often were not told much about the evaluation plan for the nodule or the rationale for CT surveillance of small nodules instead of biopsy. This uncertainty about the risk of cancer and the plan for evaluating the nodule was difficult for some patients to live with; we found that about one-quarter of patients with a small pulmonary nodule experienced mild-moderate distress during the period of radiographic surveillance. Reassuringly, high-quality patient-clinician communication was associated with lower distress and higher adherence to pulmonary nodule evaluation.4
►Dr. Kearney. The patient was educated about his diagnosis of solitary histoplasmoma. Given that the patient was otherwise well appearing with no complicating factors, he was not treated with antifungal therapy. After an 8-month-long workup, the patient was relieved to receive a diagnosis that excluded cancer and did not require any further treatment. His case provides a good example of how to proceed in the workup of a solitary pulmonary nodule and on the importance of communication and shared decision making with our patients.
1. Gould MK, Donington J, Lynch WR, et al. Evaluation of individuals with pulmonary nodules: when is it lung cancer? Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013;143(suppl 5):e93S-e120S.
2. Azar MM, Hage CA. Clinical perspectives in the diagnosis and management of histoplasmosis. Clin Chest Med. 2017;38(3):403-415.
3. Wheat LJ, Freifeld A, Kleiman MB, et al. Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America. Clin Infect Dis. 2007;45(7):807-825.
4. Slatore CG, Wiener RS. Pulmonary nodules: a small problem for many, severe distress for some, and how to communicate about it. Chest. 2018;153(4):1004-1015.
Case Presentation. A 69-year-old veteran presented with an intermittent, waxing and waning cough. He had never smoked and had no family history of lung cancer. His primary care physician ordered a chest radiograph, which revealed a nodular opacity within the lingula concerning for a parenchymal nodule. Further characterization with a chest computed tomography (CT) demonstrated a 1.4-cm left upper lobe subpleural nodule with small satellite nodules (Figure 1). Given these imaging findings, the patient was referred to the pulmonary clinic.
►Lauren Kearney, MD, Medical Resident, VA Boston Healthcare System (VABHS) and Boston Medical Center. What is the differential diagnosis of a solitary pulmonary nodule? What characteristics of the nodule do you consider to differentiate these diagnoses?
►Renda Wiener, MD, Pulmonary and Critical Care, VABHS, and Assistant Professor of Medicine, Boston University School of Medicine. Pulmonary nodules are well-defined lesions < 3 cm in diameter that are surrounded by lung parenchyma. Although cancer is a possibility (including primary lung cancers, metastatic cancers, or carcinoid tumors), most small nodules do not turn out to be malignant.1 Benign etiologies include infections, benign tumors, vascular malformations, and inflammatory conditions. Infectious causes of nodules are often granulomatous in nature, including fungi, Mycobacterium tuberculosis, and nontuberculous mycobacteria. Benign tumors are most commonly hamartomas, and these may be clearly distinguished based on imaging characteristics. Pulmonary arteriovenous malformations, hematomas, and infarcts may present as nodules as well. Inflammatory causes of nodules are important and relatively common, including granulomatosis with polyangiitis, rheumatoid arthritis, sarcoidosis, amyloidosis, and rounded atelectasis.
To distinguish benign from malignant etiologies, we look for several features of pulmonary nodules on imaging. Larger size, irregular borders, and upper lobe location all increase the likelihood of cancer, whereas solid attenuation and calcification make cancer less likely. One of the most reassuring findings that suggests a benign etiology is lack of growth over a period of surveillance; after 2 years without growth we typically consider a nodule benign.1 And of course, we also consider the patient’s symptoms and risk factors: weight loss, hemoptysis, a history of cigarette smoking or asbestos exposure, or family history of cancer all increase the likelihood of malignancy.
►Dr. Kearney. Given that the differential diagnosis is so broad, how do you think about the next step in evaluating a pulmonary nodule? How do you approach shared decision making with the patient?
►Dr. Wiener. The characteristics of the patient, the nodule, and the circumstances in which the nodule were discovered are all important to consider. Incidental pulmonary nodules are often found on chest imaging. The imaging characteristics of the nodule are important, as are the patient’s risk factors. A similarly appearing nodule can have very different implications if the patient is a never-smoker exposed to endemic fungi, or a long-time smoker enrolled in a lung cancer screening program. Consultation with a pulmonologist is often appropriate.
It’s important to note that we lack high-quality evidence on the optimal strategy to evaluate pulmonary nodules, and there is no single “right answer“ for all patients. For patients with a low risk of malignancy (< 5%-10%)—which comprises the majority of the incidental nodules discovered—we typically favor serial CT surveillance of the nodule over a period of a few years, whereas for patients at high risk of malignancy (> 65%), we favor early surgical resection if the patient is able to tolerate that. For patients with an intermediate risk of malignancy (~5%-65%), we might consider serial CT surveillance, positron emission tomography (PET) scan, or biopsy.1 The American College of Chest Physicians guidelines for pulmonary nodule evaluation recommend discussing with patients the different options and the trade-offs of these options in a shared decision-making process.1
►Dr. Kearney. The patient’s pulmonologist laid out options, including monitoring with serial CT scans, obtaining a PET scan, performing CT-guided needle biopsy, or referring for surgical excision. In this case, the patient elected to undergo CT-guided needle biopsy. Dr. Huang, can you discuss the pathology results?
►Qin Huang, MD, Pathology and Laboratory Medicine, VABHS, and Assistant Professor of Pathology, Harvard Medical School (HMS). The microscopic examination of the needle biopsy of the lung mass revealed rare clusters of atypical cells with crushed cells adjacent to an extensive area of necrosis with scarring. The atypical cells were suspicious for carcinoma. The Gomori methenamine silver (GMS) and periodic acid-Schiff (PAS) stains were negative for common bacterial and fungal microorganisms.
►Dr. Kearney. The tumor board, pulmonologist, and patient decide to move forward with video-assisted excisional biopsy with lymphadenectomy. Dr. Huang, can you interpret the pathology?
►Dr. Huang. Figure 2 showed an hemotoxylin and eosin (H&E)-stained lung resection tissue section with multiple caseating necrotic granulomas. No foreign bodies were identified. There was no evidence of malignancy. The GMS stain revealed a fungal microorganism oval with morphology typical of histoplasma capsulatum (Figure 3).
►Dr. Kearney. What are some of the different ways histoplasmosis can present? Which of these diagnoses fits this patient’s presentation?
►Judy Strymish, MD, Infectious Disease, VABHS, and Assistant Professor of Medicine, HMS. Most patients who inhale histoplasmosis spores develop asymptomatic or self-limited infection that is usually not detected. Patients at risk of symptomatic and clinically relevant disease include those who are immunocompromised, at extremes of ages, or exposed to larger inoculums. Acute pulmonary histoplasmosis can present with cough, shortness of breath, fever, chills, and less commonly, rheumatologic complaints such as erythema nodosum or erythema multiforme. Imaging often shows patchy infiltrates and enlarged mediastinal and hilar lymphadenopathy. Patients can go on to develop subacute or chronic pulmonary disease with focal opacities and mediastinal and hilar lymphadenopathy. Those with chronic disease can have cavitary lesions similar to patients with tuberculosis. Progressive disseminated histoplasmosis can develop in immunocompromised patients and disseminate through the reticuloendothelial system to other organs with the gastrointestinal tract, central nervous system, and adrenal glands.2
Pulmonary nodules are common incidental finding on chest imaging of patients who reside in histoplasmosis endemic regions, and they are often hard to differentiate from malignancies. There are 3 mediastinal manifestations: adenitis, granuloma, and fibrosis. Usually the syndromes are subclinical, but occasionally the nodes cause symptoms by impinging on other structures.2
This patient had a solitary pulmonary nodule with none of the associated features mentioned above. Pathology showed caseating granuloma and confirmed histoplasmosis.
►Dr. Kearney. Given the diagnosis of solitary histoplasmoma, how should this patient be managed?
►Dr. Strymish. The optimal therapy for histoplasmosis depends on the patient’s clinical syndrome. Most infections are self-limited and require no therapy. However, patients who are immunocompromised, exposed to large inoculum, and have progressive disease require antifungal treatment, usually with itraconazole for mild-to-moderate disease and a combination of azole therapy and amphotericin B with extensive disease. Patients with few solitary pulmonary nodules do not benefit from antifungal therapy as the nodule could represent quiescent disease that is unlikely to have clinical impact; in this case, the treatment would be higher risk than the nodule.3
►Dr. Kearney. While the discussion of the diagnosis is interesting, it is also important to acknowledge what the patient went through to arrive at this, an essentially benign diagnosis: 8 months, multiple imaging studies, and 2 invasive diagnostic procedures. Further, the patient had to grapple with the possibility of a diagnosis of cancer. Dr. Wiener, can you talk about the challenges in communicating with patients about pulmonary nodules when cancer is on the differential? What are some of the harms patients face and how can clinicians work to mitigate these harms?
►Dr. Wiener. My colleague Dr. Christopher Slatore of the Portland VA Medical Center and I studied communication about pulmonary nodules in a series of surveys and qualitative studies of patients with pulmonary nodules and the clinicians who take care of them. We found that there seems to be a disconnect between patients’ perceptions of pulmonary nodules and their clinicians, often due to inadequate communication about the nodule. Many clinicians indicated that they do not tell patients about the chance that a nodule may be cancer, because the clinicians know that cancer is unlikely (< 5% of incidentally detected pulmonary nodules turn out to be malignant), and they do not want to alarm patients unnecessarily. However, we found that patients almost immediately wondered about cancer when they learned about their pulmonary nodule, and without hearing explicitly from their clinician that cancer was unlikely, patients tended to overestimate the likelihood of a malignant nodule. Moreover, patients often were not told much about the evaluation plan for the nodule or the rationale for CT surveillance of small nodules instead of biopsy. This uncertainty about the risk of cancer and the plan for evaluating the nodule was difficult for some patients to live with; we found that about one-quarter of patients with a small pulmonary nodule experienced mild-moderate distress during the period of radiographic surveillance. Reassuringly, high-quality patient-clinician communication was associated with lower distress and higher adherence to pulmonary nodule evaluation.4
►Dr. Kearney. The patient was educated about his diagnosis of solitary histoplasmoma. Given that the patient was otherwise well appearing with no complicating factors, he was not treated with antifungal therapy. After an 8-month-long workup, the patient was relieved to receive a diagnosis that excluded cancer and did not require any further treatment. His case provides a good example of how to proceed in the workup of a solitary pulmonary nodule and on the importance of communication and shared decision making with our patients.
Case Presentation. A 69-year-old veteran presented with an intermittent, waxing and waning cough. He had never smoked and had no family history of lung cancer. His primary care physician ordered a chest radiograph, which revealed a nodular opacity within the lingula concerning for a parenchymal nodule. Further characterization with a chest computed tomography (CT) demonstrated a 1.4-cm left upper lobe subpleural nodule with small satellite nodules (Figure 1). Given these imaging findings, the patient was referred to the pulmonary clinic.
►Lauren Kearney, MD, Medical Resident, VA Boston Healthcare System (VABHS) and Boston Medical Center. What is the differential diagnosis of a solitary pulmonary nodule? What characteristics of the nodule do you consider to differentiate these diagnoses?
►Renda Wiener, MD, Pulmonary and Critical Care, VABHS, and Assistant Professor of Medicine, Boston University School of Medicine. Pulmonary nodules are well-defined lesions < 3 cm in diameter that are surrounded by lung parenchyma. Although cancer is a possibility (including primary lung cancers, metastatic cancers, or carcinoid tumors), most small nodules do not turn out to be malignant.1 Benign etiologies include infections, benign tumors, vascular malformations, and inflammatory conditions. Infectious causes of nodules are often granulomatous in nature, including fungi, Mycobacterium tuberculosis, and nontuberculous mycobacteria. Benign tumors are most commonly hamartomas, and these may be clearly distinguished based on imaging characteristics. Pulmonary arteriovenous malformations, hematomas, and infarcts may present as nodules as well. Inflammatory causes of nodules are important and relatively common, including granulomatosis with polyangiitis, rheumatoid arthritis, sarcoidosis, amyloidosis, and rounded atelectasis.
To distinguish benign from malignant etiologies, we look for several features of pulmonary nodules on imaging. Larger size, irregular borders, and upper lobe location all increase the likelihood of cancer, whereas solid attenuation and calcification make cancer less likely. One of the most reassuring findings that suggests a benign etiology is lack of growth over a period of surveillance; after 2 years without growth we typically consider a nodule benign.1 And of course, we also consider the patient’s symptoms and risk factors: weight loss, hemoptysis, a history of cigarette smoking or asbestos exposure, or family history of cancer all increase the likelihood of malignancy.
►Dr. Kearney. Given that the differential diagnosis is so broad, how do you think about the next step in evaluating a pulmonary nodule? How do you approach shared decision making with the patient?
►Dr. Wiener. The characteristics of the patient, the nodule, and the circumstances in which the nodule were discovered are all important to consider. Incidental pulmonary nodules are often found on chest imaging. The imaging characteristics of the nodule are important, as are the patient’s risk factors. A similarly appearing nodule can have very different implications if the patient is a never-smoker exposed to endemic fungi, or a long-time smoker enrolled in a lung cancer screening program. Consultation with a pulmonologist is often appropriate.
It’s important to note that we lack high-quality evidence on the optimal strategy to evaluate pulmonary nodules, and there is no single “right answer“ for all patients. For patients with a low risk of malignancy (< 5%-10%)—which comprises the majority of the incidental nodules discovered—we typically favor serial CT surveillance of the nodule over a period of a few years, whereas for patients at high risk of malignancy (> 65%), we favor early surgical resection if the patient is able to tolerate that. For patients with an intermediate risk of malignancy (~5%-65%), we might consider serial CT surveillance, positron emission tomography (PET) scan, or biopsy.1 The American College of Chest Physicians guidelines for pulmonary nodule evaluation recommend discussing with patients the different options and the trade-offs of these options in a shared decision-making process.1
►Dr. Kearney. The patient’s pulmonologist laid out options, including monitoring with serial CT scans, obtaining a PET scan, performing CT-guided needle biopsy, or referring for surgical excision. In this case, the patient elected to undergo CT-guided needle biopsy. Dr. Huang, can you discuss the pathology results?
