Pulmonology

Accumulation of pleural fluid is a common clinical problem associated with malignancy. Malignant pleural effusions (MPEs) are the second most common cause of a pleural exudate, with more than 150,000 patients diagnosed annually in the United States alone.^1,2 MPEs represent advanced disease and are generally a poor prognostic indicator. Median survival for patients with MPE ranges from 3 to 12 months and depends on the tumor origin.³ In addition, MPEs are a frequent cause of dyspnea and discomfort, which adversely affect a patient’s quality of life. This group of patients requires substantial medical support to manage the burden of their disease, and providing effective therapeutic management remains a challenge. In the United States, there are approximately 126,000 admissions for MPE annually, with a median length of stay of 5.5 days.⁴ Thirty-day readmission rates are almost 40%, which is approximately 1.5 times higher than for acute myocardial infarction and 2 times higher than for congestive heart failure.⁵ In addition, palliative measures for patients with MPE are probably underutilized.⁶

This review is the first of 2 articles focusing on the management of MPE. Here, we discuss the pathophysiology of this disease process and provide an overview of the evaluation and diagnosis of MPE; available therapeutic options for the management of MPE are reviewed in a separate article.

Pathogenesis and Etiology

Normally, the thoracic cavity contains less than 15 mL of pleural fluid. Therefore, the visceral and parietal pleura are usually in close proximity to each other and the space between them is a potential space. Negative intrapleural pressures generated during regular breathing create a gradient for fluid movement into the pleural space from the parietal pleura dictated by Starling forces. Pleural fluid normally has low protein content and is primarily drained back into lymphatics through stomata lining the parietal pleura.⁷ This system’s ability to remove pleural fluid exceeds normal fluid production by 20- to 30-fold, suggesting that accumulation of excess pleural fluid requires a combination of increased fluid production and/or impaired fluid removal.⁸

Several mechanisms have been associated with the development of MPE. Pleural involvement by malignancy may occur from direct invasion of the pleural cavity by tumor (eg, lung cancer, breast cancer, chest wall neoplasms) or hematogenous spread of tumor to the pleura (eg, metastasis, non-Hodgkin lymphoma).^9,10 Pleural malignancies can produce cytokine and inflammatory mediators, which may directly increase fluid production or indirectly alter vascular permeability.^11,12 Tumor cells can also disrupt lymphatic drainage by occluding either pleural stomata or downstream lymphatic drainage. However, tumor involvement of the pleura does not always result in the development of an effusion and is only associated with fluid accumulation in approximately 60% of cases.^13,14 MPE have also been strongly associated with mediastinal metastases, likely resulting from obstruction of mediastinal lymphatics.^13,15,16

Pleural effusions with negative fluid cytology and pleural biopsies may result from secondary effects of tumor burden without direct pleural involvement and are referred to as paramalignant effusions. Common causes include thoracic duct obstruction (eg, Hodgkin lymphoma), bronchial obstruction, pneumonia, atelectasis, pulmonary embolism, trapped lung, and effects related to radiation or chemotherapy.¹⁵

Lung cancer is the most frequent cause of MPE and accounts for approximately one-third of cases. Other common primary tumor sites include breast, lymphoma, ovary, and gastrointestinal. Combined, these etiologies comprise about 75% of cases (Table 1).^4,5 Females comprise a greater percentage of patients with MPE mainly due to the prevalence of ovarian and breast cancer. Mesothelioma-related effusions may be more prevalent in certain parts of the world due to associated exposure to asbestos.¹⁷ The primary tumor origin remains unknown in approximately 10% of cases.⁴

Clinical Presentation and Response to Therapeutic Drainage

More than 75% of patients with MPE are symptomatic. Dyspnea is the most common symptom and is present in more than half of patients.¹⁵ The mechanism of dyspnea caused by large effusions may not be solely due to impaired lung volumes or gas exchange. Other associated factors include decreased chest wall compliance, mediastinal shift causing decreased volume of the contralateral lung, paradoxical motion of the diaphragm, inefficient muscle length-tension relationships resulting from the stretch of respiratory muscles, and reflex stimulation from the lungs and chest wall.^18-20 Other common presenting symptoms include cough, orthopnea, and chest pain. Hemoptysis suggests endobronchial involvement of the large airways. And, given the advanced nature of most MPEs, patients may also present with weight loss and cachexia.

A patient’s degree of symptom palliation and physiologic improvement in response to large-volume fluid removal is important to assess as these are important clinical factors that will influence management decision-making. Upwards of 50% of patients will not have significant palliation because they may be symptom-limited by other comorbid conditions, generalized deconditioning, or incomplete lung re-expansion. Presence of impaired lung compliance during fluid removal is also important to recognize. A trapped lung refers to a lung that cannot expand completely after removal of pleural fluid. Trapped lung may result from pleural-based malignancies or metastases, loculations and adhesions, or bronchial obstruction. Trapped lung is associated with high elastance (P_el) affecting pleural pressure-volume relationships (Figure 1). While clinically often considered together, some authors differentiate the category of incomplete lung expansion into 2 subgroups. In this context, the term trapped lung is used specifically to describe a mature, fibrous membrane that prevents lung re-expansion and is caused by a prior inflammatory pleural condition.²¹Entrapped lung describes incomplete lung expansion resulting from an active disease process, such as malignancy, ongoing infection, or rheumatologic pleurisy. Differences in pleural manometry can be seen in the 2 subgroups. Pleural manometry can be helpful to monitor for the generation of high negative intrapleural pressures during fluid removal, with negative pressures in excess of –19 cm H₂O being suggestive of trapped lung physiology.²² However routine use of pleural manometry has not been shown to avoid the development of procedure-related chest discomfort that develops when the lung is unable to expand in response to the removal of fluid.²³

Pleural Fluid Analysis and Pleural Biopsy

While most MPEs are protein-rich exudates, approximately 2% to 5% may be transudates.^24,25 MPEs often appear hemorrhagic, so a ratio of pleural fluid to blood serum hematocrit greater than 0.5 is used to distinguish a true hemothorax from bloody-appearing pleural fluid.²⁶ The cell count may be lymphocyte-predominant, but other cell types, such as eosinophils, do not exclude malignancy.²⁷ Fluid may have a low glucose concentration and pH as well.

Thoracentesis with pleural fluid cytology evaluation is the most common method of diagnosis. The diagnostic sensitivity of fluid cytology ranges from 62% to 90%, with variability resulting from the extent of disease and etiology of the primary malignancy.¹ If the initial pleural fluid analysis is not diagnostic, repeat thoracentesis can improve the diagnostic yield, but subsequent sampling has diminishing utility. In one series, diagnosis of malignancy was made by fluid cytology analysis in 65% of patients from the initial thoracentesis, 27% from a second procedure, but only 5% from a third procedure.²⁸ At least 50 to 60 mL of pleural fluid should be obtained for pleural fluid cytology, but analysis of significantly larger volumes may not appreciably improve diagnostic yield.^29,30

In addition to diagnostic yield, adequate sample cellularity to test for genetic driver mutations has become increasingly important given the rapid development of targeted therapies that are now available. The relative paucity of malignant cells in pleural fluid compared to other types of biopsies can make MPEs difficult to analyze for molecular markers. Newer generation assays have increased sensitivity, with one series reporting that pleural fluid was sufficient in 71.4% of cases to analyze for a panel comprised of EGFR, KRAS, BRAF, ALK, and ROS1 mutations.³¹ Similarly, fluid analysis from patients with MPEs demonstrated that 71.3% had at least 100 tumor cells, which permitted evaluation for PD-L1, with a concordance of 0.78 when compared to matched parenchymal lung biopsies from the same patient.³²

In contrast, pleural biopsy methods may be useful to increase the diagnostic yield when pleural fluid analysis is insufficient. Closed needle biopsy may marginally improve diagnostic yields for malignancy over pleural fluid analysis alone. Diagnostic sensitivity may improve with the use of point-of-care ultrasonography to guide needle placement.^33,34 The true value of closed needle biopsy is seen in situations in which there is a high pretest probability to diagnose an alternative disseminated pleural process, such as in tuberculosis, where the diagnostic yield increases substantially with closed needle biopsy of the pleura.³³ Otherwise, the diagnosis of lung cancer and mesothelioma is superior with visually guided pleural biopsies, such as medical thoracoscopy or video-assisted thoracoscopic surgery (VATS), with diagnostic yields over 90%.^33,35 Testing for genetic driver mutations in pleural biopsies is also substantially improved, with sample adequacy of 90% to 95% for most molecular markers.^36,37 Despite the advantages, pleural biopsies are generally reserved for cases when pleural fluid analysis is insufficient or when performed in conjunction with palliative therapeutic interventions due to the increased invasive nature of the procedure.

Not all MPEs will progress in size or become symptomatic, and predicting which patients will develop symptoms from their effusions is difficult. Pleural effusions will develop in only a minority of patients with lung cancer, and only a small subset will progress and require therapeutic intervention.^38,39 Therefore, management guidelines for malignant pleural effusions discourage empiric intervention for patients with small, asymptomatic effusions.⁴⁰ However, patients with larger, symptomatic effusions are more likely to have significant and rapid fluid recurrence. In a series of 988 symptomatic patients undergoing drainage, 30% had fluid recurrence within 15 days, 40% within 30 days, 45% within 60 days, and 48% within 90 days.⁴¹ Factors associated with fluid recurrence included radiographic size of the effusion, requirement for a larger amount of fluid to be initially drained, and higher pleural fluid lactate dehydrogenase (LDH) level. Negative cytology was associated with lower likelihood for recurrence.

Prognostication of life expectancy is another important clinical assessment which impacts medical decision-making when weighing the risk and benefits of different palliation options. Patient performance status, pleural fluid LDH, serum neutrophil-to-lymphocyte ratio, and tumor origin are independently associated with prognosis in a validated scoring system (Table 2).³ In this study, the overall median survival of patients with MPE was approximately 4.5 months, while the median survival for patients with mesothelioma was 11.3 months, 6.6 months for breast cancer, and 2.5 months for lung cancer and other malignancies. When stratified based on the combination of these 4 variables, patients in the high-risk group had a median survival of just 44 days compared to 130 days for the moderate-risk group and 319 days for the low-risk group. Additional, more complex prediction systems for survival and response to MPE therapies are now emerging and may provide clinicians and patients with additional information useful in medical decision-making.⁴²

Conclusion

MPEs represent advanced stage disease and frequently adversely affect a pa­tient’s quality of life. Ideal therapeutic options, discussed in the second part of this review, should effectively palliate symptoms, provide long-term relief, be minimally invasive with few side effects, minimize hospitalization and reliance on medical assistance, and be cost-effective.

Accumulation of pleural fluid is a common clinical problem associated with malignancy. Malignant pleural effusions (MPEs) are the second most common cause of a pleural exudate, with more than 150,000 patients diagnosed annually in the United States alone.^1,2 MPEs represent advanced disease and are generally a poor prognostic indicator. Median survival for patients with MPE ranges from 3 to 12 months and depends on the tumor origin.³ In addition, MPEs are a frequent cause of dyspnea and discomfort, which adversely affect a patient’s quality of life. This group of patients requires substantial medical support to manage the burden of their disease, and providing effective therapeutic management remains a challenge. In the United States, there are approximately 126,000 admissions for MPE annually, with a median length of stay of 5.5 days.⁴ Thirty-day readmission rates are almost 40%, which is approximately 1.5 times higher than for acute myocardial infarction and 2 times higher than for congestive heart failure.⁵ In addition, palliative measures for patients with MPE are probably underutilized.⁶

This review is the first of 2 articles focusing on the management of MPE. Here, we discuss the pathophysiology of this disease process and provide an overview of the evaluation and diagnosis of MPE; available therapeutic options for the management of MPE are reviewed in a separate article.

