Pulmonology

Pulmonary arterial hypertension (PAH) is a rare disease that is associated with high mortality and is characterized by pulmonary vascular remodeling. Portopulmonary hypertension (POPH) is a form of PAH that occurs in patients with portal hypertension where no alternative cause of PAH can be identified. POPH is documented in approximately 4.5% to 8.5% of liver transplant candidates,^1,2 but there is no relationship between the existence or severity of POPH and the severity of liver dysfunction.³ Mantz and Craig described the first case of POPH in a 53-year-old woman with enlarged pulmonary arteries that exhibited forceful pulsations more characteristic of the aorta than a low-pressure pulmonary trunk.⁴ Autopsy revealed findings of chronic liver disease including a stenotic portal vein, portocaval shunt, and esophageal varices. In both PAH and POPH, pre-capillary pulmonary arteries have characteristic lesions, such as intimal thickening, endothelial proliferation, and thrombotic changes. This 2-part article reviews the diagnosis and treatment of patients with POPH. Here, we review the epidemiology, prognosis, pathogenesis, and diagnosis of POPH; current treatment options for POPH are reviewed in a separate article.

Definition

The term POPH was first used by Yoshida et al in 1993 to describe the first successful liver transplant in a patient with POPH, a 39-year-old man with chronic hepatitis.⁵ The World Health Organization (WHO) classifies POPH as a form of Group 1 PAH.⁶ The criteria that must be met to make a diagnosis of POPH are shown in the Table 1.⁷

Moderate POPH is defined as a mean pulmonary artery pressure (MPAP) between 35 mm Hg and < 45 mm Hg, whereas severe POPH is MPAP ≥ 45 mm Hg. Moderate and severe POPH are considered contraindications to liver transplant because of high perioperative and postoperative mortality rates.⁸ In 2000, the Mayo Clinic retrospectively reviewed 43 patients with POPH who underwent attempted liver transplantation.⁹ The cardiopulmonary-related mortality rate in patients with a MPAP of 35 to < 50 mm Hg was 50% and 100% for those with MPAP > 50 mm Hg. No mortality was noted in patients with a pre-liver transplant MPAP of < 35 mm Hg and transpulmonary gradient (TPG) < 15 mm Hg.

Epidemiology

In 1983, a series of 17,901 autopsied patients showed a primary pulmonary hypertension prevalence of 0.13% and a prevalence of 0.73% in patients with cirrhosis.¹⁰ In 1987, Rich et al published data from the National Institutes of Health’s national registry of primary pulmonary hypertension.¹¹ The registry included data from 187 patients from 32 centers. Further analyses by Groves et al concluded that 8.3% of the patients likely had POPH.¹² Humbert et al published data on the French pulmonary hypertension registry experience in 2006.¹³ The French registry included 674 patients from 17 university hospitals; 10.4% of these patients had POPH. The largest prospective study was published by Hadengue et al in 1991.¹⁴ In this study, 507 patients hospitalized with portal hypertension but without known pulmonary hypertension underwent cardiac catheterization; 10 patients (2%) had pulmonary hypertension and more than half were clinically asymptomatic. Finally, the Registry to Evaluate Early And Long-term pulmonary arterial hypertension disease management (REVEAL registry) documented a 5.3% frequency of POPH (174 of 3525) in the United States.¹⁵

Prognosis

Individuals with POPH have worse outcomes compared to other forms of PAH. Median survival prior to the introduction of vasodilator therapy was a dismal 6 months and mean survival was 15 months.¹⁶ The cause of death in patients with POPH is equally distributed between right heart failure from POPH and direct complications of chronic liver disease.¹ Le Pavec et al retrospectively analyzed all patients referred to the French Referral Center with POPH between 1984 and 2004 (154 patients).¹ Approximately 50% of the patients were Child-Turcotte-Pugh class B or C, and 60% were classified as New York Health Association (NYHA) class III or IV. In these patients, 1-, 3-, and 5-year survival rates were 88%, 75%, and 68%, respectively. Major independent prognostic risk factors were presence and severity of cirrhosis and preservation of right ventricular function. Interestingly, NYHA functional class was not related to survival in this study, although it has clearly been identified as a strong prognostic factor in idiopathic PAH.