►Qin Huang, MD, Pathology and Laboratory Medicine, VABHS, and Assistant Professor of Pathology, Harvard Medical School (HMS). The microscopic examination of the needle biopsy of the lung mass revealed rare clusters of atypical cells with crushed cells adjacent to an extensive area of necrosis with scarring. The atypical cells were suspicious for carcinoma. The Gomori methenamine silver (GMS) and periodic acid-Schiff (PAS) stains were negative for common bacterial and fungal microorganisms.
►Dr. Kearney. The tumor board, pulmonologist, and patient decide to move forward with video-assisted excisional biopsy with lymphadenectomy. Dr. Huang, can you interpret the pathology?
►Dr. Huang. Figure 2 showed an hemotoxylin and eosin (H&E)-stained lung resection tissue section with multiple caseating necrotic granulomas. No foreign bodies were identified. There was no evidence of malignancy. The GMS stain revealed a fungal microorganism oval with morphology typical of histoplasma capsulatum (Figure 3).
►Dr. Kearney. What are some of the different ways histoplasmosis can present? Which of these diagnoses fits this patient’s presentation?
►Judy Strymish, MD, Infectious Disease, VABHS, and Assistant Professor of Medicine, HMS. Most patients who inhale histoplasmosis spores develop asymptomatic or self-limited infection that is usually not detected. Patients at risk of symptomatic and clinically relevant disease include those who are immunocompromised, at extremes of ages, or exposed to larger inoculums. Acute pulmonary histoplasmosis can present with cough, shortness of breath, fever, chills, and less commonly, rheumatologic complaints such as erythema nodosum or erythema multiforme. Imaging often shows patchy infiltrates and enlarged mediastinal and hilar lymphadenopathy. Patients can go on to develop subacute or chronic pulmonary disease with focal opacities and mediastinal and hilar lymphadenopathy. Those with chronic disease can have cavitary lesions similar to patients with tuberculosis. Progressive disseminated histoplasmosis can develop in immunocompromised patients and disseminate through the reticuloendothelial system to other organs with the gastrointestinal tract, central nervous system, and adrenal glands.2
Pulmonary nodules are common incidental finding on chest imaging of patients who reside in histoplasmosis endemic regions, and they are often hard to differentiate from malignancies. There are 3 mediastinal manifestations: adenitis, granuloma, and fibrosis. Usually the syndromes are subclinical, but occasionally the nodes cause symptoms by impinging on other structures.2
This patient had a solitary pulmonary nodule with none of the associated features mentioned above. Pathology showed caseating granuloma and confirmed histoplasmosis.
►Dr. Kearney. Given the diagnosis of solitary histoplasmoma, how should this patient be managed?
►Dr. Strymish. The optimal therapy for histoplasmosis depends on the patient’s clinical syndrome. Most infections are self-limited and require no therapy. However, patients who are immunocompromised, exposed to large inoculum, and have progressive disease require antifungal treatment, usually with itraconazole for mild-to-moderate disease and a combination of azole therapy and amphotericin B with extensive disease. Patients with few solitary pulmonary nodules do not benefit from antifungal therapy as the nodule could represent quiescent disease that is unlikely to have clinical impact; in this case, the treatment would be higher risk than the nodule.3
►Dr. Kearney. While the discussion of the diagnosis is interesting, it is also important to acknowledge what the patient went through to arrive at this, an essentially benign diagnosis: 8 months, multiple imaging studies, and 2 invasive diagnostic procedures. Further, the patient had to grapple with the possibility of a diagnosis of cancer. Dr. Wiener, can you talk about the challenges in communicating with patients about pulmonary nodules when cancer is on the differential? What are some of the harms patients face and how can clinicians work to mitigate these harms?
►Dr. Wiener. My colleague Dr. Christopher Slatore of the Portland VA Medical Center and I studied communication about pulmonary nodules in a series of surveys and qualitative studies of patients with pulmonary nodules and the clinicians who take care of them. We found that there seems to be a disconnect between patients’ perceptions of pulmonary nodules and their clinicians, often due to inadequate communication about the nodule. Many clinicians indicated that they do not tell patients about the chance that a nodule may be cancer, because the clinicians know that cancer is unlikely (< 5% of incidentally detected pulmonary nodules turn out to be malignant), and they do not want to alarm patients unnecessarily. However, we found that patients almost immediately wondered about cancer when they learned about their pulmonary nodule, and without hearing explicitly from their clinician that cancer was unlikely, patients tended to overestimate the likelihood of a malignant nodule. Moreover, patients often were not told much about the evaluation plan for the nodule or the rationale for CT surveillance of small nodules instead of biopsy. This uncertainty about the risk of cancer and the plan for evaluating the nodule was difficult for some patients to live with; we found that about one-quarter of patients with a small pulmonary nodule experienced mild-moderate distress during the period of radiographic surveillance. Reassuringly, high-quality patient-clinician communication was associated with lower distress and higher adherence to pulmonary nodule evaluation.4
►Dr. Kearney. The patient was educated about his diagnosis of solitary histoplasmoma. Given that the patient was otherwise well appearing with no complicating factors, he was not treated with antifungal therapy. After an 8-month-long workup, the patient was relieved to receive a diagnosis that excluded cancer and did not require any further treatment. His case provides a good example of how to proceed in the workup of a solitary pulmonary nodule and on the importance of communication and shared decision making with our patients.
1. Gould MK, Donington J, Lynch WR, et al. Evaluation of individuals with pulmonary nodules: when is it lung cancer? Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013;143(suppl 5):e93S-e120S.
2. Azar MM, Hage CA. Clinical perspectives in the diagnosis and management of histoplasmosis. Clin Chest Med. 2017;38(3):403-415.
3. Wheat LJ, Freifeld A, Kleiman MB, et al. Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America. Clin Infect Dis. 2007;45(7):807-825.
4. Slatore CG, Wiener RS. Pulmonary nodules: a small problem for many, severe distress for some, and how to communicate about it. Chest. 2018;153(4):1004-1015.
1. Gould MK, Donington J, Lynch WR, et al. Evaluation of individuals with pulmonary nodules: when is it lung cancer? Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013;143(suppl 5):e93S-e120S.
2. Azar MM, Hage CA. Clinical perspectives in the diagnosis and management of histoplasmosis. Clin Chest Med. 2017;38(3):403-415.
3. Wheat LJ, Freifeld A, Kleiman MB, et al. Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America. Clin Infect Dis. 2007;45(7):807-825.
4. Slatore CG, Wiener RS. Pulmonary nodules: a small problem for many, severe distress for some, and how to communicate about it. Chest. 2018;153(4):1004-1015.
Flu records most active December since 2003
The 2019-2020 flu season took a big jump in severity during the last full week of 2019, according to the Centers for Disease Control and Prevention.
For the week ending Dec. 28, 6.9% of all outpatient visits to health care providers were for influenza-like illness (ILI), the CDC’s influenza division reported Jan. 3. That is up from 5.1% the previous week and is the highest rate recorded in December since 2003. During the flu pandemic season of 2009-2010, the rate peaked in October and dropped to relatively normal levels by the end of November, CDC data show.
This marks the eighth consecutive week that the outpatient visit rate has been at or above the nation’s baseline level of 2.4%, but the data for this week “may in part be influenced by changes in healthcare-seeking behavior that can occur during the holidays,” the CDC suggested.
All those outpatient visits mean that the ILI activity map is getting quite red. Thirty states, as well as the District of Columbia and Puerto Rico, were at the highest level on the CDC’s 1-10 activity scale during the week ending Dec. 28, compared with 20 the week before. Four states were categorized in the “high” range with activity levels of 8 and 9.
There have been approximately 6.4 million flu illnesses so far this season, the CDC estimated, along with 55,000 hospitalizations, although the ILI admission rate of 9.2 per 100,000 population is fairly typical for this time of year.
The week of Dec. 28 also brought reports of five more ILI-related pediatric deaths, which all occurred in the two previous weeks. A total of 27 children have died from the flu so far during the 2019-2020 season, the CDC said.
The 2019-2020 flu season took a big jump in severity during the last full week of 2019, according to the Centers for Disease Control and Prevention.
For the week ending Dec. 28, 6.9% of all outpatient visits to health care providers were for influenza-like illness (ILI), the CDC’s influenza division reported Jan. 3. That is up from 5.1% the previous week and is the highest rate recorded in December since 2003. During the flu pandemic season of 2009-2010, the rate peaked in October and dropped to relatively normal levels by the end of November, CDC data show.
This marks the eighth consecutive week that the outpatient visit rate has been at or above the nation’s baseline level of 2.4%, but the data for this week “may in part be influenced by changes in healthcare-seeking behavior that can occur during the holidays,” the CDC suggested.
All those outpatient visits mean that the ILI activity map is getting quite red. Thirty states, as well as the District of Columbia and Puerto Rico, were at the highest level on the CDC’s 1-10 activity scale during the week ending Dec. 28, compared with 20 the week before. Four states were categorized in the “high” range with activity levels of 8 and 9.
There have been approximately 6.4 million flu illnesses so far this season, the CDC estimated, along with 55,000 hospitalizations, although the ILI admission rate of 9.2 per 100,000 population is fairly typical for this time of year.
The week of Dec. 28 also brought reports of five more ILI-related pediatric deaths, which all occurred in the two previous weeks. A total of 27 children have died from the flu so far during the 2019-2020 season, the CDC said.
The 2019-2020 flu season took a big jump in severity during the last full week of 2019, according to the Centers for Disease Control and Prevention.
For the week ending Dec. 28, 6.9% of all outpatient visits to health care providers were for influenza-like illness (ILI), the CDC’s influenza division reported Jan. 3. That is up from 5.1% the previous week and is the highest rate recorded in December since 2003. During the flu pandemic season of 2009-2010, the rate peaked in October and dropped to relatively normal levels by the end of November, CDC data show.
This marks the eighth consecutive week that the outpatient visit rate has been at or above the nation’s baseline level of 2.4%, but the data for this week “may in part be influenced by changes in healthcare-seeking behavior that can occur during the holidays,” the CDC suggested.
All those outpatient visits mean that the ILI activity map is getting quite red. Thirty states, as well as the District of Columbia and Puerto Rico, were at the highest level on the CDC’s 1-10 activity scale during the week ending Dec. 28, compared with 20 the week before. Four states were categorized in the “high” range with activity levels of 8 and 9.
There have been approximately 6.4 million flu illnesses so far this season, the CDC estimated, along with 55,000 hospitalizations, although the ILI admission rate of 9.2 per 100,000 population is fairly typical for this time of year.
The week of Dec. 28 also brought reports of five more ILI-related pediatric deaths, which all occurred in the two previous weeks. A total of 27 children have died from the flu so far during the 2019-2020 season, the CDC said.
Despite PCV, pediatric asthma patients face pneumococcal risks
Even on-time pneumococcal vaccines don’t completely protect children with asthma from developing invasive pneumococcal disease, a meta-analysis has determined.
Despite receiving pneumococcal valent 7, 10, or 13, children with asthma were still almost twice as likely to develop the disease as were children without asthma, Jose A. Castro-Rodriguez, MD, PhD, and colleagues reported in Pediatrics (2020 Jan. doi: 10.1542/peds.2019-1200). None of the studies included rates for those who received the pneumococcal polysaccharide vaccine (PPSV23).
“For the first time, this meta-analysis reveals 90% increased odds of invasive pneumococcal disease (IPD) among [vaccinated] children with asthma,” said Dr. Castro-Rodriguez, of Pontificia Universidad Católica de Chile, Santiago, and colleagues. “If confirmed, these findings will bear clinical and public health importance,” they noted, because guidelines now recommend PPSV23 after age 2 in children with asthma only if they’re treated with prolonged high-dose oral corticosteroids.
However, because the analysis comprised only four studies, the authors cautioned that the results aren’t enough to justify changes to practice recommendations.
Asthma treatment with inhaled corticosteroids (ICS) may be driving the increased risk, Dr. Castro-Rodriguez and his coauthors suggested. ICS deposition in the oropharynx could boost oropharyngeal candidiasis risk by weakening the mucosal immune response, the researchers noted. And that same process may be at work with Streptococcus pneumoniae.
A prior study found that children with asthma who received ICS for at least 1 month were almost four times more likely to have oropharyngeal colonization by S. pneumoniae as were those who didn’t get the drugs. Thus, a higher carrier rate of S. pneumoniae in the oropharynx, along with asthma’s impaired airway clearance, might increase the risk of pneumococcal diseases, the investigators explained.
Dr. Castro-Rodriguez and colleagues analyzed four studies with more than 4,000 cases and controls, and about 26 million person-years of follow-up.
Rates and risks of IPD in the four studies were as follows:
- Among those with IPD, 27% had asthma, with 18% of those without, an adjusted odds ratio (aOR) of 1.8.
- In a European of patients who received at least 3 doses of PCV7, IPD rates per 100,000 person-years for 5-year-olds were 11.6 for children with asthma and 7.3 for those without. For 5- to 17-year-olds with and without asthma, the rates were 2.3 and 1.6, respectively.
- In 2001, a Korean found an aOR of 2.08 for IPD in children with asthma, compared with those without. In 2010, the aOR was 3.26. No vaccine types were reported in the study.
- of IPD were 3.7 per 100,000 person-years for children with asthma, compared with 2.5 for healthy controls – an adjusted relative risk of 1.5.
The pooled estimate of the four studies revealed an aOR of 1.9 for IPD among children with asthma, compared with those without, Dr. Castro-Rodriguez and his team concluded.
None of the studies reported hospital admissions, mortality, length of hospital stay, intensive care admission, invasive respiratory support, or additional medication use.
One, however, did find asthma severity was significantly associated with increasing IPD treatment costs per 100,000 person-years: $72,581 for healthy controls, compared with $100,020 for children with mild asthma, $172,002 for moderate asthma, and $638,452 for severe asthma.
In addition, treating all-cause pneumonia was more expensive in children with asthma. For all-cause pneumonia, the researchers found that estimated costs per 100,000 person-years for mild, moderate, and severe asthma were $7.5 million, $14.6 million, and $46.8 million, respectively, compared with $1.7 million for healthy controls.
The authors had no relevant financial disclosures.
SOURCE: Castro-Rodriguez J et al. Pediatrics. 2020 Jan. doi: 10.1542/peds.2019-1200.
The meta-analysis contains some important lessons for pediatricians, Tina Q. Tan, MD, wrote in an accompanying editorial.
“First, asthma remains a risk factor for invasive pneumococcal disease and pneumococcal pneumonia, even in the era of widespread use of PCV,” Dr. Tan noted. “Second, it is important that all patients, especially those with asthma, are receiving their vaccinations on time and, most notably, are up to date on their pneumococcal vaccinations. This will provide the best protection against pneumococcal infections and their complications for pediatric patients with asthma.”