Pathogenesis and Etiology

Normally, the thoracic cavity contains less than 15 mL of pleural fluid. Therefore, the visceral and parietal pleura are usually in close proximity to each other and the space between them is a potential space. Negative intrapleural pressures generated during regular breathing create a gradient for fluid movement into the pleural space from the parietal pleura dictated by Starling forces. Pleural fluid normally has low protein content and is primarily drained back into lymphatics through stomata lining the parietal pleura.⁷ This system’s ability to remove pleural fluid exceeds normal fluid production by 20- to 30-fold, suggesting that accumulation of excess pleural fluid requires a combination of increased fluid production and/or impaired fluid removal.⁸

Several mechanisms have been associated with the development of MPE. Pleural involvement by malignancy may occur from direct invasion of the pleural cavity by tumor (eg, lung cancer, breast cancer, chest wall neoplasms) or hematogenous spread of tumor to the pleura (eg, metastasis, non-Hodgkin lymphoma).^9,10 Pleural malignancies can produce cytokine and inflammatory mediators, which may directly increase fluid production or indirectly alter vascular permeability.^11,12 Tumor cells can also disrupt lymphatic drainage by occluding either pleural stomata or downstream lymphatic drainage. However, tumor involvement of the pleura does not always result in the development of an effusion and is only associated with fluid accumulation in approximately 60% of cases.^13,14 MPE have also been strongly associated with mediastinal metastases, likely resulting from obstruction of mediastinal lymphatics.^13,15,16

Pleural effusions with negative fluid cytology and pleural biopsies may result from secondary effects of tumor burden without direct pleural involvement and are referred to as paramalignant effusions. Common causes include thoracic duct obstruction (eg, Hodgkin lymphoma), bronchial obstruction, pneumonia, atelectasis, pulmonary embolism, trapped lung, and effects related to radiation or chemotherapy.¹⁵

Lung cancer is the most frequent cause of MPE and accounts for approximately one-third of cases. Other common primary tumor sites include breast, lymphoma, ovary, and gastrointestinal. Combined, these etiologies comprise about 75% of cases (Table 1).^4,5 Females comprise a greater percentage of patients with MPE mainly due to the prevalence of ovarian and breast cancer. Mesothelioma-related effusions may be more prevalent in certain parts of the world due to associated exposure to asbestos.¹⁷ The primary tumor origin remains unknown in approximately 10% of cases.⁴

Clinical Presentation and Response to Therapeutic Drainage

More than 75% of patients with MPE are symptomatic. Dyspnea is the most common symptom and is present in more than half of patients.¹⁵ The mechanism of dyspnea caused by large effusions may not be solely due to impaired lung volumes or gas exchange. Other associated factors include decreased chest wall compliance, mediastinal shift causing decreased volume of the contralateral lung, paradoxical motion of the diaphragm, inefficient muscle length-tension relationships resulting from the stretch of respiratory muscles, and reflex stimulation from the lungs and chest wall.^18-20 Other common presenting symptoms include cough, orthopnea, and chest pain. Hemoptysis suggests endobronchial involvement of the large airways. And, given the advanced nature of most MPEs, patients may also present with weight loss and cachexia.

A patient’s degree of symptom palliation and physiologic improvement in response to large-volume fluid removal is important to assess as these are important clinical factors that will influence management decision-making. Upwards of 50% of patients will not have significant palliation because they may be symptom-limited by other comorbid conditions, generalized deconditioning, or incomplete lung re-expansion. Presence of impaired lung compliance during fluid removal is also important to recognize. A trapped lung refers to a lung that cannot expand completely after removal of pleural fluid. Trapped lung may result from pleural-based malignancies or metastases, loculations and adhesions, or bronchial obstruction. Trapped lung is associated with high elastance (P_el) affecting pleural pressure-volume relationships (Figure 1). While clinically often considered together, some authors differentiate the category of incomplete lung expansion into 2 subgroups. In this context, the term trapped lung is used specifically to describe a mature, fibrous membrane that prevents lung re-expansion and is caused by a prior inflammatory pleural condition.²¹Entrapped lung describes incomplete lung expansion resulting from an active disease process, such as malignancy, ongoing infection, or rheumatologic pleurisy. Differences in pleural manometry can be seen in the 2 subgroups. Pleural manometry can be helpful to monitor for the generation of high negative intrapleural pressures during fluid removal, with negative pressures in excess of –19 cm H₂O being suggestive of trapped lung physiology.²² However routine use of pleural manometry has not been shown to avoid the development of procedure-related chest discomfort that develops when the lung is unable to expand in response to the removal of fluid.²³

Pleural Fluid Analysis and Pleural Biopsy

While most MPEs are protein-rich exudates, approximately 2% to 5% may be transudates.^24,25 MPEs often appear hemorrhagic, so a ratio of pleural fluid to blood serum hematocrit greater than 0.5 is used to distinguish a true hemothorax from bloody-appearing pleural fluid.²⁶ The cell count may be lymphocyte-predominant, but other cell types, such as eosinophils, do not exclude malignancy.²⁷ Fluid may have a low glucose concentration and pH as well.

Thoracentesis with pleural fluid cytology evaluation is the most common method of diagnosis. The diagnostic sensitivity of fluid cytology ranges from 62% to 90%, with variability resulting from the extent of disease and etiology of the primary malignancy.¹ If the initial pleural fluid analysis is not diagnostic, repeat thoracentesis can improve the diagnostic yield, but subsequent sampling has diminishing utility. In one series, diagnosis of malignancy was made by fluid cytology analysis in 65% of patients from the initial thoracentesis, 27% from a second procedure, but only 5% from a third procedure.²⁸ At least 50 to 60 mL of pleural fluid should be obtained for pleural fluid cytology, but analysis of significantly larger volumes may not appreciably improve diagnostic yield.^29,30

In addition to diagnostic yield, adequate sample cellularity to test for genetic driver mutations has become increasingly important given the rapid development of targeted therapies that are now available. The relative paucity of malignant cells in pleural fluid compared to other types of biopsies can make MPEs difficult to analyze for molecular markers. Newer generation assays have increased sensitivity, with one series reporting that pleural fluid was sufficient in 71.4% of cases to analyze for a panel comprised of EGFR, KRAS, BRAF, ALK, and ROS1 mutations.³¹ Similarly, fluid analysis from patients with MPEs demonstrated that 71.3% had at least 100 tumor cells, which permitted evaluation for PD-L1, with a concordance of 0.78 when compared to matched parenchymal lung biopsies from the same patient.³²

In contrast, pleural biopsy methods may be useful to increase the diagnostic yield when pleural fluid analysis is insufficient. Closed needle biopsy may marginally improve diagnostic yields for malignancy over pleural fluid analysis alone. Diagnostic sensitivity may improve with the use of point-of-care ultrasonography to guide needle placement.^33,34 The true value of closed needle biopsy is seen in situations in which there is a high pretest probability to diagnose an alternative disseminated pleural process, such as in tuberculosis, where the diagnostic yield increases substantially with closed needle biopsy of the pleura.³³ Otherwise, the diagnosis of lung cancer and mesothelioma is superior with visually guided pleural biopsies, such as medical thoracoscopy or video-assisted thoracoscopic surgery (VATS), with diagnostic yields over 90%.^33,35 Testing for genetic driver mutations in pleural biopsies is also substantially improved, with sample adequacy of 90% to 95% for most molecular markers.^36,37 Despite the advantages, pleural biopsies are generally reserved for cases when pleural fluid analysis is insufficient or when performed in conjunction with palliative therapeutic interventions due to the increased invasive nature of the procedure.

Not all MPEs will progress in size or become symptomatic, and predicting which patients will develop symptoms from their effusions is difficult. Pleural effusions will develop in only a minority of patients with lung cancer, and only a small subset will progress and require therapeutic intervention.^38,39 Therefore, management guidelines for malignant pleural effusions discourage empiric intervention for patients with small, asymptomatic effusions.⁴⁰ However, patients with larger, symptomatic effusions are more likely to have significant and rapid fluid recurrence. In a series of 988 symptomatic patients undergoing drainage, 30% had fluid recurrence within 15 days, 40% within 30 days, 45% within 60 days, and 48% within 90 days.⁴¹ Factors associated with fluid recurrence included radiographic size of the effusion, requirement for a larger amount of fluid to be initially drained, and higher pleural fluid lactate dehydrogenase (LDH) level. Negative cytology was associated with lower likelihood for recurrence.

Prognostication of life expectancy is another important clinical assessment which impacts medical decision-making when weighing the risk and benefits of different palliation options. Patient performance status, pleural fluid LDH, serum neutrophil-to-lymphocyte ratio, and tumor origin are independently associated with prognosis in a validated scoring system (Table 2).³ In this study, the overall median survival of patients with MPE was approximately 4.5 months, while the median survival for patients with mesothelioma was 11.3 months, 6.6 months for breast cancer, and 2.5 months for lung cancer and other malignancies. When stratified based on the combination of these 4 variables, patients in the high-risk group had a median survival of just 44 days compared to 130 days for the moderate-risk group and 319 days for the low-risk group. Additional, more complex prediction systems for survival and response to MPE therapies are now emerging and may provide clinicians and patients with additional information useful in medical decision-making.⁴²

Conclusion

MPEs represent advanced stage disease and frequently adversely affect a pa­tient’s quality of life. Ideal therapeutic options, discussed in the second part of this review, should effectively palliate symptoms, provide long-term relief, be minimally invasive with few side effects, minimize hospitalization and reliance on medical assistance, and be cost-effective.

Accumulation of pleural fluid is a common clinical problem associated with malignancy. Malignant pleural effusions (MPEs) are the second most common cause of a pleural exudate, with more than 150,000 patients diagnosed annually in the United States alone.^1,2 MPEs represent advanced disease and are generally a poor prognostic indicator. Median survival for patients with MPE ranges from 3 to 12 months and depends on the tumor origin.³ In addition, MPEs are a frequent cause of dyspnea and discomfort, which adversely affect a patient’s quality of life. This group of patients requires substantial medical support to manage the burden of their disease, and providing effective therapeutic management remains a challenge. In the United States, there are approximately 126,000 admissions for MPE annually, with a median length of stay of 5.5 days.⁴ Thirty-day readmission rates are almost 40%, which is approximately 1.5 times higher than for acute myocardial infarction and 2 times higher than for congestive heart failure.⁵ In addition, palliative measures for patients with MPE are probably underutilized.⁶

This review is the first of 2 articles focusing on the management of MPE. Here, we discuss the pathophysiology of this disease process and provide an overview of the evaluation and diagnosis of MPE; available therapeutic options for the management of MPE are reviewed in a separate article.