Krowka et al evaluated 174 patients with POPH enrolled in the REVEAL Registry,¹⁵ a multicenter, observational, US-based study comprised of more than 3500 patients with PAH. Despite having better hemodynamic parameters at diagnosis, patients with POPH had significantly poorer survival and all-cause hospitalization compared with patients with idiopathic PAH (IPAH) or hereditary PAH (HPAH). Two-year survival from enrollment was 67% in POPH versus 85% in those with IPAH/HPAH (P < 0.001). Five-year survival from time of diagnosis was 40% versus 64% (P < 0.001). Additionally, patients with POPH were less likely to be on PAH-specific therapy at enrollment, with only 25% on treatment at the time of entry. These findings were replicated in 2005 when Kawut et al retrospectively compared 13 patients with POPH with 33 patients with IPAH.¹⁷ Despite having a higher cardiac index and lower pulmonary vascular resistance than patients with IPAH, patients with POPH had a higher risk of death (hazard ratio, 2.8, P = 0.04), likely reflecting the combination of 2 serious diseases.

In 2008 the Mayo Clinic published their retrospective analysis of patients with POPH to determine the natural history of POPH.¹⁸ Patients were categorized into 3 groups: (1) no medical therapy for POPH and no liver transplant; (2) medical therapy for POPH alone; (3) medical therapy for POPH followed by liver transplant. The study included 74 patients between 1994 through 2007; 19 patients who did not receive treatment for POPH or liver transplant truly represented the natural history of POPH. Their 5-year survival was only 14%, and over half were deceased 1 year after diagnosis. The largest group consisted of patients who received therapy for POPH but no liver transplant. This group did remarkably better than those who received no therapy at all, with a 5-year survival of 45%. However, the patients with the overall best survival were those who received a combination of treatment for POPH followed by liver transplant. Their 5-year survival was 67%. Survival at 5 years was only 25% for the small group of patients who received transplant without PAH therapy. Once again, mortality did not correlate with the severity of hepatic dysfunction or baseline hemodynamic data.

Pathogenesis

The pathogenesis of POPH is unclear. Multiple studies have shown that there is minimal, if any, association with pulmonary hypertension and the severity of liver disease or portal hypertension.^19,20 Portal hypertension is the result of an increase in intrahepatic resistance and an increase in blood flow into the portal circulation. Collateral vessels develop and blood from the splanchnic circulation is allowed directly into the systemic venous circulation, bypassing the liver. One of the most widely accepted theories is that a humoral substance, that would otherwise be metabolized by the liver, is able to reach the pulmonary circulation through collaterals, resulting in POPH.²¹ Pelicelli et al evaluated the possible role of endothelin-1, interleukin-6, interleukin 1β, and tumor necrosis factor in the pathogenesis of POPH.²² Plasma concentrations of these cytokines were compared between patients with POPH and patients with cirrhosis but no POPH. Patients with POPH had higher concentrations of endothelin-1 and interleukin-6, suggesting antagonists for these cytokines may have a role in the treatment of POPH. The role of endothelin-1 was further supported by Kamath et al in 2000²³ when they determined the pulmonary vascular bed is exposed to increased levels of circulating endothelin-1a in the setting of cirrhosis. Endothelin-1 is a potent vasoconstrictor and facilitator of smooth muscle proliferation.