Pneumococcal conjugate vaccines (PCV) have impressively decreased rates of invasive pneumococcal disease (IPD) and pneumonia in children in the United States, Dr. Tan explained. Overall, incidence dropped from 95 cases per 100,000 person-years in 1998 to only 9 cases per 100,000 in 2016.
In addition, the incidence of IPD caused by 13-valent PCV serotypes fell, from 88 cases per 100,000 in 1998 to 2 cases per 100,000 in 2016.
The threat is not over, however.
“IPD still remains a leading cause of morbidity and mortality in the United States and worldwide,” Dr. Tan cautioned. “In 2017, the CDC’s Active Bacterial Core surveillance network reported that there were 31,000 cases of IPD (meningitis, bacteremia, and bacteremic pneumonia) and 3,590 deaths, of which 147 cases and 9 deaths occurred in children younger than 5 years of age.”
Dr. Tan is a professor of pediatrics at Northwestern University, Chicago. Her comments appear in Pediatrics 2020 Jan. doi: 10.1542/peds.2019-3360 .
The meta-analysis contains some important lessons for pediatricians, Tina Q. Tan, MD, wrote in an accompanying editorial.
“First, asthma remains a risk factor for invasive pneumococcal disease and pneumococcal pneumonia, even in the era of widespread use of PCV,” Dr. Tan noted. “Second, it is important that all patients, especially those with asthma, are receiving their vaccinations on time and, most notably, are up to date on their pneumococcal vaccinations. This will provide the best protection against pneumococcal infections and their complications for pediatric patients with asthma.”
Pneumococcal conjugate vaccines (PCV) have impressively decreased rates of invasive pneumococcal disease (IPD) and pneumonia in children in the United States, Dr. Tan explained. Overall, incidence dropped from 95 cases per 100,000 person-years in 1998 to only 9 cases per 100,000 in 2016.
In addition, the incidence of IPD caused by 13-valent PCV serotypes fell, from 88 cases per 100,000 in 1998 to 2 cases per 100,000 in 2016.
The threat is not over, however.
“IPD still remains a leading cause of morbidity and mortality in the United States and worldwide,” Dr. Tan cautioned. “In 2017, the CDC’s Active Bacterial Core surveillance network reported that there were 31,000 cases of IPD (meningitis, bacteremia, and bacteremic pneumonia) and 3,590 deaths, of which 147 cases and 9 deaths occurred in children younger than 5 years of age.”
Dr. Tan is a professor of pediatrics at Northwestern University, Chicago. Her comments appear in Pediatrics 2020 Jan. doi: 10.1542/peds.2019-3360 .
The meta-analysis contains some important lessons for pediatricians, Tina Q. Tan, MD, wrote in an accompanying editorial.
“First, asthma remains a risk factor for invasive pneumococcal disease and pneumococcal pneumonia, even in the era of widespread use of PCV,” Dr. Tan noted. “Second, it is important that all patients, especially those with asthma, are receiving their vaccinations on time and, most notably, are up to date on their pneumococcal vaccinations. This will provide the best protection against pneumococcal infections and their complications for pediatric patients with asthma.”
Pneumococcal conjugate vaccines (PCV) have impressively decreased rates of invasive pneumococcal disease (IPD) and pneumonia in children in the United States, Dr. Tan explained. Overall, incidence dropped from 95 cases per 100,000 person-years in 1998 to only 9 cases per 100,000 in 2016.
In addition, the incidence of IPD caused by 13-valent PCV serotypes fell, from 88 cases per 100,000 in 1998 to 2 cases per 100,000 in 2016.
The threat is not over, however.
“IPD still remains a leading cause of morbidity and mortality in the United States and worldwide,” Dr. Tan cautioned. “In 2017, the CDC’s Active Bacterial Core surveillance network reported that there were 31,000 cases of IPD (meningitis, bacteremia, and bacteremic pneumonia) and 3,590 deaths, of which 147 cases and 9 deaths occurred in children younger than 5 years of age.”
Dr. Tan is a professor of pediatrics at Northwestern University, Chicago. Her comments appear in Pediatrics 2020 Jan. doi: 10.1542/peds.2019-3360 .
Even on-time pneumococcal vaccines don’t completely protect children with asthma from developing invasive pneumococcal disease, a meta-analysis has determined.
Despite receiving pneumococcal valent 7, 10, or 13, children with asthma were still almost twice as likely to develop the disease as were children without asthma, Jose A. Castro-Rodriguez, MD, PhD, and colleagues reported in Pediatrics (2020 Jan. doi: 10.1542/peds.2019-1200). None of the studies included rates for those who received the pneumococcal polysaccharide vaccine (PPSV23).
“For the first time, this meta-analysis reveals 90% increased odds of invasive pneumococcal disease (IPD) among [vaccinated] children with asthma,” said Dr. Castro-Rodriguez, of Pontificia Universidad Católica de Chile, Santiago, and colleagues. “If confirmed, these findings will bear clinical and public health importance,” they noted, because guidelines now recommend PPSV23 after age 2 in children with asthma only if they’re treated with prolonged high-dose oral corticosteroids.
However, because the analysis comprised only four studies, the authors cautioned that the results aren’t enough to justify changes to practice recommendations.
Asthma treatment with inhaled corticosteroids (ICS) may be driving the increased risk, Dr. Castro-Rodriguez and his coauthors suggested. ICS deposition in the oropharynx could boost oropharyngeal candidiasis risk by weakening the mucosal immune response, the researchers noted. And that same process may be at work with Streptococcus pneumoniae.
A prior study found that children with asthma who received ICS for at least 1 month were almost four times more likely to have oropharyngeal colonization by S. pneumoniae as were those who didn’t get the drugs. Thus, a higher carrier rate of S. pneumoniae in the oropharynx, along with asthma’s impaired airway clearance, might increase the risk of pneumococcal diseases, the investigators explained.
Dr. Castro-Rodriguez and colleagues analyzed four studies with more than 4,000 cases and controls, and about 26 million person-years of follow-up.
Rates and risks of IPD in the four studies were as follows:
- Among those with IPD, 27% had asthma, with 18% of those without, an adjusted odds ratio (aOR) of 1.8.
- In a European of patients who received at least 3 doses of PCV7, IPD rates per 100,000 person-years for 5-year-olds were 11.6 for children with asthma and 7.3 for those without. For 5- to 17-year-olds with and without asthma, the rates were 2.3 and 1.6, respectively.
- In 2001, a Korean found an aOR of 2.08 for IPD in children with asthma, compared with those without. In 2010, the aOR was 3.26. No vaccine types were reported in the study.
- of IPD were 3.7 per 100,000 person-years for children with asthma, compared with 2.5 for healthy controls – an adjusted relative risk of 1.5.
The pooled estimate of the four studies revealed an aOR of 1.9 for IPD among children with asthma, compared with those without, Dr. Castro-Rodriguez and his team concluded.
None of the studies reported hospital admissions, mortality, length of hospital stay, intensive care admission, invasive respiratory support, or additional medication use.
One, however, did find asthma severity was significantly associated with increasing IPD treatment costs per 100,000 person-years: $72,581 for healthy controls, compared with $100,020 for children with mild asthma, $172,002 for moderate asthma, and $638,452 for severe asthma.
In addition, treating all-cause pneumonia was more expensive in children with asthma. For all-cause pneumonia, the researchers found that estimated costs per 100,000 person-years for mild, moderate, and severe asthma were $7.5 million, $14.6 million, and $46.8 million, respectively, compared with $1.7 million for healthy controls.
The authors had no relevant financial disclosures.
SOURCE: Castro-Rodriguez J et al. Pediatrics. 2020 Jan. doi: 10.1542/peds.2019-1200.
Even on-time pneumococcal vaccines don’t completely protect children with asthma from developing invasive pneumococcal disease, a meta-analysis has determined.
Despite receiving pneumococcal valent 7, 10, or 13, children with asthma were still almost twice as likely to develop the disease as were children without asthma, Jose A. Castro-Rodriguez, MD, PhD, and colleagues reported in Pediatrics (2020 Jan. doi: 10.1542/peds.2019-1200). None of the studies included rates for those who received the pneumococcal polysaccharide vaccine (PPSV23).
“For the first time, this meta-analysis reveals 90% increased odds of invasive pneumococcal disease (IPD) among [vaccinated] children with asthma,” said Dr. Castro-Rodriguez, of Pontificia Universidad Católica de Chile, Santiago, and colleagues. “If confirmed, these findings will bear clinical and public health importance,” they noted, because guidelines now recommend PPSV23 after age 2 in children with asthma only if they’re treated with prolonged high-dose oral corticosteroids.
However, because the analysis comprised only four studies, the authors cautioned that the results aren’t enough to justify changes to practice recommendations.
Asthma treatment with inhaled corticosteroids (ICS) may be driving the increased risk, Dr. Castro-Rodriguez and his coauthors suggested. ICS deposition in the oropharynx could boost oropharyngeal candidiasis risk by weakening the mucosal immune response, the researchers noted. And that same process may be at work with Streptococcus pneumoniae.
A prior study found that children with asthma who received ICS for at least 1 month were almost four times more likely to have oropharyngeal colonization by S. pneumoniae as were those who didn’t get the drugs. Thus, a higher carrier rate of S. pneumoniae in the oropharynx, along with asthma’s impaired airway clearance, might increase the risk of pneumococcal diseases, the investigators explained.
Dr. Castro-Rodriguez and colleagues analyzed four studies with more than 4,000 cases and controls, and about 26 million person-years of follow-up.
Rates and risks of IPD in the four studies were as follows:
- Among those with IPD, 27% had asthma, with 18% of those without, an adjusted odds ratio (aOR) of 1.8.
- In a European of patients who received at least 3 doses of PCV7, IPD rates per 100,000 person-years for 5-year-olds were 11.6 for children with asthma and 7.3 for those without. For 5- to 17-year-olds with and without asthma, the rates were 2.3 and 1.6, respectively.
- In 2001, a Korean found an aOR of 2.08 for IPD in children with asthma, compared with those without. In 2010, the aOR was 3.26. No vaccine types were reported in the study.
- of IPD were 3.7 per 100,000 person-years for children with asthma, compared with 2.5 for healthy controls – an adjusted relative risk of 1.5.
The pooled estimate of the four studies revealed an aOR of 1.9 for IPD among children with asthma, compared with those without, Dr. Castro-Rodriguez and his team concluded.
None of the studies reported hospital admissions, mortality, length of hospital stay, intensive care admission, invasive respiratory support, or additional medication use.
One, however, did find asthma severity was significantly associated with increasing IPD treatment costs per 100,000 person-years: $72,581 for healthy controls, compared with $100,020 for children with mild asthma, $172,002 for moderate asthma, and $638,452 for severe asthma.
In addition, treating all-cause pneumonia was more expensive in children with asthma. For all-cause pneumonia, the researchers found that estimated costs per 100,000 person-years for mild, moderate, and severe asthma were $7.5 million, $14.6 million, and $46.8 million, respectively, compared with $1.7 million for healthy controls.
The authors had no relevant financial disclosures.
SOURCE: Castro-Rodriguez J et al. Pediatrics. 2020 Jan. doi: 10.1542/peds.2019-1200.
FROM PEDIATRICS
FDA targets flavored cartridge-based e-cigarettes, but says it is not a ‘ban’
but states it is not a “ban.”
On Jan. 2, the agency issued enforcement guidance alerting companies that manufacture, distribute, and sell unauthorized flavored cartridge-based e-cigarettes within the next 30 days will risk FDA enforcement action.
FDA has had the authority to require premarket authorization of all e-cigarettes and other electronic nicotine delivery systems (ENDS) since August 2016, but thus far has exercised enforcement discretion regarding the need for premarket authorization for these types of products.
“By prioritizing enforcement against the products that are most widely used by children, our action today seeks to strike the right public health balance by maintaining e-cigarettes as a potential off-ramp for adults using combustible tobacco while ensuring these products don’t provide an on-ramp to nicotine addiction for our youth,” Department of Health & Human Services Secretary Alex Azar said in a statement.
The action comes in the wake of more than 2,500 vaping-related injuries being reported, including more than 50 deaths associated with vaping reported by the Centers for Disease Control and Prevention (although many are related to the use of tetrahydrocannabinol [THC] within vaping products) and a continued rise in youth use of e-cigarettes noted in government surveys.
The agency noted in a Jan. 2 statement announcing the enforcement action that, to date, no ENDS products have received a premarket authorization, “meaning that all ENDS products currently on the market are considered illegally marketed and are subject to enforcement, at any time, in the FDA’s discretion.”
FDA said it is prioritizing enforcement in 30 days against:
- Any flavored, cartridge-based ENDS product, other than those with a tobacco or menthol flavoring.
- All other ENDS products for which manufacturers are failing to take adequate measures to prevent access by minors.
- Any ENDS product that is targeted to minors or is likely to promote use by minors.
In the last category, this might include labeling or advertising resembling “kid-friendly food and drinks such as juice boxes or kid-friendly cereal; products marketed directly to minors by promoting ease of concealing the product or disguising it as another product; and products marketed with characters designed to appeal to youth,” according to the FDA statement.
As of May 12, FDA also will prioritize enforcement against any ENDS product for which the manufacturer has not submitted a premarket application. The agency will continue to exercise enforcement discretion for up to 1 year on these products if an application has been submitted, pending the review of that application.
“By not prioritizing enforcement against other flavored ENDS products in the same way as flavored cartridge-based ENDS products, the FDA has attempted to balance the public health concerns related to youth use of ENDS products with consideration regarding addicted adult cigarette smokers who may try to use ENDS products to transition away from combustible tobacco products,” the agency stated, adding that cartridge-based ENDS products are most commonly used among youth.
The FDA statement noted that the enforcement priorities outlined in the guidance document were not a “ban” on flavored or cartridge-based ENDS, noting the agency “has already accepted and begun review of several premarket applications for flavored ENDS products through the pathway that Congress established in the Tobacco Control Act. ... If a company can demonstrate to the FDA that a specific product meets the applicable standard set forth by Congress, including considering how the marketing of the product may affect youth initiation and use, then the FDA could authorize that product for sale.”