Pathogenesis and Etiology

Normally, the thoracic cavity contains less than 15 mL of pleural fluid. Therefore, the visceral and parietal pleura are usually in close proximity to each other and the space between them is a potential space. Negative intrapleural pressures generated during regular breathing create a gradient for fluid movement into the pleural space from the parietal pleura dictated by Starling forces. Pleural fluid normally has low protein content and is primarily drained back into lymphatics through stomata lining the parietal pleura.⁷ This system’s ability to remove pleural fluid exceeds normal fluid production by 20- to 30-fold, suggesting that accumulation of excess pleural fluid requires a combination of increased fluid production and/or impaired fluid removal.⁸

Several mechanisms have been associated with the development of MPE. Pleural involvement by malignancy may occur from direct invasion of the pleural cavity by tumor (eg, lung cancer, breast cancer, chest wall neoplasms) or hematogenous spread of tumor to the pleura (eg, metastasis, non-Hodgkin lymphoma).^9,10 Pleural malignancies can produce cytokine and inflammatory mediators, which may directly increase fluid production or indirectly alter vascular permeability.^11,12 Tumor cells can also disrupt lymphatic drainage by occluding either pleural stomata or downstream lymphatic drainage. However, tumor involvement of the pleura does not always result in the development of an effusion and is only associated with fluid accumulation in approximately 60% of cases.^13,14 MPE have also been strongly associated with mediastinal metastases, likely resulting from obstruction of mediastinal lymphatics.^13,15,16

Pleural effusions with negative fluid cytology and pleural biopsies may result from secondary effects of tumor burden without direct pleural involvement and are referred to as paramalignant effusions. Common causes include thoracic duct obstruction (eg, Hodgkin lymphoma), bronchial obstruction, pneumonia, atelectasis, pulmonary embolism, trapped lung, and effects related to radiation or chemotherapy.¹⁵

Lung cancer is the most frequent cause of MPE and accounts for approximately one-third of cases. Other common primary tumor sites include breast, lymphoma, ovary, and gastrointestinal. Combined, these etiologies comprise about 75% of cases (Table 1).^4,5 Females comprise a greater percentage of patients with MPE mainly due to the prevalence of ovarian and breast cancer. Mesothelioma-related effusions may be more prevalent in certain parts of the world due to associated exposure to asbestos.¹⁷ The primary tumor origin remains unknown in approximately 10% of cases.⁴

Clinical Presentation and Response to Therapeutic Drainage

More than 75% of patients with MPE are symptomatic. Dyspnea is the most common symptom and is present in more than half of patients.¹⁵ The mechanism of dyspnea caused by large effusions may not be solely due to impaired lung volumes or gas exchange. Other associated factors include decreased chest wall compliance, mediastinal shift causing decreased volume of the contralateral lung, paradoxical motion of the diaphragm, inefficient muscle length-tension relationships resulting from the stretch of respiratory muscles, and reflex stimulation from the lungs and chest wall.^18-20 Other common presenting symptoms include cough, orthopnea, and chest pain. Hemoptysis suggests endobronchial involvement of the large airways. And, given the advanced nature of most MPEs, patients may also present with weight loss and cachexia.

A patient’s degree of symptom palliation and physiologic improvement in response to large-volume fluid removal is important to assess as these are important clinical factors that will influence management decision-making. Upwards of 50% of patients will not have significant palliation because they may be symptom-limited by other comorbid conditions, generalized deconditioning, or incomplete lung re-expansion. Presence of impaired lung compliance during fluid removal is also important to recognize. A trapped lung refers to a lung that cannot expand completely after removal of pleural fluid. Trapped lung may result from pleural-based malignancies or metastases, loculations and adhesions, or bronchial obstruction. Trapped lung is associated with high elastance (P_el) affecting pleural pressure-volume relationships (Figure 1). While clinically often considered together, some authors differentiate the category of incomplete lung expansion into 2 subgroups. In this context, the term trapped lung is used specifically to describe a mature, fibrous membrane that prevents lung re-expansion and is caused by a prior inflammatory pleural condition.²¹Entrapped lung describes incomplete lung expansion resulting from an active disease process, such as malignancy, ongoing infection, or rheumatologic pleurisy. Differences in pleural manometry can be seen in the 2 subgroups. Pleural manometry can be helpful to monitor for the generation of high negative intrapleural pressures during fluid removal, with negative pressures in excess of –19 cm H₂O being suggestive of trapped lung physiology.²² However routine use of pleural manometry has not been shown to avoid the development of procedure-related chest discomfort that develops when the lung is unable to expand in response to the removal of fluid.²³

Pleural Fluid Analysis and Pleural Biopsy

While most MPEs are protein-rich exudates, approximately 2% to 5% may be transudates.^24,25 MPEs often appear hemorrhagic, so a ratio of pleural fluid to blood serum hematocrit greater than 0.5 is used to distinguish a true hemothorax from bloody-appearing pleural fluid.²⁶ The cell count may be lymphocyte-predominant, but other cell types, such as eosinophils, do not exclude malignancy.²⁷ Fluid may have a low glucose concentration and pH as well.

Thoracentesis with pleural fluid cytology evaluation is the most common method of diagnosis. The diagnostic sensitivity of fluid cytology ranges from 62% to 90%, with variability resulting from the extent of disease and etiology of the primary malignancy.¹ If the initial pleural fluid analysis is not diagnostic, repeat thoracentesis can improve the diagnostic yield, but subsequent sampling has diminishing utility. In one series, diagnosis of malignancy was made by fluid cytology analysis in 65% of patients from the initial thoracentesis, 27% from a second procedure, but only 5% from a third procedure.²⁸ At least 50 to 60 mL of pleural fluid should be obtained for pleural fluid cytology, but analysis of significantly larger volumes may not appreciably improve diagnostic yield.^29,30

In addition to diagnostic yield, adequate sample cellularity to test for genetic driver mutations has become increasingly important given the rapid development of targeted therapies that are now available. The relative paucity of malignant cells in pleural fluid compared to other types of biopsies can make MPEs difficult to analyze for molecular markers. Newer generation assays have increased sensitivity, with one series reporting that pleural fluid was sufficient in 71.4% of cases to analyze for a panel comprised of EGFR, KRAS, BRAF, ALK, and ROS1 mutations.³¹ Similarly, fluid analysis from patients with MPEs demonstrated that 71.3% had at least 100 tumor cells, which permitted evaluation for PD-L1, with a concordance of 0.78 when compared to matched parenchymal lung biopsies from the same patient.³²

In contrast, pleural biopsy methods may be useful to increase the diagnostic yield when pleural fluid analysis is insufficient. Closed needle biopsy may marginally improve diagnostic yields for malignancy over pleural fluid analysis alone. Diagnostic sensitivity may improve with the use of point-of-care ultrasonography to guide needle placement.^33,34 The true value of closed needle biopsy is seen in situations in which there is a high pretest probability to diagnose an alternative disseminated pleural process, such as in tuberculosis, where the diagnostic yield increases substantially with closed needle biopsy of the pleura.³³ Otherwise, the diagnosis of lung cancer and mesothelioma is superior with visually guided pleural biopsies, such as medical thoracoscopy or video-assisted thoracoscopic surgery (VATS), with diagnostic yields over 90%.^33,35 Testing for genetic driver mutations in pleural biopsies is also substantially improved, with sample adequacy of 90% to 95% for most molecular markers.^36,37 Despite the advantages, pleural biopsies are generally reserved for cases when pleural fluid analysis is insufficient or when performed in conjunction with palliative therapeutic interventions due to the increased invasive nature of the procedure.

Not all MPEs will progress in size or become symptomatic, and predicting which patients will develop symptoms from their effusions is difficult. Pleural effusions will develop in only a minority of patients with lung cancer, and only a small subset will progress and require therapeutic intervention.^38,39 Therefore, management guidelines for malignant pleural effusions discourage empiric intervention for patients with small, asymptomatic effusions.⁴⁰ However, patients with larger, symptomatic effusions are more likely to have significant and rapid fluid recurrence. In a series of 988 symptomatic patients undergoing drainage, 30% had fluid recurrence within 15 days, 40% within 30 days, 45% within 60 days, and 48% within 90 days.⁴¹ Factors associated with fluid recurrence included radiographic size of the effusion, requirement for a larger amount of fluid to be initially drained, and higher pleural fluid lactate dehydrogenase (LDH) level. Negative cytology was associated with lower likelihood for recurrence.

Prognostication of life expectancy is another important clinical assessment which impacts medical decision-making when weighing the risk and benefits of different palliation options. Patient performance status, pleural fluid LDH, serum neutrophil-to-lymphocyte ratio, and tumor origin are independently associated with prognosis in a validated scoring system (Table 2).³ In this study, the overall median survival of patients with MPE was approximately 4.5 months, while the median survival for patients with mesothelioma was 11.3 months, 6.6 months for breast cancer, and 2.5 months for lung cancer and other malignancies. When stratified based on the combination of these 4 variables, patients in the high-risk group had a median survival of just 44 days compared to 130 days for the moderate-risk group and 319 days for the low-risk group. Additional, more complex prediction systems for survival and response to MPE therapies are now emerging and may provide clinicians and patients with additional information useful in medical decision-making.⁴²

Conclusion

MPEs represent advanced stage disease and frequently adversely affect a pa­tient’s quality of life. Ideal therapeutic options, discussed in the second part of this review, should effectively palliate symptoms, provide long-term relief, be minimally invasive with few side effects, minimize hospitalization and reliance on medical assistance, and be cost-effective.

The first death to occur in a patient with severe lung illness associated with e-cigarette product use has been reported in Illinois, officials announced at a Centers for Disease Control and Prevention telebriefing.

The cause for the mysterious lung illnesses has not been determined, but an infectious disease does not appear to be implicated. As of yesterday, 193 potential cases have been identified in 22 states since June 28.

No specific product has been implicated in all cases, and it is unclear if there is a common cause or if these are several diseases with a similar presentation.

Wisconsin and Illinois have asked the CDC to directly assist them in their investigations of cases. Other states are handling their own investigations. Further information is available from the CDC at cdc.gov/e-cigarettes.

There have been 22 cases of the illness in Illinois and an additional 12 individuals are being evaluated as possible cases, according to Jennifer Layden, MD, PhD, chief medical officer and state epidemiologist, Illinois Department of Public Health.

Illinois is working with the CDC and the Food and Drug Administration to investigate devices that affected patients have used. No specific product has been implicated across all cases; all patients have reported vaping in recent months Several patients in Illinois have reported using tetrahydrocannabinol (THC) product oils, but Dr. Layden reiterated the investigations are reliant on information reported by affected patients only.

Mitch Zeller, JD, director, Center for Tobacco Products at the FDA, said product samples from a number of states are being evaluated to determine their contents. The FDA is examining samples sent and trying to identify product contents.

The cases reported to date have been in adults aged 17-38 years and have occurred primarily men. The investigation is in a relatively early stage and is working with incomplete case reports. These will become standardized to include more specific information, such as the name of the product, where it was purchased, and whether it was used as intended or whether other products were added, he said.

As e-cigarettes are not a new product, it’s possible that cases of this illness has been occurring but that the link was not recognized, and the cases were neither captured nor reported, said Brian King, PhD, MPH, deputy director, Research Translation, Office on Smoking and Health, CDC. He noted that e-cigarettes may contain “a variety of constituents that could be problematic in terms of pulmonary illness,” such as ingredients in certain flavorings and ultrafine particulates.

The agencies are now trying to harmonize reporting across all states so cases can be evaluated in a more standardized way. Information on standardized reporting on a national level will be issued in the next few days, according to the CDC.

The CDC notified U.S. health care systems and clinicians about the illnesses and what to watch for via a Clinician Outreach and Communication Activity Clinical Action Message.