In addition to collateral circulation allowing mediators to reach the pulmonary arterial bed in portal hypertension, high flow may trigger a vasoproliferative process in the pulmonary vascular bed. Patients with advanced liver disease have a low systemic vascular resistance, with a compensatory increase in cardiac output. An increase in cardiac output can lead to shear stress of the pulmonary vascular endothelial layer. Although the resistance of the pulmonary vasculature may decrease rapidly to help normalize pulmonary pressures, persistent circulatory overload could result in irreversible vascular changes. Autopsy and lung explant studies show that POPH is characterized by obstructive and remodeling changes in the pulmonary arterial bed.²⁴ Initially, medial hypertrophy with smooth muscle proliferation is present. As the disease advances, platelet aggregates, in situ thrombosis, and intimal fibrosis develop. Finally, web-like lesions involving the entire pulmonary wall develop with recanalization for the passage of pulmonary arterial flow. These changes are identical to the changes observed in patients with other forms of PAH.

Not all patients with portal hypertension develop POPH, suggesting that genetic predisposition may play a role in POPH development. The Pulmonary Vascular Complications of Liver Study Group published a multicenter case-control study that attempted to identify genetic risk factors for POPH in patients with advanced liver disease.²⁵ More than 1000 common single nucleotide polymorphisms (SNPs) in 93 candidate genes were genotyped in each patient. When compared to controls, multiple SNPs in the genes coding for estrogen receptor 1, aromatase, phosphodiesterase 5, angiopoietin 1, and calcium binding protein A4 were associated with an increased risk of POPH. One year earlier, the same study group concluded that female sex (adjusted odds ratio [OR], 2.90) and autoimmune hepatitis (adjusted OR, 4.02) were associated with a higher risk for POPH, whereas hepatitis C was associated with a decreased risk.²⁰

Clinical Presentation

Clinical presentation is variable in POPH. Patients referred to a pulmonologist will usually present with symptoms similar to patients with other forms of PAH. In a retrospective analysis of patients referred to the French Referral Center for Pulmonary Hypertension, 60% of the patients belonged to NYHA functional class III or IV.¹ In a series of 78 patients with POPH, the most common presenting pulmonary symptom was dyspnea on exertion (81%), followed by syncope, chest pain, and fatigue (< 33%).¹⁶ Symptoms such as syncope and chest pain are usually markers of severe POPH.³ Stigmata of portal hypertension, such as ascites, spider angiomata, and palmar erythema, may be present on exam. An accentuated pulmonary component of the second heart sound can be seen in 82% of patients and a systolic murmur caused by tricuspid regurgitation in 69% of patients.¹⁶ Patients with severe POPH may have jugular vein distention, peripheral edema, and a third heart sound.

Diagnostic Evaluation

Chest x-rays may show prominent pulmonary arteries and cardiomegaly in patients with POPH, whereas electrocardiogram can suggest right ventricular hypertrophy and right axis deviation. The best screening test for POPH in patients with portal hypertension is echocardiography. Routine screening for POPH is recommended during liver transplant evaluation in the practice guidelines from the American Association for the Study of Liver Disease.²⁶ Right-sided cardiac chamber enlargement and right ventricular pressure or volume overload can be assessed on echocardiography. Colle et al followed 165 patients evaluated for liver transplantation who underwent transthoracic Doppler echocardiography and right heart catheterization.²⁷ Seventeen patients met the criteria for POPH on echocardiography (presence of tricuspid regurgitation and calculated systolic pulmonary artery pressure over 30 mm Hg) and right heart catheterization confirmed the diagnosis in 10 patients. Right ventricular systolic pressure (RVSP) estimate of ≤ 30 mm Hg on 2-dimensional echo had a 100% sensitivity and negative predictive value. Positive predictive value was poor at 59%, reiterating the need for right heart catheterization in the diagnosis of POPH. When Kim et al used a RVSP threshold of 50 mm Hg, 72% had at least moderate pulmonary hypertension, including 30% with severe pulmonary hypertension.²⁸ Raevens et al analyzed data from 152 patients who underwent pretransplant echocardiography and catheterization.² Their data show a RVSP threshold of greater than 38 mm Hg by echocardiography had a specificity of 82% and sensitivity and negative predictive value of 100%. The European Respiratory Society recommendations state that PAH should be considered unlikely if echocardiography estimates a RVSP ≤36 mm Hg and likely if the RVSP is estimated at > 50 mm Hg.²⁹ We recommend repeating echocardiography every 6 to 12 months in patients listed for liver transplantation, as pulmonary hemodynamics may change over time.