“Coupled with the recently signed legislation increasing the minimum age of sale of tobacco to 21, we believe this policy balances the urgency with which we must address the public health threat of youth use of e-cigarette products with the potential role that e-cigarettes may play in helping adult smokers transition completely away from combustible tobacco to a potentially less risky form of nicotine delivery,” FDA Commissioner Stephen Hahn, MD, said in a statement. “While we expect that responsible members of industry will comply with premarket requirements, we’re ready to take action against any unauthorized e-cigarette products as outlined in our priorities. We’ll also closely monitor the use rates of all e-cigarette products and take additional steps to address youth use as necessary.”
The American Medical Association criticized the action as not going far enough, even though it was a step in the right direction.
“The AMA is disappointed that menthol flavors, one of the most popular, will still be allowed, and that flavored e-liquids will remain on the market, leaving young people with easy access to alternative flavored e-cigarette products,” AMA President Patrice A. Harris, MD, said in a statement. “If we are serious about tackling this epidemic and keeping these harmful products out of the hands of young people, a total ban on all flavored e-cigarettes, in all forms and at all locations, is prudent and urgently needed. We are pleased the administration committed today to closely monitoring the situation and trends in e-cigarette use among young people, and to taking further action if needed.”
but states it is not a “ban.”
On Jan. 2, the agency issued enforcement guidance alerting companies that manufacture, distribute, and sell unauthorized flavored cartridge-based e-cigarettes within the next 30 days will risk FDA enforcement action.
FDA has had the authority to require premarket authorization of all e-cigarettes and other electronic nicotine delivery systems (ENDS) since August 2016, but thus far has exercised enforcement discretion regarding the need for premarket authorization for these types of products.
“By prioritizing enforcement against the products that are most widely used by children, our action today seeks to strike the right public health balance by maintaining e-cigarettes as a potential off-ramp for adults using combustible tobacco while ensuring these products don’t provide an on-ramp to nicotine addiction for our youth,” Department of Health & Human Services Secretary Alex Azar said in a statement.
The action comes in the wake of more than 2,500 vaping-related injuries being reported, including more than 50 deaths associated with vaping reported by the Centers for Disease Control and Prevention (although many are related to the use of tetrahydrocannabinol [THC] within vaping products) and a continued rise in youth use of e-cigarettes noted in government surveys.
The agency noted in a Jan. 2 statement announcing the enforcement action that, to date, no ENDS products have received a premarket authorization, “meaning that all ENDS products currently on the market are considered illegally marketed and are subject to enforcement, at any time, in the FDA’s discretion.”
FDA said it is prioritizing enforcement in 30 days against:
- Any flavored, cartridge-based ENDS product, other than those with a tobacco or menthol flavoring.
- All other ENDS products for which manufacturers are failing to take adequate measures to prevent access by minors.
- Any ENDS product that is targeted to minors or is likely to promote use by minors.
In the last category, this might include labeling or advertising resembling “kid-friendly food and drinks such as juice boxes or kid-friendly cereal; products marketed directly to minors by promoting ease of concealing the product or disguising it as another product; and products marketed with characters designed to appeal to youth,” according to the FDA statement.
As of May 12, FDA also will prioritize enforcement against any ENDS product for which the manufacturer has not submitted a premarket application. The agency will continue to exercise enforcement discretion for up to 1 year on these products if an application has been submitted, pending the review of that application.
“By not prioritizing enforcement against other flavored ENDS products in the same way as flavored cartridge-based ENDS products, the FDA has attempted to balance the public health concerns related to youth use of ENDS products with consideration regarding addicted adult cigarette smokers who may try to use ENDS products to transition away from combustible tobacco products,” the agency stated, adding that cartridge-based ENDS products are most commonly used among youth.
The FDA statement noted that the enforcement priorities outlined in the guidance document were not a “ban” on flavored or cartridge-based ENDS, noting the agency “has already accepted and begun review of several premarket applications for flavored ENDS products through the pathway that Congress established in the Tobacco Control Act. ... If a company can demonstrate to the FDA that a specific product meets the applicable standard set forth by Congress, including considering how the marketing of the product may affect youth initiation and use, then the FDA could authorize that product for sale.”
“Coupled with the recently signed legislation increasing the minimum age of sale of tobacco to 21, we believe this policy balances the urgency with which we must address the public health threat of youth use of e-cigarette products with the potential role that e-cigarettes may play in helping adult smokers transition completely away from combustible tobacco to a potentially less risky form of nicotine delivery,” FDA Commissioner Stephen Hahn, MD, said in a statement. “While we expect that responsible members of industry will comply with premarket requirements, we’re ready to take action against any unauthorized e-cigarette products as outlined in our priorities. We’ll also closely monitor the use rates of all e-cigarette products and take additional steps to address youth use as necessary.”
The American Medical Association criticized the action as not going far enough, even though it was a step in the right direction.
“The AMA is disappointed that menthol flavors, one of the most popular, will still be allowed, and that flavored e-liquids will remain on the market, leaving young people with easy access to alternative flavored e-cigarette products,” AMA President Patrice A. Harris, MD, said in a statement. “If we are serious about tackling this epidemic and keeping these harmful products out of the hands of young people, a total ban on all flavored e-cigarettes, in all forms and at all locations, is prudent and urgently needed. We are pleased the administration committed today to closely monitoring the situation and trends in e-cigarette use among young people, and to taking further action if needed.”
but states it is not a “ban.”
On Jan. 2, the agency issued enforcement guidance alerting companies that manufacture, distribute, and sell unauthorized flavored cartridge-based e-cigarettes within the next 30 days will risk FDA enforcement action.
FDA has had the authority to require premarket authorization of all e-cigarettes and other electronic nicotine delivery systems (ENDS) since August 2016, but thus far has exercised enforcement discretion regarding the need for premarket authorization for these types of products.
“By prioritizing enforcement against the products that are most widely used by children, our action today seeks to strike the right public health balance by maintaining e-cigarettes as a potential off-ramp for adults using combustible tobacco while ensuring these products don’t provide an on-ramp to nicotine addiction for our youth,” Department of Health & Human Services Secretary Alex Azar said in a statement.
The action comes in the wake of more than 2,500 vaping-related injuries being reported, including more than 50 deaths associated with vaping reported by the Centers for Disease Control and Prevention (although many are related to the use of tetrahydrocannabinol [THC] within vaping products) and a continued rise in youth use of e-cigarettes noted in government surveys.
The agency noted in a Jan. 2 statement announcing the enforcement action that, to date, no ENDS products have received a premarket authorization, “meaning that all ENDS products currently on the market are considered illegally marketed and are subject to enforcement, at any time, in the FDA’s discretion.”
FDA said it is prioritizing enforcement in 30 days against:
- Any flavored, cartridge-based ENDS product, other than those with a tobacco or menthol flavoring.
- All other ENDS products for which manufacturers are failing to take adequate measures to prevent access by minors.
- Any ENDS product that is targeted to minors or is likely to promote use by minors.
In the last category, this might include labeling or advertising resembling “kid-friendly food and drinks such as juice boxes or kid-friendly cereal; products marketed directly to minors by promoting ease of concealing the product or disguising it as another product; and products marketed with characters designed to appeal to youth,” according to the FDA statement.
As of May 12, FDA also will prioritize enforcement against any ENDS product for which the manufacturer has not submitted a premarket application. The agency will continue to exercise enforcement discretion for up to 1 year on these products if an application has been submitted, pending the review of that application.
“By not prioritizing enforcement against other flavored ENDS products in the same way as flavored cartridge-based ENDS products, the FDA has attempted to balance the public health concerns related to youth use of ENDS products with consideration regarding addicted adult cigarette smokers who may try to use ENDS products to transition away from combustible tobacco products,” the agency stated, adding that cartridge-based ENDS products are most commonly used among youth.
The FDA statement noted that the enforcement priorities outlined in the guidance document were not a “ban” on flavored or cartridge-based ENDS, noting the agency “has already accepted and begun review of several premarket applications for flavored ENDS products through the pathway that Congress established in the Tobacco Control Act. ... If a company can demonstrate to the FDA that a specific product meets the applicable standard set forth by Congress, including considering how the marketing of the product may affect youth initiation and use, then the FDA could authorize that product for sale.”
“Coupled with the recently signed legislation increasing the minimum age of sale of tobacco to 21, we believe this policy balances the urgency with which we must address the public health threat of youth use of e-cigarette products with the potential role that e-cigarettes may play in helping adult smokers transition completely away from combustible tobacco to a potentially less risky form of nicotine delivery,” FDA Commissioner Stephen Hahn, MD, said in a statement. “While we expect that responsible members of industry will comply with premarket requirements, we’re ready to take action against any unauthorized e-cigarette products as outlined in our priorities. We’ll also closely monitor the use rates of all e-cigarette products and take additional steps to address youth use as necessary.”
The American Medical Association criticized the action as not going far enough, even though it was a step in the right direction.
“The AMA is disappointed that menthol flavors, one of the most popular, will still be allowed, and that flavored e-liquids will remain on the market, leaving young people with easy access to alternative flavored e-cigarette products,” AMA President Patrice A. Harris, MD, said in a statement. “If we are serious about tackling this epidemic and keeping these harmful products out of the hands of young people, a total ban on all flavored e-cigarettes, in all forms and at all locations, is prudent and urgently needed. We are pleased the administration committed today to closely monitoring the situation and trends in e-cigarette use among young people, and to taking further action if needed.”
Dual e-cigarette and combustible tobacco use compound respiratory disease risk
according to recent longitudinal analysis published in the American Journal of Preventive Medicine.
E-cigarettes have been promoted as a safer alternative to combustible tobacco, and until recently, there has been little and conflicting evidence by which to test this hypothesis. This study conducted by Dharma N. Bhatta, PhD, and Stanton A. Glantz, PhD, of the Center for Tobacco Control Research and Education at the University of California, San Francisco, is one of the first longitudinal examinations of e-cigarette use and controlling for combustible tobacco use.
Dr. Bhatta and Dr. Glantz performed a multivariable, logistic regression analysis of adults enrolled in the nationally representative, population-based, longitudinal Population Assessment of Tobacco and Health study. The researchers analyzed the tobacco use of adults in the study in three waves, following them through wave 1 (September 2013 to December 2014), wave 2 (October 2014 to October 2015), and wave 3 (October 2015 to October 2016), analyzing the data between 2018 and 2019. Overall, wave 1 began with 32,320 participants, and 15.1% of adults reported respiratory disease at baseline.
Lung or respiratory disease was assessed by asking participants whether they had been told by a health professional that they had chronic obstructive pulmonary disease, chronic bronchitis, emphysema, or asthma. The researchers defined e-cigarette and combustible tobacco use as participants who never, currently, or formerly used e-cigarettes or smoked combustible tobacco. Participants who indicated they used e-cigarettes or combustible tobacco frequently or infrequently were placed in the current-user group, while past users were those participants who said they used to, but no longer use e-cigarettes or combustible tobacco.
The results showed former e-cigarette use (adjusted odds ratio, 1.34; 95% confidence interval, 1.23-1.46) and current e-cigarette use (aOR, 1.32; 95% CI, 1.17-1.49) were associated with an increased risk of having incident respiratory disease.
The data showed a not unexpected statistically significant association between former combustible tobacco use (aOR, 1.29; 95% CI, 1.14-1.47) as well as current combustible tobacco use (aOR, 1.61; 95% CI, 1.42-1.82) and incident respiratory disease risk.
There was a statistically significant association between respiratory disease and former or current e-cigarette use for adults who did not have respiratory disease at baseline, after adjusting for factors such as current combustible tobacco use, clinical variables, and demographic differences. Participants in wave 1 who reported former (aOR, 1.31; 95% CI, 1.07-1.60) or current e-cigarette use (aOR, 1.29; 95% CI, 1.03-1.61) had a significantly higher risk of developing incident respiratory disease in subsequent waves. There was also a statistically significant association between use of combustible tobacco and subsequent respiratory disease in later waves of the study (aOR, 2.56; 95% CI, 1.92-3.41), which the researchers noted was independent of the usual risks associated with combustible tobacco.
The investigators also looked at the link between dual use of e-cigarettes and combustible tobacco and respiratory disease risk. “The much more common pattern is dual use, in which an e-cigarette user continues to smoke combusted tobacco products at the same time (93.7% of e-cigarette users at wave 2 and 91.2% at wave 3 also used combustible tobacco; 73.3% of e-cigarette users at wave 2 and 64.9% at wave 3 also smoked cigarettes),” they wrote.
The odds of developing respiratory disease for participants who used both e-cigarettes and combustible tobacco were 3.30, compared with a participant who never used e-cigarettes, with similar results seen when comparing e-cigarettes and cigarettes.
“Although switching from combustible tobacco, including cigarettes, to e-cigarettes theoretically could reduce the risk of developing respiratory disease, current evidence indicates a high prevalence of dual use, which is associated with in-creased risk beyond combustible tobacco use,” the investigators wrote.
Harold J. Farber, MD, FCCP, professor of pediatrics in the pulmonary section at Baylor College of Medicine and Texas Children’s Hospital, both in Houston, said in an interview that the increased respiratory risk among dual users, who are likely using e-cigarettes and combustible tobacco together as a way to quit smoking, is particularly concerning.
“There is substantial reason to be concerned about efficacy of electronic cigarette products. Real-world observational studies have shown that, on average, tobacco smokers who use electronic cigarettes are less likely to stop smoking than those who do not use electronic cigarettes,” he said. “People who have stopped tobacco smoking but use electronic cigarettes are more likely to relapse to tobacco smoking than those who do not use electronic cigarettes.”
Dr. Farber noted that there are other Food and Drug Administration–approved medications for treating tobacco addiction. In addition, the World Health Organization, American Medical Association, Centers for Disease Control and Prevention, and FDA have all advised that e-cigarettes should not be used as smoking cessation aids, he said, especially in light of current outbreak of life-threatening e-cigarette and vaping lung injuries currently being investigated by the CDC and FDA.
“These study results suggest that the CDC reports of e-cigarette, or vaping, product use–associated lung injury are likely to be just the tip of the iceberg,” he said. “Although the CDC has identified vitamin E acetate–containing products as an important culprit, it is unlikely to be the only one. There are many substances in the emissions of e-cigarettes that have known irritant and/or toxic effects on the airways.”
Dr. Bhatta and Dr. Glantz acknowledged several limitations in their analysis, including the possibility of recall bias, not distinguishing between nondaily and daily e-cigarette or combustible tobacco use, and combining respiratory conditions together to achieve adequate power. The study shows an association, but the mechanism by which e-cigarettes may contribute to the development of lung disease remains under investigation.