In general, patients have reported a gradual onset of symptoms including shortness of breath or chest pain that increased over days or weeks before hospital admission. Gastrointestinal symptoms including vomiting, diarrhea, and fatigue have been reported by some.
 

[email protected]

The first death to occur in a patient with severe lung illness associated with e-cigarette product use has been reported in Illinois, officials announced at a Centers for Disease Control and Prevention telebriefing.

The cause for the mysterious lung illnesses has not been determined, but an infectious disease does not appear to be implicated. As of yesterday, 193 potential cases have been identified in 22 states since June 28.

No specific product has been implicated in all cases, and it is unclear if there is a common cause or if these are several diseases with a similar presentation.

Wisconsin and Illinois have asked the CDC to directly assist them in their investigations of cases. Other states are handling their own investigations. Further information is available from the CDC at cdc.gov/e-cigarettes.

There have been 22 cases of the illness in Illinois and an additional 12 individuals are being evaluated as possible cases, according to Jennifer Layden, MD, PhD, chief medical officer and state epidemiologist, Illinois Department of Public Health.

Illinois is working with the CDC and the Food and Drug Administration to investigate devices that affected patients have used. No specific product has been implicated across all cases; all patients have reported vaping in recent months Several patients in Illinois have reported using tetrahydrocannabinol (THC) product oils, but Dr. Layden reiterated the investigations are reliant on information reported by affected patients only.

Mitch Zeller, JD, director, Center for Tobacco Products at the FDA, said product samples from a number of states are being evaluated to determine their contents. The FDA is examining samples sent and trying to identify product contents.

The cases reported to date have been in adults aged 17-38 years and have occurred primarily men. The investigation is in a relatively early stage and is working with incomplete case reports. These will become standardized to include more specific information, such as the name of the product, where it was purchased, and whether it was used as intended or whether other products were added, he said.

As e-cigarettes are not a new product, it’s possible that cases of this illness has been occurring but that the link was not recognized, and the cases were neither captured nor reported, said Brian King, PhD, MPH, deputy director, Research Translation, Office on Smoking and Health, CDC. He noted that e-cigarettes may contain “a variety of constituents that could be problematic in terms of pulmonary illness,” such as ingredients in certain flavorings and ultrafine particulates.

The agencies are now trying to harmonize reporting across all states so cases can be evaluated in a more standardized way. Information on standardized reporting on a national level will be issued in the next few days, according to the CDC.

The CDC notified U.S. health care systems and clinicians about the illnesses and what to watch for via a Clinician Outreach and Communication Activity Clinical Action Message.

In general, patients have reported a gradual onset of symptoms including shortness of breath or chest pain that increased over days or weeks before hospital admission. Gastrointestinal symptoms including vomiting, diarrhea, and fatigue have been reported by some.
 

[email protected]

The first death to occur in a patient with severe lung illness associated with e-cigarette product use has been reported in Illinois, officials announced at a Centers for Disease Control and Prevention telebriefing.

The cause for the mysterious lung illnesses has not been determined, but an infectious disease does not appear to be implicated. As of yesterday, 193 potential cases have been identified in 22 states since June 28.

No specific product has been implicated in all cases, and it is unclear if there is a common cause or if these are several diseases with a similar presentation.

Wisconsin and Illinois have asked the CDC to directly assist them in their investigations of cases. Other states are handling their own investigations. Further information is available from the CDC at cdc.gov/e-cigarettes.

There have been 22 cases of the illness in Illinois and an additional 12 individuals are being evaluated as possible cases, according to Jennifer Layden, MD, PhD, chief medical officer and state epidemiologist, Illinois Department of Public Health.

Illinois is working with the CDC and the Food and Drug Administration to investigate devices that affected patients have used. No specific product has been implicated across all cases; all patients have reported vaping in recent months Several patients in Illinois have reported using tetrahydrocannabinol (THC) product oils, but Dr. Layden reiterated the investigations are reliant on information reported by affected patients only.

Mitch Zeller, JD, director, Center for Tobacco Products at the FDA, said product samples from a number of states are being evaluated to determine their contents. The FDA is examining samples sent and trying to identify product contents.

The cases reported to date have been in adults aged 17-38 years and have occurred primarily men. The investigation is in a relatively early stage and is working with incomplete case reports. These will become standardized to include more specific information, such as the name of the product, where it was purchased, and whether it was used as intended or whether other products were added, he said.

As e-cigarettes are not a new product, it’s possible that cases of this illness has been occurring but that the link was not recognized, and the cases were neither captured nor reported, said Brian King, PhD, MPH, deputy director, Research Translation, Office on Smoking and Health, CDC. He noted that e-cigarettes may contain “a variety of constituents that could be problematic in terms of pulmonary illness,” such as ingredients in certain flavorings and ultrafine particulates.

The agencies are now trying to harmonize reporting across all states so cases can be evaluated in a more standardized way. Information on standardized reporting on a national level will be issued in the next few days, according to the CDC.

The CDC notified U.S. health care systems and clinicians about the illnesses and what to watch for via a Clinician Outreach and Communication Activity Clinical Action Message.

In general, patients have reported a gradual onset of symptoms including shortness of breath or chest pain that increased over days or weeks before hospital admission. Gastrointestinal symptoms including vomiting, diarrhea, and fatigue have been reported by some.
 

[email protected]

John E. Parker, MD, was working at a West Virginia hospital in 2015 when a 31-year-old female patient was admitted with acute respiratory problems. A team of doctors ultimately suspected that her mysterious case of lipoid pneumonia might be related to vaping and weren’t sure they had seen anything like it before. They were intrigued enough to submit the case for presentation at the CHEST Annual Meeting that year (Chest. 2015;148:382A. doi: 10.1378/chest.2274860).

Now, almost 4 years later, federal officials have begun investigating a national outbreak of severe lung illnesses linked to vaping that has struck more than 150 patients in 16 states. In an interview, Dr. Parker, a professor of pulmonary critical care and sleep medicine at West Virginia University, Morgantown, described what happened.
 

Q: Can you describe what the patient’s symptoms were when she arrived?

We would view them as classic for what is getting to be called vaping-associated lung disease. She was very, very short of breath and had a cough, and we were, of course, very worried that she might have pneumonia or some other acute respiratory illness. And then she was so sick she needed to be intubated.

Q: What happens next in cases like this?

We look for things like a [hemorrhage] or an active infection. And then for lipid-containing macrophages. And then we usually start some antibiotics [and a] low-dose steroid and then support the patient with a ventilator and oxygen and nutrition. And then just kind of wait and see if any other cultures come back to prove anything different than what you might be thinking.

Early on, we just felt like it was an unusual case and may not be a common viral or bacterial infection.
 

Q: How did you figure out the cause of her lipoid pneumonia was e-cigarettes?

It’s a diagnosis of exclusion. We excluded other [options], and it became the most likely cause.

We were convinced enough that the case was submitted for [presentation at the CHEST annual meeting] and was accepted.
 

Q: Once you figured out the cause could be e-cigarettes, did you contact the Centers for Disease Control and Prevention or the Food and Drug Administration or any other regulatory agency to tell them about this?

We did not. We felt at the time that putting it in the medical literature was appropriate. And if other case reports from other parts of the country came forward, then we’d have more of a clustering of findings that might then warrant research agencies [getting a] better understanding [about] the cause of the disease.

Q: Which federal agency would you report it to, if you did?

In 2015, the FDA, of course, was still regulating cigarettes, but I don’t think the government had yet decided who would regulate vaping products. So I’m sure it was unclear who we should call.

Q: So did you or your team think this was a one-off event when you witnessed it?

We really felt that it wasn’t going to be a one-off event and that it was what we usually called in public health a “sentinel” health event … that it was an example of a respiratory illness that can be caused by this exposure and that it probably wasn’t the first case ever seen nor would it be the last.

Q: Was it the first case that you had seen at your institution?

To our knowledge it was our first case, but we are humble enough clinicians to realize we may have missed some other cases that we interpreted [as] viral pneumonia or bacterial pneumonia.

Q: Have you seen more cases since then?

I know we’ve seen a case [of alveolar hemorrhage syndrome] that we published, and in polling some colleagues, we think we’ve probably also seen [cases of] cryptogenic organizing pneumonia as well as lipoid pneumonia and acute eosinophilic pneumonia. Yeah, we’ve certainly seen at least probably four forms of lung disease from vaping.

Q: If your team was seeing this back in 2015, is it possible that it’s been happening in the four years since then and people just don’t know about it?

I really have every reason to think we were not the first ones to see it, by any means.

And I don’t think we were even the first ones to report it. I think that there were some clusters in Wisconsin and some other places in the United States. I also know that the Japanese have been very interested. They’ve probably got four or five papers at least in the medical literature about vaping-related lung injury.
 

Q: Do you have a theory of what might be causing the lipoid pneumonia cases? Do you think there may be certain chemicals that are irritants?

We need a strong multidisciplinary team to understand the real etiology and cause of lung injury from inhalation. I think it could be any number of components in the mixtures. Lungs don’t like oil, in general, and probably the most specific agent that’s been studied recently is diacetyl, which was studied in popcorn-flavoring lung disease.

Q: Have these kinds of cases changed the way you approach patients?

Yeah, we search very carefully for a history of vaping. … I think it’s quite important to understand if they might be using inhaled agents or vaping that might present new toxicities to the lung.

Q: Will these illnesses have long-term health effects?

An inhalational injury may cause an acute lung injury that’s life-threatening and that someone may survive from and have no long-term sequelae [condition]. But there also is the possibility that long-term [e-cigarette] use may cause more insidious or chronic diseases from which there may not be a full recovery.

Kaiser Health News is a nonprofit news service covering health issues. It is an editorially independent program of the Kaiser Family Foundation, which is not affiliated with Kaiser Permanente.

John E. Parker, MD, was working at a West Virginia hospital in 2015 when a 31-year-old female patient was admitted with acute respiratory problems. A team of doctors ultimately suspected that her mysterious case of lipoid pneumonia might be related to vaping and weren’t sure they had seen anything like it before. They were intrigued enough to submit the case for presentation at the CHEST Annual Meeting that year (Chest. 2015;148:382A. doi: 10.1378/chest.2274860).

Now, almost 4 years later, federal officials have begun investigating a national outbreak of severe lung illnesses linked to vaping that has struck more than 150 patients in 16 states. In an interview, Dr. Parker, a professor of pulmonary critical care and sleep medicine at West Virginia University, Morgantown, described what happened.
 

Q: Can you describe what the patient’s symptoms were when she arrived?

We would view them as classic for what is getting to be called vaping-associated lung disease. She was very, very short of breath and had a cough, and we were, of course, very worried that she might have pneumonia or some other acute respiratory illness. And then she was so sick she needed to be intubated.

Q: What happens next in cases like this?

We look for things like a [hemorrhage] or an active infection. And then for lipid-containing macrophages. And then we usually start some antibiotics [and a] low-dose steroid and then support the patient with a ventilator and oxygen and nutrition. And then just kind of wait and see if any other cultures come back to prove anything different than what you might be thinking.

Early on, we just felt like it was an unusual case and may not be a common viral or bacterial infection.
 

Q: How did you figure out the cause of her lipoid pneumonia was e-cigarettes?

It’s a diagnosis of exclusion. We excluded other [options], and it became the most likely cause.

We were convinced enough that the case was submitted for [presentation at the CHEST annual meeting] and was accepted.
 