This study was supported by grants from the National Institute on Drug Abuse; the National Cancer Institute; the FDA Center for Tobacco Products; the National Heart, Lung, and Blood Institute; and the University of California, San Francisco Helen Diller Family Comprehensive Cancer Center Global Cancer Program. Dr. Bhatta and Dr. Glantz reported no relevant conflicts of interest.
SOURCE: Bhatta DN, Glantz SA. Am J Prev Med. 2019 Dec 16. doi: 10.1016/j.amepre.2019.07.028.
according to recent longitudinal analysis published in the American Journal of Preventive Medicine.
E-cigarettes have been promoted as a safer alternative to combustible tobacco, and until recently, there has been little and conflicting evidence by which to test this hypothesis. This study conducted by Dharma N. Bhatta, PhD, and Stanton A. Glantz, PhD, of the Center for Tobacco Control Research and Education at the University of California, San Francisco, is one of the first longitudinal examinations of e-cigarette use and controlling for combustible tobacco use.
Dr. Bhatta and Dr. Glantz performed a multivariable, logistic regression analysis of adults enrolled in the nationally representative, population-based, longitudinal Population Assessment of Tobacco and Health study. The researchers analyzed the tobacco use of adults in the study in three waves, following them through wave 1 (September 2013 to December 2014), wave 2 (October 2014 to October 2015), and wave 3 (October 2015 to October 2016), analyzing the data between 2018 and 2019. Overall, wave 1 began with 32,320 participants, and 15.1% of adults reported respiratory disease at baseline.
Lung or respiratory disease was assessed by asking participants whether they had been told by a health professional that they had chronic obstructive pulmonary disease, chronic bronchitis, emphysema, or asthma. The researchers defined e-cigarette and combustible tobacco use as participants who never, currently, or formerly used e-cigarettes or smoked combustible tobacco. Participants who indicated they used e-cigarettes or combustible tobacco frequently or infrequently were placed in the current-user group, while past users were those participants who said they used to, but no longer use e-cigarettes or combustible tobacco.
The results showed former e-cigarette use (adjusted odds ratio, 1.34; 95% confidence interval, 1.23-1.46) and current e-cigarette use (aOR, 1.32; 95% CI, 1.17-1.49) were associated with an increased risk of having incident respiratory disease.
The data showed a not unexpected statistically significant association between former combustible tobacco use (aOR, 1.29; 95% CI, 1.14-1.47) as well as current combustible tobacco use (aOR, 1.61; 95% CI, 1.42-1.82) and incident respiratory disease risk.
There was a statistically significant association between respiratory disease and former or current e-cigarette use for adults who did not have respiratory disease at baseline, after adjusting for factors such as current combustible tobacco use, clinical variables, and demographic differences. Participants in wave 1 who reported former (aOR, 1.31; 95% CI, 1.07-1.60) or current e-cigarette use (aOR, 1.29; 95% CI, 1.03-1.61) had a significantly higher risk of developing incident respiratory disease in subsequent waves. There was also a statistically significant association between use of combustible tobacco and subsequent respiratory disease in later waves of the study (aOR, 2.56; 95% CI, 1.92-3.41), which the researchers noted was independent of the usual risks associated with combustible tobacco.
The investigators also looked at the link between dual use of e-cigarettes and combustible tobacco and respiratory disease risk. “The much more common pattern is dual use, in which an e-cigarette user continues to smoke combusted tobacco products at the same time (93.7% of e-cigarette users at wave 2 and 91.2% at wave 3 also used combustible tobacco; 73.3% of e-cigarette users at wave 2 and 64.9% at wave 3 also smoked cigarettes),” they wrote.
The odds of developing respiratory disease for participants who used both e-cigarettes and combustible tobacco were 3.30, compared with a participant who never used e-cigarettes, with similar results seen when comparing e-cigarettes and cigarettes.
“Although switching from combustible tobacco, including cigarettes, to e-cigarettes theoretically could reduce the risk of developing respiratory disease, current evidence indicates a high prevalence of dual use, which is associated with in-creased risk beyond combustible tobacco use,” the investigators wrote.
Harold J. Farber, MD, FCCP, professor of pediatrics in the pulmonary section at Baylor College of Medicine and Texas Children’s Hospital, both in Houston, said in an interview that the increased respiratory risk among dual users, who are likely using e-cigarettes and combustible tobacco together as a way to quit smoking, is particularly concerning.
“There is substantial reason to be concerned about efficacy of electronic cigarette products. Real-world observational studies have shown that, on average, tobacco smokers who use electronic cigarettes are less likely to stop smoking than those who do not use electronic cigarettes,” he said. “People who have stopped tobacco smoking but use electronic cigarettes are more likely to relapse to tobacco smoking than those who do not use electronic cigarettes.”
Dr. Farber noted that there are other Food and Drug Administration–approved medications for treating tobacco addiction. In addition, the World Health Organization, American Medical Association, Centers for Disease Control and Prevention, and FDA have all advised that e-cigarettes should not be used as smoking cessation aids, he said, especially in light of current outbreak of life-threatening e-cigarette and vaping lung injuries currently being investigated by the CDC and FDA.
“These study results suggest that the CDC reports of e-cigarette, or vaping, product use–associated lung injury are likely to be just the tip of the iceberg,” he said. “Although the CDC has identified vitamin E acetate–containing products as an important culprit, it is unlikely to be the only one. There are many substances in the emissions of e-cigarettes that have known irritant and/or toxic effects on the airways.”
Dr. Bhatta and Dr. Glantz acknowledged several limitations in their analysis, including the possibility of recall bias, not distinguishing between nondaily and daily e-cigarette or combustible tobacco use, and combining respiratory conditions together to achieve adequate power. The study shows an association, but the mechanism by which e-cigarettes may contribute to the development of lung disease remains under investigation.
This study was supported by grants from the National Institute on Drug Abuse; the National Cancer Institute; the FDA Center for Tobacco Products; the National Heart, Lung, and Blood Institute; and the University of California, San Francisco Helen Diller Family Comprehensive Cancer Center Global Cancer Program. Dr. Bhatta and Dr. Glantz reported no relevant conflicts of interest.
SOURCE: Bhatta DN, Glantz SA. Am J Prev Med. 2019 Dec 16. doi: 10.1016/j.amepre.2019.07.028.
according to recent longitudinal analysis published in the American Journal of Preventive Medicine.
E-cigarettes have been promoted as a safer alternative to combustible tobacco, and until recently, there has been little and conflicting evidence by which to test this hypothesis. This study conducted by Dharma N. Bhatta, PhD, and Stanton A. Glantz, PhD, of the Center for Tobacco Control Research and Education at the University of California, San Francisco, is one of the first longitudinal examinations of e-cigarette use and controlling for combustible tobacco use.
Dr. Bhatta and Dr. Glantz performed a multivariable, logistic regression analysis of adults enrolled in the nationally representative, population-based, longitudinal Population Assessment of Tobacco and Health study. The researchers analyzed the tobacco use of adults in the study in three waves, following them through wave 1 (September 2013 to December 2014), wave 2 (October 2014 to October 2015), and wave 3 (October 2015 to October 2016), analyzing the data between 2018 and 2019. Overall, wave 1 began with 32,320 participants, and 15.1% of adults reported respiratory disease at baseline.
Lung or respiratory disease was assessed by asking participants whether they had been told by a health professional that they had chronic obstructive pulmonary disease, chronic bronchitis, emphysema, or asthma. The researchers defined e-cigarette and combustible tobacco use as participants who never, currently, or formerly used e-cigarettes or smoked combustible tobacco. Participants who indicated they used e-cigarettes or combustible tobacco frequently or infrequently were placed in the current-user group, while past users were those participants who said they used to, but no longer use e-cigarettes or combustible tobacco.
The results showed former e-cigarette use (adjusted odds ratio, 1.34; 95% confidence interval, 1.23-1.46) and current e-cigarette use (aOR, 1.32; 95% CI, 1.17-1.49) were associated with an increased risk of having incident respiratory disease.
The data showed a not unexpected statistically significant association between former combustible tobacco use (aOR, 1.29; 95% CI, 1.14-1.47) as well as current combustible tobacco use (aOR, 1.61; 95% CI, 1.42-1.82) and incident respiratory disease risk.
There was a statistically significant association between respiratory disease and former or current e-cigarette use for adults who did not have respiratory disease at baseline, after adjusting for factors such as current combustible tobacco use, clinical variables, and demographic differences. Participants in wave 1 who reported former (aOR, 1.31; 95% CI, 1.07-1.60) or current e-cigarette use (aOR, 1.29; 95% CI, 1.03-1.61) had a significantly higher risk of developing incident respiratory disease in subsequent waves. There was also a statistically significant association between use of combustible tobacco and subsequent respiratory disease in later waves of the study (aOR, 2.56; 95% CI, 1.92-3.41), which the researchers noted was independent of the usual risks associated with combustible tobacco.
The investigators also looked at the link between dual use of e-cigarettes and combustible tobacco and respiratory disease risk. “The much more common pattern is dual use, in which an e-cigarette user continues to smoke combusted tobacco products at the same time (93.7% of e-cigarette users at wave 2 and 91.2% at wave 3 also used combustible tobacco; 73.3% of e-cigarette users at wave 2 and 64.9% at wave 3 also smoked cigarettes),” they wrote.
The odds of developing respiratory disease for participants who used both e-cigarettes and combustible tobacco were 3.30, compared with a participant who never used e-cigarettes, with similar results seen when comparing e-cigarettes and cigarettes.
“Although switching from combustible tobacco, including cigarettes, to e-cigarettes theoretically could reduce the risk of developing respiratory disease, current evidence indicates a high prevalence of dual use, which is associated with in-creased risk beyond combustible tobacco use,” the investigators wrote.
Harold J. Farber, MD, FCCP, professor of pediatrics in the pulmonary section at Baylor College of Medicine and Texas Children’s Hospital, both in Houston, said in an interview that the increased respiratory risk among dual users, who are likely using e-cigarettes and combustible tobacco together as a way to quit smoking, is particularly concerning.
“There is substantial reason to be concerned about efficacy of electronic cigarette products. Real-world observational studies have shown that, on average, tobacco smokers who use electronic cigarettes are less likely to stop smoking than those who do not use electronic cigarettes,” he said. “People who have stopped tobacco smoking but use electronic cigarettes are more likely to relapse to tobacco smoking than those who do not use electronic cigarettes.”
Dr. Farber noted that there are other Food and Drug Administration–approved medications for treating tobacco addiction. In addition, the World Health Organization, American Medical Association, Centers for Disease Control and Prevention, and FDA have all advised that e-cigarettes should not be used as smoking cessation aids, he said, especially in light of current outbreak of life-threatening e-cigarette and vaping lung injuries currently being investigated by the CDC and FDA.
“These study results suggest that the CDC reports of e-cigarette, or vaping, product use–associated lung injury are likely to be just the tip of the iceberg,” he said. “Although the CDC has identified vitamin E acetate–containing products as an important culprit, it is unlikely to be the only one. There are many substances in the emissions of e-cigarettes that have known irritant and/or toxic effects on the airways.”
Dr. Bhatta and Dr. Glantz acknowledged several limitations in their analysis, including the possibility of recall bias, not distinguishing between nondaily and daily e-cigarette or combustible tobacco use, and combining respiratory conditions together to achieve adequate power. The study shows an association, but the mechanism by which e-cigarettes may contribute to the development of lung disease remains under investigation.
This study was supported by grants from the National Institute on Drug Abuse; the National Cancer Institute; the FDA Center for Tobacco Products; the National Heart, Lung, and Blood Institute; and the University of California, San Francisco Helen Diller Family Comprehensive Cancer Center Global Cancer Program. Dr. Bhatta and Dr. Glantz reported no relevant conflicts of interest.
SOURCE: Bhatta DN, Glantz SA. Am J Prev Med. 2019 Dec 16. doi: 10.1016/j.amepre.2019.07.028.
FROM THE AMERICAN JOURNAL OF PREVENTIVE MEDICINE
Early increase in flu activity shows no signs of slowing
An important measure of U.S. flu activity for the 2019-2020 season has already surpassed last season’s high, and more than half the states are experiencing high levels of activity, according to the Centers for Disease Control and Prevention.
reported Dec. 27.
The last time the outpatient visit rate was higher than that was in February of the 2017-2018 season, when it peaked at 7.5%. The peak month of flu activity occurs most often – about once every 3 years – in February, and the odds of a December peak are about one in five, the CDC has said.
Outpatient illness activity also increased at the state level during the week ending Dec. 21. There were 20 jurisdictions – 18 states, the District of Columbia, and Puerto Rico – at level 10 on the CDC’s 1-10 scale of activity, compared with 13 the previous week, and the number of jurisdictions in the “high” range (levels 8-10) jumped from 21 to 28, the CDC data show.
The influenza division estimated that there have been 4.6 million flu illnesses so far this season, nearly a million more than the total after last week, along with 39,000 hospitalizations. The overall hospitalization rate for the season is up to 6.6 per 100,000 population, which is about average at this point. The proportion of deaths attributed to pneumonia and influenza increased to 5.7%, which is below the epidemic threshold, the CDC said.
Three pediatric deaths related to influenza-like illness were reported during the week ending Dec. 21, two of which occurred in an earlier week. For the 2019-2020 season so far, a total of 22 pediatric deaths have been reported to the CDC.
An important measure of U.S. flu activity for the 2019-2020 season has already surpassed last season’s high, and more than half the states are experiencing high levels of activity, according to the Centers for Disease Control and Prevention.
reported Dec. 27.
The last time the outpatient visit rate was higher than that was in February of the 2017-2018 season, when it peaked at 7.5%. The peak month of flu activity occurs most often – about once every 3 years – in February, and the odds of a December peak are about one in five, the CDC has said.
Outpatient illness activity also increased at the state level during the week ending Dec. 21. There were 20 jurisdictions – 18 states, the District of Columbia, and Puerto Rico – at level 10 on the CDC’s 1-10 scale of activity, compared with 13 the previous week, and the number of jurisdictions in the “high” range (levels 8-10) jumped from 21 to 28, the CDC data show.
The influenza division estimated that there have been 4.6 million flu illnesses so far this season, nearly a million more than the total after last week, along with 39,000 hospitalizations. The overall hospitalization rate for the season is up to 6.6 per 100,000 population, which is about average at this point. The proportion of deaths attributed to pneumonia and influenza increased to 5.7%, which is below the epidemic threshold, the CDC said.
Three pediatric deaths related to influenza-like illness were reported during the week ending Dec. 21, two of which occurred in an earlier week. For the 2019-2020 season so far, a total of 22 pediatric deaths have been reported to the CDC.
An important measure of U.S. flu activity for the 2019-2020 season has already surpassed last season’s high, and more than half the states are experiencing high levels of activity, according to the Centers for Disease Control and Prevention.
reported Dec. 27.
The last time the outpatient visit rate was higher than that was in February of the 2017-2018 season, when it peaked at 7.5%. The peak month of flu activity occurs most often – about once every 3 years – in February, and the odds of a December peak are about one in five, the CDC has said.
Outpatient illness activity also increased at the state level during the week ending Dec. 21. There were 20 jurisdictions – 18 states, the District of Columbia, and Puerto Rico – at level 10 on the CDC’s 1-10 scale of activity, compared with 13 the previous week, and the number of jurisdictions in the “high” range (levels 8-10) jumped from 21 to 28, the CDC data show.
The influenza division estimated that there have been 4.6 million flu illnesses so far this season, nearly a million more than the total after last week, along with 39,000 hospitalizations. The overall hospitalization rate for the season is up to 6.6 per 100,000 population, which is about average at this point. The proportion of deaths attributed to pneumonia and influenza increased to 5.7%, which is below the epidemic threshold, the CDC said.
Three pediatric deaths related to influenza-like illness were reported during the week ending Dec. 21, two of which occurred in an earlier week. For the 2019-2020 season so far, a total of 22 pediatric deaths have been reported to the CDC.
New cystic fibrosis therapy raises hopes among specialists and patients
A newly approved triple-combination modulator to treat cystic fibrosis (CF) has raised expectations of a treatment turning point among patients and specialists. If the early results are sustained, elexacaftor/ivacaftor/tezacaftor (Trikafta) could prove to be the rare case of a much-touted new medicine that meets high expectations.
“CF even in infants causes inflammation, so we know that lung damage can start early and progress,” said Susan Millard, MD, FCCP, of Helen DeVos Children’s Hospital in Grand Rapids, Mich., and the local clinical research director for the pediatric pulmonary and sleep medicine section. “This oral drug therapy is actually treating the underlying problem, as opposed to many of the therapies we have that take hours to nebulize and only work locally in the airways.”
Dr. Millard is the recent past pediatric editor for Chest Physician and has been a local principal investigator at Helen DeVos Children’s Hospital for many Vertex-sponsored clinical studies.
The pivotal studies
The Food and Drug Administration approval of Trikafta rested on two pivotal phase 3, placebo-controlled studies, one in patients with two copies of the most common CF mutations, F508del, and the second in patients with one copy of F508del and a second mutation that was called a “minimal-function” mutation. The findings have ignited the hopes of many people with CF and their physicians. The drug was approved in October 2019 for patients aged 12 years and older who have at least one F508del mutation of the cystic fibrosis transmembrane conductance regulator gene. About 90% of patients in the United States have at least one copy of F508del. In the study looking at patients with one copy of F508del, the mean predicted forced expiratory volume in 1 second increased 13.8% in patients taking the drug versus placebo (N Engl J Med. 2019 Oct 31. doi: 10.1056/NEJMoa1908639). The number of pulmonary exacerbations decreased by 63% in the Trikafta group, compared with placebo. Pulmonary exacerbations were described as a change in specific symptoms that required treatment with a new oral, intravenous, or inhaled antibiotic. Serious adverse drug reactions that occurred more frequently in patients receiving Trikafta, compared with placebo, were rash and influenza events.
In the study that included patients with two copies of F508del, on average, the lung function increased 10% versus patients on ivacaftor/tezacaftor at 4 weeks. In addition, there was a 45.1 mmol/L on average decrease in the sweat chloride level in the Trikafta group, compared with ivacaftor/tezacaftor.
A hopeful start
Robert Giusti, MD, a pediatric pulmonologist at New York University Langone Health, is also hopeful. “This could be the kind of treatment that will make a revolution in terms of [cystic fibrosis] care if it can be started very early in life shortly after diagnosis. We anticipate that patients will be disease free for a longer period of time.”
The Cystic Fibrosis Foundation’s (CFF) “venture philanthropy” initiative played an important role in the development of the drug by Vertex Pharmaceuticals. The CFF has invested many millions of dollars in research by drug companies since the 1980s and was an early backer of Vertex. According to a statement on the CFF website, the Foundation sold its royalty rights for treatments developed by Vertex for $3.3 billion in 2014. The drug has a list price of about $311,000 a year. Payment issues may arise in the future, but for now, Vertex has stated that insurers and some Medicaid programs have begun paying claims for Trikafta
Specialists who treat CF now are watching to see how well patients tolerate this highly anticipated drug – and how well it meets expectations. The Therapeutic Development Network, the clinical research division of the CFF, is enrolling patients taking Trikafta in an observational study to follow for long-term follow-up.
Meeting expectations
“[Long-term efficacy is] something that we’re always concerned about. When the drug comes to market, is it going to be as effective as we thought it might be?” said Ryan Thomas, MD, director of the Cystic Fibrosis Center at Michigan State University, East Lansing. The MSU Cystic Fibrosis Center receives funding from the Cystic Fibrosis Foundation.
Almost one in five patients could not tolerate treatment with Orkambi, most often because of adverse breathing events, according to a French study published in the American Journal of Respiratory and Critical Care Medicine. The investigators wrote: “Among the 845 patients (292 adolescents, 553 adults) who initiated lumacaftor/ivacaftor, 18.2% (154 patients) discontinued treatment, often due to respiratory (48.1%, 74 patients) or nonrespiratory (27.9%, 43 patients) adverse events” and that the discontinuation rate was considerably higher than previously reported in clinical trials.
“We thought [Orkambi] was going to be something that could have a big effect,” Dr. Thomas said. “It turned out that it was harder for people to tolerate than we thought and the improvements weren’t as sustained as we thought they might be. I really don’t think this will end up being the case with Trikafta.”
Longer-term data are starting to emerge, which may ease some of the concerns inherent in working with a newer medicine. “These [data] suggest that this is going to be a game changer,” Dr. Thomas said. “If Trikafta is this efficacious, well, we’re talking about having people with CF who will live full lifespans without a lung transplant, and that is so rare.”
The decrease in hospitalizations, improved CT scans, and lower rates of lung function decline suggest it could be “the Holy Grail,” Dr. Thomas said.
A different disease
Trikafta is the latest in a series of improvements of CF treatment in recent decades, recalled Dr. Giusti, who has been in this field for about 3 decades. “It used to be that I attended many funerals for children with CF. Now with patients living longer and healthier lives I am invited to attend their weddings and even their children’s baptisms and bris ceremonies. It is a very different disease than it used to be.”
The promise of Trikafta leaves behind the minority of patients for whom the drug won’t work. This is for the 10% of patients that have rare mutations. That can lead to difficult conversations with parents about why this new option is not a choice for their child, Dr. Millard said. “It just crushes you, but the Cystic Fibrosis Foundation is committing a lot of new research in that direction. Their mantra is ‘until it is done.’ ”
Realistic expectations
William (Randy) Hunt, MD, FAAP, FACP, assistant professor of medicine in the Division of Pulmonary, Allergy, Critical Care and Sleep, Emory University School of Medicine, Atlanta, agrees that Trikafta is an exciting development in CF treatment. He noted, “Starting this medication early in life may very well significantly attenuate the disease, but it is not a cure. For individuals who already have significant disease, we may not see the same level of improvements in lung function as what we saw in the studies. The studies generally excluded individuals with ppFEV1 < 40%. Nevertheless, I remain optimistic and have been prescribing it to nearly everyone that qualifies after a discussion.”
Dr. Hunt added, “Patients are asking if they can stop their current chronic CF therapies once they start Trikafta. The answer is “no, at least not right now.” While all the relatively short-term data around Trikafta are very promising, we do not yet know how sustained the long-term benefits will be. Still, safely removing therapeutic burden from our patient population is a real interest. There are plans underway by the CFF and other institutions to systematically research whether discontinuing chronic CF therapies is safe in the setting of Trikafta.”
He concluded that 10% of individuals with CF mutations still do not respond to the modulators currently available. “We will not leave that population behind, but treating these remaining mutations is going to take continued efforts and likely modulators that are therapeutically differently from the mechanism of actions of those that are currently available,” he said.
Therese Borden contributed to this article.
1/2/2020 - This story was updated.
A newly approved triple-combination modulator to treat cystic fibrosis (CF) has raised expectations of a treatment turning point among patients and specialists. If the early results are sustained, elexacaftor/ivacaftor/tezacaftor (Trikafta) could prove to be the rare case of a much-touted new medicine that meets high expectations.
“CF even in infants causes inflammation, so we know that lung damage can start early and progress,” said Susan Millard, MD, FCCP, of Helen DeVos Children’s Hospital in Grand Rapids, Mich., and the local clinical research director for the pediatric pulmonary and sleep medicine section. “This oral drug therapy is actually treating the underlying problem, as opposed to many of the therapies we have that take hours to nebulize and only work locally in the airways.”
Dr. Millard is the recent past pediatric editor for Chest Physician and has been a local principal investigator at Helen DeVos Children’s Hospital for many Vertex-sponsored clinical studies.
The pivotal studies
The Food and Drug Administration approval of Trikafta rested on two pivotal phase 3, placebo-controlled studies, one in patients with two copies of the most common CF mutations, F508del, and the second in patients with one copy of F508del and a second mutation that was called a “minimal-function” mutation. The findings have ignited the hopes of many people with CF and their physicians. The drug was approved in October 2019 for patients aged 12 years and older who have at least one F508del mutation of the cystic fibrosis transmembrane conductance regulator gene. About 90% of patients in the United States have at least one copy of F508del. In the study looking at patients with one copy of F508del, the mean predicted forced expiratory volume in 1 second increased 13.8% in patients taking the drug versus placebo (N Engl J Med. 2019 Oct 31. doi: 10.1056/NEJMoa1908639). The number of pulmonary exacerbations decreased by 63% in the Trikafta group, compared with placebo. Pulmonary exacerbations were described as a change in specific symptoms that required treatment with a new oral, intravenous, or inhaled antibiotic. Serious adverse drug reactions that occurred more frequently in patients receiving Trikafta, compared with placebo, were rash and influenza events.
In the study that included patients with two copies of F508del, on average, the lung function increased 10% versus patients on ivacaftor/tezacaftor at 4 weeks. In addition, there was a 45.1 mmol/L on average decrease in the sweat chloride level in the Trikafta group, compared with ivacaftor/tezacaftor.
A hopeful start
Robert Giusti, MD, a pediatric pulmonologist at New York University Langone Health, is also hopeful. “This could be the kind of treatment that will make a revolution in terms of [cystic fibrosis] care if it can be started very early in life shortly after diagnosis. We anticipate that patients will be disease free for a longer period of time.”
The Cystic Fibrosis Foundation’s (CFF) “venture philanthropy” initiative played an important role in the development of the drug by Vertex Pharmaceuticals. The CFF has invested many millions of dollars in research by drug companies since the 1980s and was an early backer of Vertex. According to a statement on the CFF website, the Foundation sold its royalty rights for treatments developed by Vertex for $3.3 billion in 2014. The drug has a list price of about $311,000 a year. Payment issues may arise in the future, but for now, Vertex has stated that insurers and some Medicaid programs have begun paying claims for Trikafta
Specialists who treat CF now are watching to see how well patients tolerate this highly anticipated drug – and how well it meets expectations. The Therapeutic Development Network, the clinical research division of the CFF, is enrolling patients taking Trikafta in an observational study to follow for long-term follow-up.
Meeting expectations
“[Long-term efficacy is] something that we’re always concerned about. When the drug comes to market, is it going to be as effective as we thought it might be?” said Ryan Thomas, MD, director of the Cystic Fibrosis Center at Michigan State University, East Lansing. The MSU Cystic Fibrosis Center receives funding from the Cystic Fibrosis Foundation.
Almost one in five patients could not tolerate treatment with Orkambi, most often because of adverse breathing events, according to a French study published in the American Journal of Respiratory and Critical Care Medicine. The investigators wrote: “Among the 845 patients (292 adolescents, 553 adults) who initiated lumacaftor/ivacaftor, 18.2% (154 patients) discontinued treatment, often due to respiratory (48.1%, 74 patients) or nonrespiratory (27.9%, 43 patients) adverse events” and that the discontinuation rate was considerably higher than previously reported in clinical trials.
“We thought [Orkambi] was going to be something that could have a big effect,” Dr. Thomas said. “It turned out that it was harder for people to tolerate than we thought and the improvements weren’t as sustained as we thought they might be. I really don’t think this will end up being the case with Trikafta.”
Longer-term data are starting to emerge, which may ease some of the concerns inherent in working with a newer medicine. “These [data] suggest that this is going to be a game changer,” Dr. Thomas said. “If Trikafta is this efficacious, well, we’re talking about having people with CF who will live full lifespans without a lung transplant, and that is so rare.”
The decrease in hospitalizations, improved CT scans, and lower rates of lung function decline suggest it could be “the Holy Grail,” Dr. Thomas said.
A different disease
Trikafta is the latest in a series of improvements of CF treatment in recent decades, recalled Dr. Giusti, who has been in this field for about 3 decades. “It used to be that I attended many funerals for children with CF. Now with patients living longer and healthier lives I am invited to attend their weddings and even their children’s baptisms and bris ceremonies. It is a very different disease than it used to be.”
The promise of Trikafta leaves behind the minority of patients for whom the drug won’t work. This is for the 10% of patients that have rare mutations. That can lead to difficult conversations with parents about why this new option is not a choice for their child, Dr. Millard said. “It just crushes you, but the Cystic Fibrosis Foundation is committing a lot of new research in that direction. Their mantra is ‘until it is done.’ ”
Realistic expectations
William (Randy) Hunt, MD, FAAP, FACP, assistant professor of medicine in the Division of Pulmonary, Allergy, Critical Care and Sleep, Emory University School of Medicine, Atlanta, agrees that Trikafta is an exciting development in CF treatment. He noted, “Starting this medication early in life may very well significantly attenuate the disease, but it is not a cure. For individuals who already have significant disease, we may not see the same level of improvements in lung function as what we saw in the studies. The studies generally excluded individuals with ppFEV1 < 40%. Nevertheless, I remain optimistic and have been prescribing it to nearly everyone that qualifies after a discussion.”