Q: Once you figured out the cause could be e-cigarettes, did you contact the Centers for Disease Control and Prevention or the Food and Drug Administration or any other regulatory agency to tell them about this?

We did not. We felt at the time that putting it in the medical literature was appropriate. And if other case reports from other parts of the country came forward, then we’d have more of a clustering of findings that might then warrant research agencies [getting a] better understanding [about] the cause of the disease.

Q: Which federal agency would you report it to, if you did?

In 2015, the FDA, of course, was still regulating cigarettes, but I don’t think the government had yet decided who would regulate vaping products. So I’m sure it was unclear who we should call.

Q: So did you or your team think this was a one-off event when you witnessed it?

We really felt that it wasn’t going to be a one-off event and that it was what we usually called in public health a “sentinel” health event … that it was an example of a respiratory illness that can be caused by this exposure and that it probably wasn’t the first case ever seen nor would it be the last.

Q: Was it the first case that you had seen at your institution?

To our knowledge it was our first case, but we are humble enough clinicians to realize we may have missed some other cases that we interpreted [as] viral pneumonia or bacterial pneumonia.

Q: Have you seen more cases since then?

I know we’ve seen a case [of alveolar hemorrhage syndrome] that we published, and in polling some colleagues, we think we’ve probably also seen [cases of] cryptogenic organizing pneumonia as well as lipoid pneumonia and acute eosinophilic pneumonia. Yeah, we’ve certainly seen at least probably four forms of lung disease from vaping.

Q: If your team was seeing this back in 2015, is it possible that it’s been happening in the four years since then and people just don’t know about it?

I really have every reason to think we were not the first ones to see it, by any means.

And I don’t think we were even the first ones to report it. I think that there were some clusters in Wisconsin and some other places in the United States. I also know that the Japanese have been very interested. They’ve probably got four or five papers at least in the medical literature about vaping-related lung injury.
 

Q: Do you have a theory of what might be causing the lipoid pneumonia cases? Do you think there may be certain chemicals that are irritants?

We need a strong multidisciplinary team to understand the real etiology and cause of lung injury from inhalation. I think it could be any number of components in the mixtures. Lungs don’t like oil, in general, and probably the most specific agent that’s been studied recently is diacetyl, which was studied in popcorn-flavoring lung disease.

Q: Have these kinds of cases changed the way you approach patients?

Yeah, we search very carefully for a history of vaping. … I think it’s quite important to understand if they might be using inhaled agents or vaping that might present new toxicities to the lung.

Q: Will these illnesses have long-term health effects?

An inhalational injury may cause an acute lung injury that’s life-threatening and that someone may survive from and have no long-term sequelae [condition]. But there also is the possibility that long-term [e-cigarette] use may cause more insidious or chronic diseases from which there may not be a full recovery.

Kaiser Health News is a nonprofit news service covering health issues. It is an editorially independent program of the Kaiser Family Foundation, which is not affiliated with Kaiser Permanente.

John E. Parker, MD, was working at a West Virginia hospital in 2015 when a 31-year-old female patient was admitted with acute respiratory problems. A team of doctors ultimately suspected that her mysterious case of lipoid pneumonia might be related to vaping and weren’t sure they had seen anything like it before. They were intrigued enough to submit the case for presentation at the CHEST Annual Meeting that year (Chest. 2015;148:382A. doi: 10.1378/chest.2274860).

Now, almost 4 years later, federal officials have begun investigating a national outbreak of severe lung illnesses linked to vaping that has struck more than 150 patients in 16 states. In an interview, Dr. Parker, a professor of pulmonary critical care and sleep medicine at West Virginia University, Morgantown, described what happened.
 

Q: Can you describe what the patient’s symptoms were when she arrived?

We would view them as classic for what is getting to be called vaping-associated lung disease. She was very, very short of breath and had a cough, and we were, of course, very worried that she might have pneumonia or some other acute respiratory illness. And then she was so sick she needed to be intubated.

Q: What happens next in cases like this?

We look for things like a [hemorrhage] or an active infection. And then for lipid-containing macrophages. And then we usually start some antibiotics [and a] low-dose steroid and then support the patient with a ventilator and oxygen and nutrition. And then just kind of wait and see if any other cultures come back to prove anything different than what you might be thinking.

Early on, we just felt like it was an unusual case and may not be a common viral or bacterial infection.
 

Q: How did you figure out the cause of her lipoid pneumonia was e-cigarettes?

It’s a diagnosis of exclusion. We excluded other [options], and it became the most likely cause.

We were convinced enough that the case was submitted for [presentation at the CHEST annual meeting] and was accepted.
 

Q: Once you figured out the cause could be e-cigarettes, did you contact the Centers for Disease Control and Prevention or the Food and Drug Administration or any other regulatory agency to tell them about this?

We did not. We felt at the time that putting it in the medical literature was appropriate. And if other case reports from other parts of the country came forward, then we’d have more of a clustering of findings that might then warrant research agencies [getting a] better understanding [about] the cause of the disease.

Q: Which federal agency would you report it to, if you did?

In 2015, the FDA, of course, was still regulating cigarettes, but I don’t think the government had yet decided who would regulate vaping products. So I’m sure it was unclear who we should call.

Q: So did you or your team think this was a one-off event when you witnessed it?

We really felt that it wasn’t going to be a one-off event and that it was what we usually called in public health a “sentinel” health event … that it was an example of a respiratory illness that can be caused by this exposure and that it probably wasn’t the first case ever seen nor would it be the last.

Q: Was it the first case that you had seen at your institution?

To our knowledge it was our first case, but we are humble enough clinicians to realize we may have missed some other cases that we interpreted [as] viral pneumonia or bacterial pneumonia.

Q: Have you seen more cases since then?

I know we’ve seen a case [of alveolar hemorrhage syndrome] that we published, and in polling some colleagues, we think we’ve probably also seen [cases of] cryptogenic organizing pneumonia as well as lipoid pneumonia and acute eosinophilic pneumonia. Yeah, we’ve certainly seen at least probably four forms of lung disease from vaping.

Q: If your team was seeing this back in 2015, is it possible that it’s been happening in the four years since then and people just don’t know about it?

I really have every reason to think we were not the first ones to see it, by any means.

And I don’t think we were even the first ones to report it. I think that there were some clusters in Wisconsin and some other places in the United States. I also know that the Japanese have been very interested. They’ve probably got four or five papers at least in the medical literature about vaping-related lung injury.
 

Q: Do you have a theory of what might be causing the lipoid pneumonia cases? Do you think there may be certain chemicals that are irritants?

We need a strong multidisciplinary team to understand the real etiology and cause of lung injury from inhalation. I think it could be any number of components in the mixtures. Lungs don’t like oil, in general, and probably the most specific agent that’s been studied recently is diacetyl, which was studied in popcorn-flavoring lung disease.

Q: Have these kinds of cases changed the way you approach patients?

Yeah, we search very carefully for a history of vaping. … I think it’s quite important to understand if they might be using inhaled agents or vaping that might present new toxicities to the lung.

Q: Will these illnesses have long-term health effects?

An inhalational injury may cause an acute lung injury that’s life-threatening and that someone may survive from and have no long-term sequelae [condition]. But there also is the possibility that long-term [e-cigarette] use may cause more insidious or chronic diseases from which there may not be a full recovery.

Kaiser Health News is a nonprofit news service covering health issues. It is an editorially independent program of the Kaiser Family Foundation, which is not affiliated with Kaiser Permanente.

LJUBLJANA, SLOVENIA – Fever of unknown origin and pneumonia are two clinical features useful in distinguishing between influenza and respiratory syncytial virus infection as the cause of hospitalization in infants and young children, Cihan Papan, MD, reported at the annual meeting of the European Society for Paediatric Infectious Diseases.

Bruce Jancin/MDedge News

Dr. Papan, a pediatrician at University Children’s Hospital Mannheim (Germany) and Heidelberg (Germany) University, presented a retrospective single-center study of all 573 children aged under 2 years hospitalized over the course of several seasons for respiratory syncytial virus (RSV) or influenza as confirmed by rapid antigen testing. Even though these are two of the leading causes of hospitalization among young children, there is surprisingly sparse data comparing the two in terms of disease severity and hospital resource utilization, including antibiotic consumption. That information gap provided the basis for this study.

There were 476 children with confirmed RSV, 96 with influenza, and 1 RSV/influenza coinfection. Notably, even though the RSV group had lower temperatures and C-reactive protein levels, they were nevertheless more likely to be treated with antibiotics, by a margin of 29% to 23%.

“These findings open new possibilities for antimicrobial stewardship in these groups of virally infected children,” observed Dr. Papan.

Fever of unknown origin was present in 68.8% of the influenza-positive patients, compared with just 0.2% of the RSV-positive children. In contrast, 50.2% of the RSV group had pneumonia and 49.6% had bronchitis or bronchiolitis, versus just 22.9% and 6.3% of the influenza patients, respectively. A larger proportion of the young children with RSV infection presented in a severely ill–looking condition. Children with RSV infection also were significantly younger.

Dr. Papan reported having no financial conflicts regarding his study.

[email protected]

LJUBLJANA, SLOVENIA – Fever of unknown origin and pneumonia are two clinical features useful in distinguishing between influenza and respiratory syncytial virus infection as the cause of hospitalization in infants and young children, Cihan Papan, MD, reported at the annual meeting of the European Society for Paediatric Infectious Diseases.

Bruce Jancin/MDedge News

Dr. Papan, a pediatrician at University Children’s Hospital Mannheim (Germany) and Heidelberg (Germany) University, presented a retrospective single-center study of all 573 children aged under 2 years hospitalized over the course of several seasons for respiratory syncytial virus (RSV) or influenza as confirmed by rapid antigen testing. Even though these are two of the leading causes of hospitalization among young children, there is surprisingly sparse data comparing the two in terms of disease severity and hospital resource utilization, including antibiotic consumption. That information gap provided the basis for this study.

There were 476 children with confirmed RSV, 96 with influenza, and 1 RSV/influenza coinfection. Notably, even though the RSV group had lower temperatures and C-reactive protein levels, they were nevertheless more likely to be treated with antibiotics, by a margin of 29% to 23%.

“These findings open new possibilities for antimicrobial stewardship in these groups of virally infected children,” observed Dr. Papan.

Fever of unknown origin was present in 68.8% of the influenza-positive patients, compared with just 0.2% of the RSV-positive children. In contrast, 50.2% of the RSV group had pneumonia and 49.6% had bronchitis or bronchiolitis, versus just 22.9% and 6.3% of the influenza patients, respectively. A larger proportion of the young children with RSV infection presented in a severely ill–looking condition. Children with RSV infection also were significantly younger.

Dr. Papan reported having no financial conflicts regarding his study.

[email protected]

LJUBLJANA, SLOVENIA – Fever of unknown origin and pneumonia are two clinical features useful in distinguishing between influenza and respiratory syncytial virus infection as the cause of hospitalization in infants and young children, Cihan Papan, MD, reported at the annual meeting of the European Society for Paediatric Infectious Diseases.

Bruce Jancin/MDedge News

Dr. Papan, a pediatrician at University Children’s Hospital Mannheim (Germany) and Heidelberg (Germany) University, presented a retrospective single-center study of all 573 children aged under 2 years hospitalized over the course of several seasons for respiratory syncytial virus (RSV) or influenza as confirmed by rapid antigen testing. Even though these are two of the leading causes of hospitalization among young children, there is surprisingly sparse data comparing the two in terms of disease severity and hospital resource utilization, including antibiotic consumption. That information gap provided the basis for this study.

There were 476 children with confirmed RSV, 96 with influenza, and 1 RSV/influenza coinfection. Notably, even though the RSV group had lower temperatures and C-reactive protein levels, they were nevertheless more likely to be treated with antibiotics, by a margin of 29% to 23%.

“These findings open new possibilities for antimicrobial stewardship in these groups of virally infected children,” observed Dr. Papan.

Fever of unknown origin was present in 68.8% of the influenza-positive patients, compared with just 0.2% of the RSV-positive children. In contrast, 50.2% of the RSV group had pneumonia and 49.6% had bronchitis or bronchiolitis, versus just 22.9% and 6.3% of the influenza patients, respectively. A larger proportion of the young children with RSV infection presented in a severely ill–looking condition. Children with RSV infection also were significantly younger.

Dr. Papan reported having no financial conflicts regarding his study.

[email protected]

More than 150 cases of severe lung illness possibly related to e-cigarette use in adolescents and young adults have been reported in 16 states, according to an Aug. 21 update from officials at the Centers for Disease Control and Prevention.

licsiren/iStock/Getty Images

Officials from the CDC and the Food and Drug Administration are working with state health officials to gather information on the cases as well as any products or substances that might be involved.

A total of 153 potential cases were reported between June 28 and Aug. 20 in 16 states – California, Connecticut, Florida, Illinois, Indiana, Iowa, Michigan, Minnesota, New Jersey, New Mexico, New York, North Carolina, Pennsylvania, Texas, Utah, and Wisconsin.

Health officials have yet to find a cause for these illnesses; however, all patients have reported e-cigarette use or vaping, according to a CDC statement. Evidence to date does not seem to indicate that an infectious agent is the cause.

In general, patients have reported a gradual onset of symptoms including shortness of breath and/or chest pain that increased over days or weeks before hospital admission. Gastrointestinal symptoms including vomiting, diarrhea, and fatigue have been reported by some.

Many patients reported using products containing tetrahydrocannabinol, though no specific or consistent product has been linked definitively.

While cases reported across the country seem to be similar, there is no evidence currently indicating they have a common cause, according to the CDC statement.

The CDC is urging health care professionals to report possible cases to their state or local health department and the FDA is urging the public to provide detailed reports of any unusual or unexpected health concerns related to tobacco use or e-cigarette use through its Safety Reporting Portal.

[email protected]

More than 150 cases of severe lung illness possibly related to e-cigarette use in adolescents and young adults have been reported in 16 states, according to an Aug. 21 update from officials at the Centers for Disease Control and Prevention.

licsiren/iStock/Getty Images

Officials from the CDC and the Food and Drug Administration are working with state health officials to gather information on the cases as well as any products or substances that might be involved.

A total of 153 potential cases were reported between June 28 and Aug. 20 in 16 states – California, Connecticut, Florida, Illinois, Indiana, Iowa, Michigan, Minnesota, New Jersey, New Mexico, New York, North Carolina, Pennsylvania, Texas, Utah, and Wisconsin.

Health officials have yet to find a cause for these illnesses; however, all patients have reported e-cigarette use or vaping, according to a CDC statement. Evidence to date does not seem to indicate that an infectious agent is the cause.

In general, patients have reported a gradual onset of symptoms including shortness of breath and/or chest pain that increased over days or weeks before hospital admission. Gastrointestinal symptoms including vomiting, diarrhea, and fatigue have been reported by some.

Many patients reported using products containing tetrahydrocannabinol, though no specific or consistent product has been linked definitively.

While cases reported across the country seem to be similar, there is no evidence currently indicating they have a common cause, according to the CDC statement.

The CDC is urging health care professionals to report possible cases to their state or local health department and the FDA is urging the public to provide detailed reports of any unusual or unexpected health concerns related to tobacco use or e-cigarette use through its Safety Reporting Portal.

[email protected]

More than 150 cases of severe lung illness possibly related to e-cigarette use in adolescents and young adults have been reported in 16 states, according to an Aug. 21 update from officials at the Centers for Disease Control and Prevention.

licsiren/iStock/Getty Images

Officials from the CDC and the Food and Drug Administration are working with state health officials to gather information on the cases as well as any products or substances that might be involved.

A total of 153 potential cases were reported between June 28 and Aug. 20 in 16 states – California, Connecticut, Florida, Illinois, Indiana, Iowa, Michigan, Minnesota, New Jersey, New Mexico, New York, North Carolina, Pennsylvania, Texas, Utah, and Wisconsin.

Health officials have yet to find a cause for these illnesses; however, all patients have reported e-cigarette use or vaping, according to a CDC statement. Evidence to date does not seem to indicate that an infectious agent is the cause.

In general, patients have reported a gradual onset of symptoms including shortness of breath and/or chest pain that increased over days or weeks before hospital admission. Gastrointestinal symptoms including vomiting, diarrhea, and fatigue have been reported by some.

Many patients reported using products containing tetrahydrocannabinol, though no specific or consistent product has been linked definitively.

While cases reported across the country seem to be similar, there is no evidence currently indicating they have a common cause, according to the CDC statement.

The CDC is urging health care professionals to report possible cases to their state or local health department and the FDA is urging the public to provide detailed reports of any unusual or unexpected health concerns related to tobacco use or e-cigarette use through its Safety Reporting Portal.

[email protected]

Regardless of where people live in the world, air pollution is linked to increased rates of cardiovascular disease, respiratory problems, and all-cause mortality, according to one of the largest studies ever to assess the effects of inhalable particulate matter (PM), published Aug. 21 in the New England Journal of Medicine.

“These data reinforce the evidence of a link between mortality and PM concentration established in regional and local studies,” reported Cong Liu of the Huazhong University of Science and Technology in Wuhan, China, and an international team of researchers.

“Many people are experiencing worse allergy and asthma symptoms in the setting of increased heat and worse air quality,” Caren G. Solomon, MD, of Harvard Medical School, Boston, said in an interview. “It is often not appreciated that these are complications of climate change.”

Other such complications include heat-related illnesses and severe weather events, as well as the less visible manifestations, such as shifts in the epidemiology of vector-borne infectious disease, Dr. Solomon and colleagues wrote in an editorial accompanying Mr. Liu’s study.

“The stark reality is that high levels of greenhouse gases caused by the combustion of fossil fuels – and the resulting rise in temperature and sea levels and intensification of extreme weather – are having profound consequences for human health and health systems,” Dr. Solomon and colleagues wrote (N Engl J Med. 2019;381:773-4.).

In the new air pollution study, Mr. Liu and colleagues analyzed 59.6 million deaths from 652 cities across 24 countries, “thereby greatly increasing the generalizability of the association and decreasing the likelihood that the reported associations are subject to confounding bias,” wrote John R. Balmes, MD, of the University of California, San Francisco, and the University of California, Berkeley, in an editorial about the study (N Engl J Med. 2019;381:774-6).

The researchers compared air pollution data from 1986-2015 from the Multi-City Multi-Country (MCC) Collaborative Research Network to mortality data reported from individual countries. They assessed PM with an aerodynamic diameter of 10 mcg or less (PM10; n = 598 cities) and PM with an aerodynamic diameter of 2.5 mcg or less (PM_2.5; n=499 cities).

Mr. Liu’s team used a time-series analysis – a standard upon which the majority of air pollution research relies. These studies “include daily measures of health events (e.g., daily mortality), regressed against concentrations of PM (e.g., 24-hour average PM_2.5) and weather variables (e.g., daily average temperature) for a given geographic area,” Dr. Balmes wrote. “The population serves as its own control, and confounding by population characteristics is negligible because these are stable over short time frames.”

The researchers found a 0.44% increase in daily all-cause mortality for each 10-mcg/m³ increase in the 2-day moving average (current and previous day) of PM₁₀. The same increase was linked to a 0.36% increase in daily cardiovascular mortality and a 0.47% increase in daily respiratory mortality. Similarly, a 10-mcg/m³ increase in the PM_2.5 average was linked to 0.68% increase in all-cause mortality, a 0.55% increase in cardiovascular mortality, and 0.74% increase in respiratory mortality.

Locations with higher annual mean temperatures showed stronger associations, and all these associations remained statistically significant after the researchers adjusted for gaseous pollutants.

Although the majority of countries and cities included in the study came from the northern hemisphere, the researchers noted that the magnitude of effect they found, particularly for PM₁₀ concentrations, matched up with that seen in previous studies of multiple cities or countries.

Still, they found “significant evidence of spatial heterogeneity in the associations between PM concentration and daily mortality across countries and regions.” Among the factors that could contribute to those variations are “different PM components, long-term air pollution levels, population susceptibility, and different lengths of study periods,” they speculated.

What makes this study remarkable – despite decades of previous similar studies – is its size and the implications of a curvilinear shape in its concentration-response relation, according to Dr. Balmes.

“The current study of PM data from many regions around the world provides the strongest evidence to date that higher levels of exposure may be associated with a lower per-unit risk,” Dr. Balmes wrote. “Regions that have lower exposures had a higher per-unit risk. This finding has profound policy implications, especially given that no threshold of effect was found. Even high-income countries, such as the United States, with relatively good air quality could still see public health benefits from further reduction of ambient PM concentrations.”

The policy implications, however, extend well beyond clean air regulations because the findings represent just one aspect of climate change’s negative effects on health, which are “frighteningly broad,” Dr. Solomon and colleagues wrote.

“As climate change continues to alter disease patterns and disrupt health systems, its effects on human health will become harder to ignore,” they wrote. “We, as a medical community, have the responsibility and the opportunity to mobilize the urgent, large-scale climate action required to protect health – as well as the ingenuity to develop novel and bold interventions to avert the most catastrophic outcomes.”

The new research and associated commentary marked the introduction of a new NEJM topic on climate change effects on health and health systems.
 

SOURCE: Liu C et al. N Engl J Med. 2019;381:705-15.

This article was updated 8/22/19.

Regardless of where people live in the world, air pollution is linked to increased rates of cardiovascular disease, respiratory problems, and all-cause mortality, according to one of the largest studies ever to assess the effects of inhalable particulate matter (PM), published Aug. 21 in the New England Journal of Medicine.

“These data reinforce the evidence of a link between mortality and PM concentration established in regional and local studies,” reported Cong Liu of the Huazhong University of Science and Technology in Wuhan, China, and an international team of researchers.

“Many people are experiencing worse allergy and asthma symptoms in the setting of increased heat and worse air quality,” Caren G. Solomon, MD, of Harvard Medical School, Boston, said in an interview. “It is often not appreciated that these are complications of climate change.”

Other such complications include heat-related illnesses and severe weather events, as well as the less visible manifestations, such as shifts in the epidemiology of vector-borne infectious disease, Dr. Solomon and colleagues wrote in an editorial accompanying Mr. Liu’s study.

“The stark reality is that high levels of greenhouse gases caused by the combustion of fossil fuels – and the resulting rise in temperature and sea levels and intensification of extreme weather – are having profound consequences for human health and health systems,” Dr. Solomon and colleagues wrote (N Engl J Med. 2019;381:773-4.).

In the new air pollution study, Mr. Liu and colleagues analyzed 59.6 million deaths from 652 cities across 24 countries, “thereby greatly increasing the generalizability of the association and decreasing the likelihood that the reported associations are subject to confounding bias,” wrote John R. Balmes, MD, of the University of California, San Francisco, and the University of California, Berkeley, in an editorial about the study (N Engl J Med. 2019;381:774-6).