Dr. Hunt added, “Patients are asking if they can stop their current chronic CF therapies once they start Trikafta. The answer is “no, at least not right now.” While all the relatively short-term data around Trikafta are very promising, we do not yet know how sustained the long-term benefits will be. Still, safely removing therapeutic burden from our patient population is a real interest. There are plans underway by the CFF and other institutions to systematically research whether discontinuing chronic CF therapies is safe in the setting of Trikafta.”
He concluded that 10% of individuals with CF mutations still do not respond to the modulators currently available. “We will not leave that population behind, but treating these remaining mutations is going to take continued efforts and likely modulators that are therapeutically differently from the mechanism of actions of those that are currently available,” he said.
Therese Borden contributed to this article.
1/2/2020 - This story was updated.
A newly approved triple-combination modulator to treat cystic fibrosis (CF) has raised expectations of a treatment turning point among patients and specialists. If the early results are sustained, elexacaftor/ivacaftor/tezacaftor (Trikafta) could prove to be the rare case of a much-touted new medicine that meets high expectations.
“CF even in infants causes inflammation, so we know that lung damage can start early and progress,” said Susan Millard, MD, FCCP, of Helen DeVos Children’s Hospital in Grand Rapids, Mich., and the local clinical research director for the pediatric pulmonary and sleep medicine section. “This oral drug therapy is actually treating the underlying problem, as opposed to many of the therapies we have that take hours to nebulize and only work locally in the airways.”
Dr. Millard is the recent past pediatric editor for Chest Physician and has been a local principal investigator at Helen DeVos Children’s Hospital for many Vertex-sponsored clinical studies.
The pivotal studies
The Food and Drug Administration approval of Trikafta rested on two pivotal phase 3, placebo-controlled studies, one in patients with two copies of the most common CF mutations, F508del, and the second in patients with one copy of F508del and a second mutation that was called a “minimal-function” mutation. The findings have ignited the hopes of many people with CF and their physicians. The drug was approved in October 2019 for patients aged 12 years and older who have at least one F508del mutation of the cystic fibrosis transmembrane conductance regulator gene. About 90% of patients in the United States have at least one copy of F508del. In the study looking at patients with one copy of F508del, the mean predicted forced expiratory volume in 1 second increased 13.8% in patients taking the drug versus placebo (N Engl J Med. 2019 Oct 31. doi: 10.1056/NEJMoa1908639). The number of pulmonary exacerbations decreased by 63% in the Trikafta group, compared with placebo. Pulmonary exacerbations were described as a change in specific symptoms that required treatment with a new oral, intravenous, or inhaled antibiotic. Serious adverse drug reactions that occurred more frequently in patients receiving Trikafta, compared with placebo, were rash and influenza events.
In the study that included patients with two copies of F508del, on average, the lung function increased 10% versus patients on ivacaftor/tezacaftor at 4 weeks. In addition, there was a 45.1 mmol/L on average decrease in the sweat chloride level in the Trikafta group, compared with ivacaftor/tezacaftor.
A hopeful start
Robert Giusti, MD, a pediatric pulmonologist at New York University Langone Health, is also hopeful. “This could be the kind of treatment that will make a revolution in terms of [cystic fibrosis] care if it can be started very early in life shortly after diagnosis. We anticipate that patients will be disease free for a longer period of time.”
The Cystic Fibrosis Foundation’s (CFF) “venture philanthropy” initiative played an important role in the development of the drug by Vertex Pharmaceuticals. The CFF has invested many millions of dollars in research by drug companies since the 1980s and was an early backer of Vertex. According to a statement on the CFF website, the Foundation sold its royalty rights for treatments developed by Vertex for $3.3 billion in 2014. The drug has a list price of about $311,000 a year. Payment issues may arise in the future, but for now, Vertex has stated that insurers and some Medicaid programs have begun paying claims for Trikafta
Specialists who treat CF now are watching to see how well patients tolerate this highly anticipated drug – and how well it meets expectations. The Therapeutic Development Network, the clinical research division of the CFF, is enrolling patients taking Trikafta in an observational study to follow for long-term follow-up.
Meeting expectations
“[Long-term efficacy is] something that we’re always concerned about. When the drug comes to market, is it going to be as effective as we thought it might be?” said Ryan Thomas, MD, director of the Cystic Fibrosis Center at Michigan State University, East Lansing. The MSU Cystic Fibrosis Center receives funding from the Cystic Fibrosis Foundation.
Almost one in five patients could not tolerate treatment with Orkambi, most often because of adverse breathing events, according to a French study published in the American Journal of Respiratory and Critical Care Medicine. The investigators wrote: “Among the 845 patients (292 adolescents, 553 adults) who initiated lumacaftor/ivacaftor, 18.2% (154 patients) discontinued treatment, often due to respiratory (48.1%, 74 patients) or nonrespiratory (27.9%, 43 patients) adverse events” and that the discontinuation rate was considerably higher than previously reported in clinical trials.
“We thought [Orkambi] was going to be something that could have a big effect,” Dr. Thomas said. “It turned out that it was harder for people to tolerate than we thought and the improvements weren’t as sustained as we thought they might be. I really don’t think this will end up being the case with Trikafta.”
Longer-term data are starting to emerge, which may ease some of the concerns inherent in working with a newer medicine. “These [data] suggest that this is going to be a game changer,” Dr. Thomas said. “If Trikafta is this efficacious, well, we’re talking about having people with CF who will live full lifespans without a lung transplant, and that is so rare.”
The decrease in hospitalizations, improved CT scans, and lower rates of lung function decline suggest it could be “the Holy Grail,” Dr. Thomas said.
A different disease
Trikafta is the latest in a series of improvements of CF treatment in recent decades, recalled Dr. Giusti, who has been in this field for about 3 decades. “It used to be that I attended many funerals for children with CF. Now with patients living longer and healthier lives I am invited to attend their weddings and even their children’s baptisms and bris ceremonies. It is a very different disease than it used to be.”
The promise of Trikafta leaves behind the minority of patients for whom the drug won’t work. This is for the 10% of patients that have rare mutations. That can lead to difficult conversations with parents about why this new option is not a choice for their child, Dr. Millard said. “It just crushes you, but the Cystic Fibrosis Foundation is committing a lot of new research in that direction. Their mantra is ‘until it is done.’ ”
Realistic expectations
William (Randy) Hunt, MD, FAAP, FACP, assistant professor of medicine in the Division of Pulmonary, Allergy, Critical Care and Sleep, Emory University School of Medicine, Atlanta, agrees that Trikafta is an exciting development in CF treatment. He noted, “Starting this medication early in life may very well significantly attenuate the disease, but it is not a cure. For individuals who already have significant disease, we may not see the same level of improvements in lung function as what we saw in the studies. The studies generally excluded individuals with ppFEV1 < 40%. Nevertheless, I remain optimistic and have been prescribing it to nearly everyone that qualifies after a discussion.”
Dr. Hunt added, “Patients are asking if they can stop their current chronic CF therapies once they start Trikafta. The answer is “no, at least not right now.” While all the relatively short-term data around Trikafta are very promising, we do not yet know how sustained the long-term benefits will be. Still, safely removing therapeutic burden from our patient population is a real interest. There are plans underway by the CFF and other institutions to systematically research whether discontinuing chronic CF therapies is safe in the setting of Trikafta.”
He concluded that 10% of individuals with CF mutations still do not respond to the modulators currently available. “We will not leave that population behind, but treating these remaining mutations is going to take continued efforts and likely modulators that are therapeutically differently from the mechanism of actions of those that are currently available,” he said.
Therese Borden contributed to this article.
1/2/2020 - This story was updated.
The measles comeback of 2019
Measles made a comeback in 2019.
The Centers for Disease Control and Prevention reported that, as of Dec. 5, 2019, 1,276 individual cases of measles of measles were confirmed in 31 states, the largest number since 1992. This number is a major uptick in cases, compared with previous years since 2000 when the CDC declared measles eliminated from the United States. No deaths have been reported for 2019.
Three-quarters of these cases in 2019 were linked to recent outbreaks in New York and occurred in primarily in underimmunized, close-knit communities and in patients with links to international travel. A total of 124 of the people who got measles this year were hospitalized, and 61 reported having complications, including pneumonia and encephalitis. The overall median patient age was 6 years (31% aged 1-4 years, 27% aged 5-17 years, and 29% aged at least 18 years).
The good news is that most of these cases occurred in unvaccinated patients. The national vaccination rate for the almost 4 million kindergartners reported as enrolled in 2018-2019 was 94.7% for two doses of the MMR vaccine, falling just short of the CDC recommended 95% vaccination rate threshold. The CDC reported an approximate 2.5% rate of vaccination exemptions among school-age children.
The bad news is that, despite the high rate of MMR vaccination rates among U.S. children, there are gaps in measles protection in the U.S. population because of factors leaving patients immunocompromised and antivaccination sentiment that has led some parents to defer or refuse the MMR.
In addition, adults who were vaccinated prior to 1968 with either inactivated measles vaccine or measles vaccine of unknown type may have limited immunity. The inactivated measles vaccine, which was available in 1963-1967, did not achieve effective measles protection.
A global measles surge
While antivaccination sentiment contributed to the 2019 measles cases, a more significant factor may be the global surge of measles. More than 140,000 people worldwide died from measles in 2018, according to the World Health Organization and the CDC.
“[Recent data on measles] indicates that during the first 6 months of the year there have been more measles cases reported worldwide than in any year since 2006. From Jan. 1 to July 31, 2019, 182 countries reported 364,808 measles cases to the WHO. This surpasses the 129,239 reported during the same time period in 2018. WHO regions with the biggest increases in cases include the African region (900%), the Western Pacific region (230%), and the European region (150%),” according to a CDC report.
Studies on hospitalization and complications linked to measles in the United States are scarce, but two outbreaks in Minnesota (2011 and 2017) provided some data on what to expect if the measles surge continues into 2020. The investigators found that poor feeding was a primary reason for admission (97%); additional complications included otitis media (42%), pneumonia (30%), and tracheitis (6%). Three-quarters received antibiotics, 30% required oxygen, and 21% received vitamin A. Median length of stay was 3.7 days (range, 1.1-26.2 days) (Pediatr Infect Dis J. 2019 Jun;38[6]:547-52. doi: 10.1097/INF.0000000000002221).
‘Immunological amnesia’
Infection with the measles virus appears to reduce immunity to other pathogens, according to a paper published in Science (2019 Nov 1;366[6465]599-606).
The hypothesis that the measles virus could cause “immunological amnesia” by impairing immune memory is supported by early research showing children with measles had negative cutaneous tuberculin reactions after having previously tested positive.
“Subsequent studies have shown decreased interferon signaling, skewed cytokine responses, lymphopenia, and suppression of lymphocyte proliferation shortly after infection,” wrote Michael Mina, MD, from Brigham and Women’s Hospital in Boston, and coauthors.
“Given the variation in the degree of immune repertoire modulation we observed, we anticipate that future risk of morbidity and mortality after measles would not be homogeneous but would be skewed toward individuals with the most severe elimination of immunological memory,” they wrote. “These findings underscore the crucial need for continued widespread vaccination.”
In this study, researchers compared the levels of around 400 pathogen-specific antibodies in blood samples from 77 unvaccinated children, taken before and 2 months after natural measles infection, with 5 unvaccinated children who did not contract measles. A total of 34 children experienced mild measles, and 43 had severe measles.
They found that the samples taken after measles infection showed “substantial” reductions in the number of pathogen epitopes, compared with the samples from children who did not get infected with measles.
This amounted to approximately a 20% mean reduction in overall diversity or size of the antibody repertoire. However, in children who experienced severe measles, there was a median loss of 40% (range, 11%-62%) of antibody repertoire, compared with a median of 33% (range, 12%-73%) range in children who experienced mild infection. Meanwhile, the control subjects retained approximately 90% of their antibody repertoire over a similar or longer time period. Some children lost up to 70% of antibodies for specific pathogens.
Maternal-acquired immunity fades
In another study of measles immunity, maternal antibodies were found to be insufficient to provide immunity to infants after 6 months.
The study of 196 infants showed that maternal measles antibodies had dropped below the protective threshold by 3 months of age – well before the recommended age of 12-15 months for the first dose of MMR vaccine.
The odds of inadequate protection doubled for each additional month of age, Michelle Science, MD, of the University of Toronto and associates reported in Pediatrics (2019 Dec 1. doi 10.1542/peds.2019-0630).
“The widening gap between loss of maternal antibodies and measles vaccination described in our study leaves infants vulnerable to measles for much of their infancy and highlights the need for further research to support public health policy,” Dr. Science and colleagues wrote.
The researchers randomly selected 25 samples for each of eight different age groups: up to 30 days old; 1 month (31-60 days), 2 months (61-89 days), 3 months (90-119 days), 4 months, 5 months, 6-9 months, and 9-11 months.
Just over half the babies (56%) were male, and 35% had an underlying condition, but none had conditions that might affect antibody levels. The conditions were primarily a developmental delay or otherwise affecting the central nervous system, liver, or gastrointestinal function. Mean maternal age was 32 years.
To ensure high test sensitivity, the researchers used the plaque-reduction neutralization test to test for measles-neutralizing antibodies instead of using enzyme-linked immunosorbent assay, because “ELISA sensitivity decreases as antibody titers decrease,” Dr. Science and colleagues wrote. They used a neutralization titer of less than 192 mIU/mL as the threshold for protection against measles.
When the researchers calculated the predicted standardized mean antibody titer for infants with a mother aged 32 years, they determined their mean to be 541 mIU/mL at 1 month, 142 mIU/mL at 3 months (below the measles threshold of susceptibility of 192 mIU/mL), and 64 mIU/mL at 6 months. None of the infants had measles antibodies above the protective threshold at 6 months old, the authors noted.
Children’s odds of susceptibility to measles doubled for each additional month of age, after adjustment for infant sex and maternal age (odds ratio, 2.13). Children’s likelihood of susceptibility to measles modestly increased as maternal age increased in 5-year increments from 25 to 40 years.
Children with an underlying conditions had greater susceptibility to measles (83%), compared with those without a comorbidity (68%, P = .03). No difference in susceptibility existed between males and females or based on gestational age at birth (ranging from 37 to 41 weeks).
The Advisory Committee on Immunization Practices permits measles vaccination “as early as 6 months for infants who plan to travel internationally, infants with ongoing risk for exposure during measles outbreaks and as postexposure prophylaxis,” Huong Q. McLean, PhD, of Marshfield (Wisc.) Clinic Research Institute, and Walter A. Orenstein, MD, of Emory University, Atlanta, noted in an editorial.
The research was funded by the Public Health Ontario Project Initiation Fund. The authors had no relevant financial disclosures.
Bianca Nogrady and Tara Haelle contributed to this story.
Measles made a comeback in 2019.
The Centers for Disease Control and Prevention reported that, as of Dec. 5, 2019, 1,276 individual cases of measles of measles were confirmed in 31 states, the largest number since 1992. This number is a major uptick in cases, compared with previous years since 2000 when the CDC declared measles eliminated from the United States. No deaths have been reported for 2019.
Three-quarters of these cases in 2019 were linked to recent outbreaks in New York and occurred in primarily in underimmunized, close-knit communities and in patients with links to international travel. A total of 124 of the people who got measles this year were hospitalized, and 61 reported having complications, including pneumonia and encephalitis. The overall median patient age was 6 years (31% aged 1-4 years, 27% aged 5-17 years, and 29% aged at least 18 years).
The good news is that most of these cases occurred in unvaccinated patients. The national vaccination rate for the almost 4 million kindergartners reported as enrolled in 2018-2019 was 94.7% for two doses of the MMR vaccine, falling just short of the CDC recommended 95% vaccination rate threshold. The CDC reported an approximate 2.5% rate of vaccination exemptions among school-age children.
The bad news is that, despite the high rate of MMR vaccination rates among U.S. children, there are gaps in measles protection in the U.S. population because of factors leaving patients immunocompromised and antivaccination sentiment that has led some parents to defer or refuse the MMR.
In addition, adults who were vaccinated prior to 1968 with either inactivated measles vaccine or measles vaccine of unknown type may have limited immunity. The inactivated measles vaccine, which was available in 1963-1967, did not achieve effective measles protection.
A global measles surge
While antivaccination sentiment contributed to the 2019 measles cases, a more significant factor may be the global surge of measles. More than 140,000 people worldwide died from measles in 2018, according to the World Health Organization and the CDC.
“[Recent data on measles] indicates that during the first 6 months of the year there have been more measles cases reported worldwide than in any year since 2006. From Jan. 1 to July 31, 2019, 182 countries reported 364,808 measles cases to the WHO. This surpasses the 129,239 reported during the same time period in 2018. WHO regions with the biggest increases in cases include the African region (900%), the Western Pacific region (230%), and the European region (150%),” according to a CDC report.
Studies on hospitalization and complications linked to measles in the United States are scarce, but two outbreaks in Minnesota (2011 and 2017) provided some data on what to expect if the measles surge continues into 2020. The investigators found that poor feeding was a primary reason for admission (97%); additional complications included otitis media (42%), pneumonia (30%), and tracheitis (6%). Three-quarters received antibiotics, 30% required oxygen, and 21% received vitamin A. Median length of stay was 3.7 days (range, 1.1-26.2 days) (Pediatr Infect Dis J. 2019 Jun;38[6]:547-52. doi: 10.1097/INF.0000000000002221).
‘Immunological amnesia’
Infection with the measles virus appears to reduce immunity to other pathogens, according to a paper published in Science (2019 Nov 1;366[6465]599-606).
The hypothesis that the measles virus could cause “immunological amnesia” by impairing immune memory is supported by early research showing children with measles had negative cutaneous tuberculin reactions after having previously tested positive.
“Subsequent studies have shown decreased interferon signaling, skewed cytokine responses, lymphopenia, and suppression of lymphocyte proliferation shortly after infection,” wrote Michael Mina, MD, from Brigham and Women’s Hospital in Boston, and coauthors.
“Given the variation in the degree of immune repertoire modulation we observed, we anticipate that future risk of morbidity and mortality after measles would not be homogeneous but would be skewed toward individuals with the most severe elimination of immunological memory,” they wrote. “These findings underscore the crucial need for continued widespread vaccination.”
In this study, researchers compared the levels of around 400 pathogen-specific antibodies in blood samples from 77 unvaccinated children, taken before and 2 months after natural measles infection, with 5 unvaccinated children who did not contract measles. A total of 34 children experienced mild measles, and 43 had severe measles.
They found that the samples taken after measles infection showed “substantial” reductions in the number of pathogen epitopes, compared with the samples from children who did not get infected with measles.
This amounted to approximately a 20% mean reduction in overall diversity or size of the antibody repertoire. However, in children who experienced severe measles, there was a median loss of 40% (range, 11%-62%) of antibody repertoire, compared with a median of 33% (range, 12%-73%) range in children who experienced mild infection. Meanwhile, the control subjects retained approximately 90% of their antibody repertoire over a similar or longer time period. Some children lost up to 70% of antibodies for specific pathogens.
Maternal-acquired immunity fades
In another study of measles immunity, maternal antibodies were found to be insufficient to provide immunity to infants after 6 months.
The study of 196 infants showed that maternal measles antibodies had dropped below the protective threshold by 3 months of age – well before the recommended age of 12-15 months for the first dose of MMR vaccine.
The odds of inadequate protection doubled for each additional month of age, Michelle Science, MD, of the University of Toronto and associates reported in Pediatrics (2019 Dec 1. doi 10.1542/peds.2019-0630).
“The widening gap between loss of maternal antibodies and measles vaccination described in our study leaves infants vulnerable to measles for much of their infancy and highlights the need for further research to support public health policy,” Dr. Science and colleagues wrote.
The researchers randomly selected 25 samples for each of eight different age groups: up to 30 days old; 1 month (31-60 days), 2 months (61-89 days), 3 months (90-119 days), 4 months, 5 months, 6-9 months, and 9-11 months.
Just over half the babies (56%) were male, and 35% had an underlying condition, but none had conditions that might affect antibody levels. The conditions were primarily a developmental delay or otherwise affecting the central nervous system, liver, or gastrointestinal function. Mean maternal age was 32 years.
To ensure high test sensitivity, the researchers used the plaque-reduction neutralization test to test for measles-neutralizing antibodies instead of using enzyme-linked immunosorbent assay, because “ELISA sensitivity decreases as antibody titers decrease,” Dr. Science and colleagues wrote. They used a neutralization titer of less than 192 mIU/mL as the threshold for protection against measles.
When the researchers calculated the predicted standardized mean antibody titer for infants with a mother aged 32 years, they determined their mean to be 541 mIU/mL at 1 month, 142 mIU/mL at 3 months (below the measles threshold of susceptibility of 192 mIU/mL), and 64 mIU/mL at 6 months. None of the infants had measles antibodies above the protective threshold at 6 months old, the authors noted.
Children’s odds of susceptibility to measles doubled for each additional month of age, after adjustment for infant sex and maternal age (odds ratio, 2.13). Children’s likelihood of susceptibility to measles modestly increased as maternal age increased in 5-year increments from 25 to 40 years.
Children with an underlying conditions had greater susceptibility to measles (83%), compared with those without a comorbidity (68%, P = .03). No difference in susceptibility existed between males and females or based on gestational age at birth (ranging from 37 to 41 weeks).
The Advisory Committee on Immunization Practices permits measles vaccination “as early as 6 months for infants who plan to travel internationally, infants with ongoing risk for exposure during measles outbreaks and as postexposure prophylaxis,” Huong Q. McLean, PhD, of Marshfield (Wisc.) Clinic Research Institute, and Walter A. Orenstein, MD, of Emory University, Atlanta, noted in an editorial.
The research was funded by the Public Health Ontario Project Initiation Fund. The authors had no relevant financial disclosures.
Bianca Nogrady and Tara Haelle contributed to this story.
Measles made a comeback in 2019.
The Centers for Disease Control and Prevention reported that, as of Dec. 5, 2019, 1,276 individual cases of measles of measles were confirmed in 31 states, the largest number since 1992. This number is a major uptick in cases, compared with previous years since 2000 when the CDC declared measles eliminated from the United States. No deaths have been reported for 2019.
Three-quarters of these cases in 2019 were linked to recent outbreaks in New York and occurred in primarily in underimmunized, close-knit communities and in patients with links to international travel. A total of 124 of the people who got measles this year were hospitalized, and 61 reported having complications, including pneumonia and encephalitis. The overall median patient age was 6 years (31% aged 1-4 years, 27% aged 5-17 years, and 29% aged at least 18 years).
The good news is that most of these cases occurred in unvaccinated patients. The national vaccination rate for the almost 4 million kindergartners reported as enrolled in 2018-2019 was 94.7% for two doses of the MMR vaccine, falling just short of the CDC recommended 95% vaccination rate threshold. The CDC reported an approximate 2.5% rate of vaccination exemptions among school-age children.
The bad news is that, despite the high rate of MMR vaccination rates among U.S. children, there are gaps in measles protection in the U.S. population because of factors leaving patients immunocompromised and antivaccination sentiment that has led some parents to defer or refuse the MMR.
In addition, adults who were vaccinated prior to 1968 with either inactivated measles vaccine or measles vaccine of unknown type may have limited immunity. The inactivated measles vaccine, which was available in 1963-1967, did not achieve effective measles protection.
A global measles surge
While antivaccination sentiment contributed to the 2019 measles cases, a more significant factor may be the global surge of measles. More than 140,000 people worldwide died from measles in 2018, according to the World Health Organization and the CDC.
“[Recent data on measles] indicates that during the first 6 months of the year there have been more measles cases reported worldwide than in any year since 2006. From Jan. 1 to July 31, 2019, 182 countries reported 364,808 measles cases to the WHO. This surpasses the 129,239 reported during the same time period in 2018. WHO regions with the biggest increases in cases include the African region (900%), the Western Pacific region (230%), and the European region (150%),” according to a CDC report.
Studies on hospitalization and complications linked to measles in the United States are scarce, but two outbreaks in Minnesota (2011 and 2017) provided some data on what to expect if the measles surge continues into 2020. The investigators found that poor feeding was a primary reason for admission (97%); additional complications included otitis media (42%), pneumonia (30%), and tracheitis (6%). Three-quarters received antibiotics, 30% required oxygen, and 21% received vitamin A. Median length of stay was 3.7 days (range, 1.1-26.2 days) (Pediatr Infect Dis J. 2019 Jun;38[6]:547-52. doi: 10.1097/INF.0000000000002221).
‘Immunological amnesia’
Infection with the measles virus appears to reduce immunity to other pathogens, according to a paper published in Science (2019 Nov 1;366[6465]599-606).
The hypothesis that the measles virus could cause “immunological amnesia” by impairing immune memory is supported by early research showing children with measles had negative cutaneous tuberculin reactions after having previously tested positive.
“Subsequent studies have shown decreased interferon signaling, skewed cytokine responses, lymphopenia, and suppression of lymphocyte proliferation shortly after infection,” wrote Michael Mina, MD, from Brigham and Women’s Hospital in Boston, and coauthors.
“Given the variation in the degree of immune repertoire modulation we observed, we anticipate that future risk of morbidity and mortality after measles would not be homogeneous but would be skewed toward individuals with the most severe elimination of immunological memory,” they wrote. “These findings underscore the crucial need for continued widespread vaccination.”
In this study, researchers compared the levels of around 400 pathogen-specific antibodies in blood samples from 77 unvaccinated children, taken before and 2 months after natural measles infection, with 5 unvaccinated children who did not contract measles. A total of 34 children experienced mild measles, and 43 had severe measles.
They found that the samples taken after measles infection showed “substantial” reductions in the number of pathogen epitopes, compared with the samples from children who did not get infected with measles.
This amounted to approximately a 20% mean reduction in overall diversity or size of the antibody repertoire. However, in children who experienced severe measles, there was a median loss of 40% (range, 11%-62%) of antibody repertoire, compared with a median of 33% (range, 12%-73%) range in children who experienced mild infection. Meanwhile, the control subjects retained approximately 90% of their antibody repertoire over a similar or longer time period. Some children lost up to 70% of antibodies for specific pathogens.
Maternal-acquired immunity fades
In another study of measles immunity, maternal antibodies were found to be insufficient to provide immunity to infants after 6 months.
The study of 196 infants showed that maternal measles antibodies had dropped below the protective threshold by 3 months of age – well before the recommended age of 12-15 months for the first dose of MMR vaccine.
The odds of inadequate protection doubled for each additional month of age, Michelle Science, MD, of the University of Toronto and associates reported in Pediatrics (2019 Dec 1. doi 10.1542/peds.2019-0630).
“The widening gap between loss of maternal antibodies and measles vaccination described in our study leaves infants vulnerable to measles for much of their infancy and highlights the need for further research to support public health policy,” Dr. Science and colleagues wrote.
The researchers randomly selected 25 samples for each of eight different age groups: up to 30 days old; 1 month (31-60 days), 2 months (61-89 days), 3 months (90-119 days), 4 months, 5 months, 6-9 months, and 9-11 months.
Just over half the babies (56%) were male, and 35% had an underlying condition, but none had conditions that might affect antibody levels. The conditions were primarily a developmental delay or otherwise affecting the central nervous system, liver, or gastrointestinal function. Mean maternal age was 32 years.
To ensure high test sensitivity, the researchers used the plaque-reduction neutralization test to test for measles-neutralizing antibodies instead of using enzyme-linked immunosorbent assay, because “ELISA sensitivity decreases as antibody titers decrease,” Dr. Science and colleagues wrote. They used a neutralization titer of less than 192 mIU/mL as the threshold for protection against measles.
When the researchers calculated the predicted standardized mean antibody titer for infants with a mother aged 32 years, they determined their mean to be 541 mIU/mL at 1 month, 142 mIU/mL at 3 months (below the measles threshold of susceptibility of 192 mIU/mL), and 64 mIU/mL at 6 months. None of the infants had measles antibodies above the protective threshold at 6 months old, the authors noted.
Children’s odds of susceptibility to measles doubled for each additional month of age, after adjustment for infant sex and maternal age (odds ratio, 2.13). Children’s likelihood of susceptibility to measles modestly increased as maternal age increased in 5-year increments from 25 to 40 years.
Children with an underlying conditions had greater susceptibility to measles (83%), compared with those without a comorbidity (68%, P = .03). No difference in susceptibility existed between males and females or based on gestational age at birth (ranging from 37 to 41 weeks).
The Advisory Committee on Immunization Practices permits measles vaccination “as early as 6 months for infants who plan to travel internationally, infants with ongoing risk for exposure during measles outbreaks and as postexposure prophylaxis,” Huong Q. McLean, PhD, of Marshfield (Wisc.) Clinic Research Institute, and Walter A. Orenstein, MD, of Emory University, Atlanta, noted in an editorial.
The research was funded by the Public Health Ontario Project Initiation Fund. The authors had no relevant financial disclosures.
Bianca Nogrady and Tara Haelle contributed to this story.