The researchers compared air pollution data from 1986-2015 from the Multi-City Multi-Country (MCC) Collaborative Research Network to mortality data reported from individual countries. They assessed PM with an aerodynamic diameter of 10 mcg or less (PM10; n = 598 cities) and PM with an aerodynamic diameter of 2.5 mcg or less (PM_2.5; n=499 cities).

Mr. Liu’s team used a time-series analysis – a standard upon which the majority of air pollution research relies. These studies “include daily measures of health events (e.g., daily mortality), regressed against concentrations of PM (e.g., 24-hour average PM_2.5) and weather variables (e.g., daily average temperature) for a given geographic area,” Dr. Balmes wrote. “The population serves as its own control, and confounding by population characteristics is negligible because these are stable over short time frames.”

The researchers found a 0.44% increase in daily all-cause mortality for each 10-mcg/m³ increase in the 2-day moving average (current and previous day) of PM₁₀. The same increase was linked to a 0.36% increase in daily cardiovascular mortality and a 0.47% increase in daily respiratory mortality. Similarly, a 10-mcg/m³ increase in the PM_2.5 average was linked to 0.68% increase in all-cause mortality, a 0.55% increase in cardiovascular mortality, and 0.74% increase in respiratory mortality.

Locations with higher annual mean temperatures showed stronger associations, and all these associations remained statistically significant after the researchers adjusted for gaseous pollutants.

Although the majority of countries and cities included in the study came from the northern hemisphere, the researchers noted that the magnitude of effect they found, particularly for PM₁₀ concentrations, matched up with that seen in previous studies of multiple cities or countries.

Still, they found “significant evidence of spatial heterogeneity in the associations between PM concentration and daily mortality across countries and regions.” Among the factors that could contribute to those variations are “different PM components, long-term air pollution levels, population susceptibility, and different lengths of study periods,” they speculated.

What makes this study remarkable – despite decades of previous similar studies – is its size and the implications of a curvilinear shape in its concentration-response relation, according to Dr. Balmes.

“The current study of PM data from many regions around the world provides the strongest evidence to date that higher levels of exposure may be associated with a lower per-unit risk,” Dr. Balmes wrote. “Regions that have lower exposures had a higher per-unit risk. This finding has profound policy implications, especially given that no threshold of effect was found. Even high-income countries, such as the United States, with relatively good air quality could still see public health benefits from further reduction of ambient PM concentrations.”

The policy implications, however, extend well beyond clean air regulations because the findings represent just one aspect of climate change’s negative effects on health, which are “frighteningly broad,” Dr. Solomon and colleagues wrote.

“As climate change continues to alter disease patterns and disrupt health systems, its effects on human health will become harder to ignore,” they wrote. “We, as a medical community, have the responsibility and the opportunity to mobilize the urgent, large-scale climate action required to protect health – as well as the ingenuity to develop novel and bold interventions to avert the most catastrophic outcomes.”

The new research and associated commentary marked the introduction of a new NEJM topic on climate change effects on health and health systems.
 

SOURCE: Liu C et al. N Engl J Med. 2019;381:705-15.

This article was updated 8/22/19.

Regardless of where people live in the world, air pollution is linked to increased rates of cardiovascular disease, respiratory problems, and all-cause mortality, according to one of the largest studies ever to assess the effects of inhalable particulate matter (PM), published Aug. 21 in the New England Journal of Medicine.

“These data reinforce the evidence of a link between mortality and PM concentration established in regional and local studies,” reported Cong Liu of the Huazhong University of Science and Technology in Wuhan, China, and an international team of researchers.

“Many people are experiencing worse allergy and asthma symptoms in the setting of increased heat and worse air quality,” Caren G. Solomon, MD, of Harvard Medical School, Boston, said in an interview. “It is often not appreciated that these are complications of climate change.”

Other such complications include heat-related illnesses and severe weather events, as well as the less visible manifestations, such as shifts in the epidemiology of vector-borne infectious disease, Dr. Solomon and colleagues wrote in an editorial accompanying Mr. Liu’s study.

“The stark reality is that high levels of greenhouse gases caused by the combustion of fossil fuels – and the resulting rise in temperature and sea levels and intensification of extreme weather – are having profound consequences for human health and health systems,” Dr. Solomon and colleagues wrote (N Engl J Med. 2019;381:773-4.).

In the new air pollution study, Mr. Liu and colleagues analyzed 59.6 million deaths from 652 cities across 24 countries, “thereby greatly increasing the generalizability of the association and decreasing the likelihood that the reported associations are subject to confounding bias,” wrote John R. Balmes, MD, of the University of California, San Francisco, and the University of California, Berkeley, in an editorial about the study (N Engl J Med. 2019;381:774-6).

The researchers compared air pollution data from 1986-2015 from the Multi-City Multi-Country (MCC) Collaborative Research Network to mortality data reported from individual countries. They assessed PM with an aerodynamic diameter of 10 mcg or less (PM10; n = 598 cities) and PM with an aerodynamic diameter of 2.5 mcg or less (PM_2.5; n=499 cities).

Mr. Liu’s team used a time-series analysis – a standard upon which the majority of air pollution research relies. These studies “include daily measures of health events (e.g., daily mortality), regressed against concentrations of PM (e.g., 24-hour average PM_2.5) and weather variables (e.g., daily average temperature) for a given geographic area,” Dr. Balmes wrote. “The population serves as its own control, and confounding by population characteristics is negligible because these are stable over short time frames.”

The researchers found a 0.44% increase in daily all-cause mortality for each 10-mcg/m³ increase in the 2-day moving average (current and previous day) of PM₁₀. The same increase was linked to a 0.36% increase in daily cardiovascular mortality and a 0.47% increase in daily respiratory mortality. Similarly, a 10-mcg/m³ increase in the PM_2.5 average was linked to 0.68% increase in all-cause mortality, a 0.55% increase in cardiovascular mortality, and 0.74% increase in respiratory mortality.

Locations with higher annual mean temperatures showed stronger associations, and all these associations remained statistically significant after the researchers adjusted for gaseous pollutants.

Although the majority of countries and cities included in the study came from the northern hemisphere, the researchers noted that the magnitude of effect they found, particularly for PM₁₀ concentrations, matched up with that seen in previous studies of multiple cities or countries.

Still, they found “significant evidence of spatial heterogeneity in the associations between PM concentration and daily mortality across countries and regions.” Among the factors that could contribute to those variations are “different PM components, long-term air pollution levels, population susceptibility, and different lengths of study periods,” they speculated.

What makes this study remarkable – despite decades of previous similar studies – is its size and the implications of a curvilinear shape in its concentration-response relation, according to Dr. Balmes.

“The current study of PM data from many regions around the world provides the strongest evidence to date that higher levels of exposure may be associated with a lower per-unit risk,” Dr. Balmes wrote. “Regions that have lower exposures had a higher per-unit risk. This finding has profound policy implications, especially given that no threshold of effect was found. Even high-income countries, such as the United States, with relatively good air quality could still see public health benefits from further reduction of ambient PM concentrations.”

The policy implications, however, extend well beyond clean air regulations because the findings represent just one aspect of climate change’s negative effects on health, which are “frighteningly broad,” Dr. Solomon and colleagues wrote.

“As climate change continues to alter disease patterns and disrupt health systems, its effects on human health will become harder to ignore,” they wrote. “We, as a medical community, have the responsibility and the opportunity to mobilize the urgent, large-scale climate action required to protect health – as well as the ingenuity to develop novel and bold interventions to avert the most catastrophic outcomes.”

The new research and associated commentary marked the introduction of a new NEJM topic on climate change effects on health and health systems.
 

SOURCE: Liu C et al. N Engl J Med. 2019;381:705-15.

This article was updated 8/22/19.

The Food and Drug Administration has announced its approval of lefamulin (Xenleta) for the treatment of community-acquired bacterial pneumonia in adults.

Olivier Le Moal/Getty Images

Approval was based on results of two clinical trials assessing a total of 1,289 people with community-acquired bacterial pneumonia. In these trials, lefamulin was compared with moxifloxacin with and without linezolid. Patients who received lefamulin had similar rates of treatment success as those taking moxifloxacin alone or moxifloxacin plus linezolid.

The most common adverse reactions associated with lefamulin include diarrhea, nausea, reactions at the injection site, elevated liver enzymes, and vomiting. Patients with prolonged QT interval, patients with arrhythmias, patients receiving treatment with antiarrhythmic agents, and patients receiving other drugs that prolong the QT interval are contraindicated. In addition, because of evidence of fetal harm in animal studies, pregnant women should be advised of potential risks before receiving lefamulin.

“This new drug provides another option for the treatment of patients with community-acquired bacterial pneumonia, a serious disease. For managing this serious disease, it is important for physicians and patients to have treatment options,” Ed Cox, MD, MPH, director of the FDA’s Office of Antimicrobial Products, said in the press release.

[email protected]

The Food and Drug Administration has announced its approval of lefamulin (Xenleta) for the treatment of community-acquired bacterial pneumonia in adults.

Olivier Le Moal/Getty Images

Approval was based on results of two clinical trials assessing a total of 1,289 people with community-acquired bacterial pneumonia. In these trials, lefamulin was compared with moxifloxacin with and without linezolid. Patients who received lefamulin had similar rates of treatment success as those taking moxifloxacin alone or moxifloxacin plus linezolid.

The most common adverse reactions associated with lefamulin include diarrhea, nausea, reactions at the injection site, elevated liver enzymes, and vomiting. Patients with prolonged QT interval, patients with arrhythmias, patients receiving treatment with antiarrhythmic agents, and patients receiving other drugs that prolong the QT interval are contraindicated. In addition, because of evidence of fetal harm in animal studies, pregnant women should be advised of potential risks before receiving lefamulin.

“This new drug provides another option for the treatment of patients with community-acquired bacterial pneumonia, a serious disease. For managing this serious disease, it is important for physicians and patients to have treatment options,” Ed Cox, MD, MPH, director of the FDA’s Office of Antimicrobial Products, said in the press release.

[email protected]

The Food and Drug Administration has announced its approval of lefamulin (Xenleta) for the treatment of community-acquired bacterial pneumonia in adults.

Olivier Le Moal/Getty Images

Approval was based on results of two clinical trials assessing a total of 1,289 people with community-acquired bacterial pneumonia. In these trials, lefamulin was compared with moxifloxacin with and without linezolid. Patients who received lefamulin had similar rates of treatment success as those taking moxifloxacin alone or moxifloxacin plus linezolid.

The most common adverse reactions associated with lefamulin include diarrhea, nausea, reactions at the injection site, elevated liver enzymes, and vomiting. Patients with prolonged QT interval, patients with arrhythmias, patients receiving treatment with antiarrhythmic agents, and patients receiving other drugs that prolong the QT interval are contraindicated. In addition, because of evidence of fetal harm in animal studies, pregnant women should be advised of potential risks before receiving lefamulin.

“This new drug provides another option for the treatment of patients with community-acquired bacterial pneumonia, a serious disease. For managing this serious disease, it is important for physicians and patients to have treatment options,” Ed Cox, MD, MPH, director of the FDA’s Office of Antimicrobial Products, said in the press release.

[email protected]

Quitting smoking significantly reduces the risk of cardiovascular disease, but past smokers are still at elevated cardiovascular risk, compared with nonsmokers, for up to 25 years after smoking cessation, research in JAMA suggests.

AtnoYdur/Thinkstock

A retrospective analysis of data from 8,770 individuals in the Framingham Heart Study compared the incidence of myocardial infarction, stroke, heart failure, or cardiovascular death in ever-smokers with that of never smokers.

Only 40% of the total cohort had never smoked. Of the 4,115 current smokers at baseline, 38.6% quit during the course of the study and did not relapse but 51.4% continued to smoke until they developed cardiovascular disease or dropped out of the study.

Current smokers had a significant 4.68-fold higher incidence of cardiovascular disease, compared with those who had never smoked, but those who stopped smoking showed a 39% decline in their risk of cardiovascular disease within 5 years of cessation.

However, individuals who were formerly heavy smokers – defined as at least 20 pack-years of smoking – retained a risk of cardiovascular disease 25% higher than that of never smokers until 10-15 years after quitting smoking. At 16 years, the 95% confidence interval for cardiovascular disease risk among former smokers versus that of never smokers finally and consistently included the null value of 1.

The study pooled two cohorts; the original cohort, who attended their fourth examination during 1954-1958 and an offspring cohort who attended their first examination during 1971-1975. The authors saw a difference between the two cohorts in the time course of cardiovascular disease risk in heavy smokers.

In the original cohort, former heavy smoking ceased to be significantly associated with increased cardiovascular disease risk within 5-10 years of cessation, but in the offspring cohort, it took 25 years after cessation for the incidence to decline to the same level of risk seen in never smokers.

“The upper estimate of this time course is a decade longer than that of the Nurses’ Health Study results for coronary heart disease and cardiovascular death and more than 20 years longer than in some prior reports for coronary heart disease and stroke,” wrote Meredith S. Duncan from the division of cardiovascular medicine at the Vanderbilt University Medical Center, Nashville, Tenn., and coauthors. “Although the exact amount of time after quitting at which former smokers’ CVD risk ceases to differ significantly from that of never smokers is unknown (and may further depend on cumulative exposure), these findings support a longer time course of risk reduction than was previously thought, yielding implications for CVD risk stratification of former smokers.”

However, they did note that the study could not account for environmental tobacco smoke exposure and that the participants were mostly of white European ancestry, which limited the generalizability of the findings to other populations.

The Framingham Health Study was supported by the National Heart, Lung, and Blood Institute. One author declared a consultancy with a pharmaceutical company on a proposed clinical trial. No other conflicts of interest were declared.

SOURCE: Duncan M et al. JAMA 2019. doi: 10.1001/jama.2019.10298.

Quitting smoking significantly reduces the risk of cardiovascular disease, but past smokers are still at elevated cardiovascular risk, compared with nonsmokers, for up to 25 years after smoking cessation, research in JAMA suggests.

AtnoYdur/Thinkstock

A retrospective analysis of data from 8,770 individuals in the Framingham Heart Study compared the incidence of myocardial infarction, stroke, heart failure, or cardiovascular death in ever-smokers with that of never smokers.

Only 40% of the total cohort had never smoked. Of the 4,115 current smokers at baseline, 38.6% quit during the course of the study and did not relapse but 51.4% continued to smoke until they developed cardiovascular disease or dropped out of the study.

Current smokers had a significant 4.68-fold higher incidence of cardiovascular disease, compared with those who had never smoked, but those who stopped smoking showed a 39% decline in their risk of cardiovascular disease within 5 years of cessation.

However, individuals who were formerly heavy smokers – defined as at least 20 pack-years of smoking – retained a risk of cardiovascular disease 25% higher than that of never smokers until 10-15 years after quitting smoking. At 16 years, the 95% confidence interval for cardiovascular disease risk among former smokers versus that of never smokers finally and consistently included the null value of 1.

The study pooled two cohorts; the original cohort, who attended their fourth examination during 1954-1958 and an offspring cohort who attended their first examination during 1971-1975. The authors saw a difference between the two cohorts in the time course of cardiovascular disease risk in heavy smokers.

In the original cohort, former heavy smoking ceased to be significantly associated with increased cardiovascular disease risk within 5-10 years of cessation, but in the offspring cohort, it took 25 years after cessation for the incidence to decline to the same level of risk seen in never smokers.

“The upper estimate of this time course is a decade longer than that of the Nurses’ Health Study results for coronary heart disease and cardiovascular death and more than 20 years longer than in some prior reports for coronary heart disease and stroke,” wrote Meredith S. Duncan from the division of cardiovascular medicine at the Vanderbilt University Medical Center, Nashville, Tenn., and coauthors. “Although the exact amount of time after quitting at which former smokers’ CVD risk ceases to differ significantly from that of never smokers is unknown (and may further depend on cumulative exposure), these findings support a longer time course of risk reduction than was previously thought, yielding implications for CVD risk stratification of former smokers.”

However, they did note that the study could not account for environmental tobacco smoke exposure and that the participants were mostly of white European ancestry, which limited the generalizability of the findings to other populations.

The Framingham Health Study was supported by the National Heart, Lung, and Blood Institute. One author declared a consultancy with a pharmaceutical company on a proposed clinical trial. No other conflicts of interest were declared.

SOURCE: Duncan M et al. JAMA 2019. doi: 10.1001/jama.2019.10298.

Quitting smoking significantly reduces the risk of cardiovascular disease, but past smokers are still at elevated cardiovascular risk, compared with nonsmokers, for up to 25 years after smoking cessation, research in JAMA suggests.

AtnoYdur/Thinkstock

A retrospective analysis of data from 8,770 individuals in the Framingham Heart Study compared the incidence of myocardial infarction, stroke, heart failure, or cardiovascular death in ever-smokers with that of never smokers.

Only 40% of the total cohort had never smoked. Of the 4,115 current smokers at baseline, 38.6% quit during the course of the study and did not relapse but 51.4% continued to smoke until they developed cardiovascular disease or dropped out of the study.

Current smokers had a significant 4.68-fold higher incidence of cardiovascular disease, compared with those who had never smoked, but those who stopped smoking showed a 39% decline in their risk of cardiovascular disease within 5 years of cessation.

However, individuals who were formerly heavy smokers – defined as at least 20 pack-years of smoking – retained a risk of cardiovascular disease 25% higher than that of never smokers until 10-15 years after quitting smoking. At 16 years, the 95% confidence interval for cardiovascular disease risk among former smokers versus that of never smokers finally and consistently included the null value of 1.

The study pooled two cohorts; the original cohort, who attended their fourth examination during 1954-1958 and an offspring cohort who attended their first examination during 1971-1975. The authors saw a difference between the two cohorts in the time course of cardiovascular disease risk in heavy smokers.

In the original cohort, former heavy smoking ceased to be significantly associated with increased cardiovascular disease risk within 5-10 years of cessation, but in the offspring cohort, it took 25 years after cessation for the incidence to decline to the same level of risk seen in never smokers.

“The upper estimate of this time course is a decade longer than that of the Nurses’ Health Study results for coronary heart disease and cardiovascular death and more than 20 years longer than in some prior reports for coronary heart disease and stroke,” wrote Meredith S. Duncan from the division of cardiovascular medicine at the Vanderbilt University Medical Center, Nashville, Tenn., and coauthors. “Although the exact amount of time after quitting at which former smokers’ CVD risk ceases to differ significantly from that of never smokers is unknown (and may further depend on cumulative exposure), these findings support a longer time course of risk reduction than was previously thought, yielding implications for CVD risk stratification of former smokers.”

However, they did note that the study could not account for environmental tobacco smoke exposure and that the participants were mostly of white European ancestry, which limited the generalizability of the findings to other populations.

The Framingham Health Study was supported by the National Heart, Lung, and Blood Institute. One author declared a consultancy with a pharmaceutical company on a proposed clinical trial. No other conflicts of interest were declared.

SOURCE: Duncan M et al. JAMA 2019. doi: 10.1001/jama.2019.10298.

The Food and Drug Administration has announced its approval of lefamulin (Xenleta) for the treatment of community-acquired bacterial pneumonia in adults.

Olivier Le Moal/Getty Images

Approval was based on results of two clinical trials assessing a total of 1,289 people with community-acquired bacterial pneumonia. In these trials, lefamulin was compared with moxifloxacin with and without linezolid. Patients who received lefamulin had similar rates of treatment success as those taking moxifloxacin alone or moxifloxacin plus linezolid.

The most common adverse reactions associated with lefamulin include diarrhea, nausea, reactions at the injection site, elevated liver enzymes, and vomiting. Patients with prolonged QT interval, patients with arrhythmias, patients receiving treatment with antiarrhythmic agents, and patients receiving other drugs that prolong the QT interval are contraindicated. In addition, because of evidence of fetal harm in animal studies, pregnant women should be advised of potential risks before receiving lefamulin.

“This new drug provides another option for the treatment of patients with community-acquired bacterial pneumonia, a serious disease. For managing this serious disease, it is important for physicians and patients to have treatment options,” Ed Cox, MD, MPH, director of the FDA’s Office of Antimicrobial Products, said in the press release.

[email protected]

The Food and Drug Administration has announced its approval of lefamulin (Xenleta) for the treatment of community-acquired bacterial pneumonia in adults.

Olivier Le Moal/Getty Images

Approval was based on results of two clinical trials assessing a total of 1,289 people with community-acquired bacterial pneumonia. In these trials, lefamulin was compared with moxifloxacin with and without linezolid. Patients who received lefamulin had similar rates of treatment success as those taking moxifloxacin alone or moxifloxacin plus linezolid.

The most common adverse reactions associated with lefamulin include diarrhea, nausea, reactions at the injection site, elevated liver enzymes, and vomiting. Patients with prolonged QT interval, patients with arrhythmias, patients receiving treatment with antiarrhythmic agents, and patients receiving other drugs that prolong the QT interval are contraindicated. In addition, because of evidence of fetal harm in animal studies, pregnant women should be advised of potential risks before receiving lefamulin.

“This new drug provides another option for the treatment of patients with community-acquired bacterial pneumonia, a serious disease. For managing this serious disease, it is important for physicians and patients to have treatment options,” Ed Cox, MD, MPH, director of the FDA’s Office of Antimicrobial Products, said in the press release.

[email protected]

The Food and Drug Administration has announced its approval of lefamulin (Xenleta) for the treatment of community-acquired bacterial pneumonia in adults.

Olivier Le Moal/Getty Images

Approval was based on results of two clinical trials assessing a total of 1,289 people with community-acquired bacterial pneumonia. In these trials, lefamulin was compared with moxifloxacin with and without linezolid. Patients who received lefamulin had similar rates of treatment success as those taking moxifloxacin alone or moxifloxacin plus linezolid.

The most common adverse reactions associated with lefamulin include diarrhea, nausea, reactions at the injection site, elevated liver enzymes, and vomiting. Patients with prolonged QT interval, patients with arrhythmias, patients receiving treatment with antiarrhythmic agents, and patients receiving other drugs that prolong the QT interval are contraindicated. In addition, because of evidence of fetal harm in animal studies, pregnant women should be advised of potential risks before receiving lefamulin.

“This new drug provides another option for the treatment of patients with community-acquired bacterial pneumonia, a serious disease. For managing this serious disease, it is important for physicians and patients to have treatment options,” Ed Cox, MD, MPH, director of the FDA’s Office of Antimicrobial Products, said in the press release.

[email protected]