Computed tomography (CT) may have a complementary role in the future for the noninvasive detection of POPH. In a study published in 2014, 49 patients referred for liver transplantation were retrospectively reviewed.³⁰ Measured CT signs included the main pulmonary artery/ascending aorta diameter ratio, the mean left and right main pulmonary artery diameter, and the enlargement of the pulmonary artery compared to the ascending aorta. Compared to the transthoracic echocardiography alone, an algorithm incorporating CT and echocardiography improved the detection of POPH (area under curve = 0.8, P < 0.0001).

A diagnosis of POPH can only be confirmed when PAH exists in a patient with portal hypertension, as determined by right heart catheterization, and no other cause of PAH can be identified. MPAP should be 25 mm Hg or greater, PVR of 240 dynes/s/cm^–5, wedge pressure of 15 mm Hg or less, and TPG greater than 12 mm Hg. Krowka et al showed the value of right heart catheterization in their 10-year prospective, echocardiography-catheterization algorithm study.¹⁹ Of 1235 liver transplant candidates who underwent echocardiography, 104 patients had a RVSP exceeding 50 mm Hg. Almost all of these patients had a right heart catheterization. All cause pulmonary hypertension (MPAP > 25 mm Hg) was confirmed in 90% of the patients, and 35% had a PVR < 240 dynes/s/cm^–5 and pulmonary capillary wedge pressure (PCWP) > 15 mm Hg, suggesting fluid overload. Forty-one patients had significant POPH, with a PVR > 400 dynes/s/cm^–5, and 24% also had an elevated PCWP. TPG was > 12 mm Hg in all of these patients, confirming POPH. As demonstrated by this study, right heart catheterization is required to confirm the diagnosis of POPH because high flow and fluid overload can lead to elevated pulmonary artery pressures.

Patients with POPH have a unique clinical profile with characteristics common to patients with primary pulmonary hypertension and chronic liver disease. In a retrospective review that compared 30 patients with PAH, 30 patients with chronic liver disease only, and 30 patients with catheterization-proved POPH,³¹ patients with POPH had elevated MPAP similar to those with primary PAH, but they also had reduced SVR and elevated cardiac index similar to those with chronic liver disease alone.

Besides POPH, 2 other common causes can lead to increased pulmonary arterial blood flow in patients with portal hypertension. First is a high-flow condition caused by increased cardiac output but with a normal PVR and PCWP. Fluid overload can also lead to pulmonary venous hypertension with increased PCWP, normal cardiac output, and normal PVR. Up to 25% of patients with POPH may present with marked excess volume caused by fluid retention.³ There can be an increase in both PCWP and PVR depending on the presence and the degree of fluid retention. TPG (MPAP – PCWP) > 12 mm Hg was introduced to make such patients less confusing and to help correct for increased PCWP secondary to fluid overload. Obstruction to pulmonary arterial flow is manifest by an increased TPG (Table 2).

POPH should be distinguished from hepatopulmonary syndrome (HPS), which is another pulmonary vascular consequence of liver disease. Unlike POPH, HPS is characterized by a defect in arterial oxygenation induced by pulmonary vascular dilation.³² Similar to other patients with liver disease, patients with HPS have a normal PVR and increased cardiac output secondary to a high-flow state. HPS is diagnosed by confirmation of an intrapulmonary shunt by echocardiogram. Injection of agitated saline results in saline bubbles being visualized in the left atrium 3 or more cardiac cycles after they appear in the right atrium. Currently, there is no effective medical treatment for HPS and liver transplantation is the only successful treatment.

Conclusion

POPH is an uncommon complication of chronic liver disease. It is defined as PAH in a patient with portal hypertension excluding other causes of PAH. The following criteria must be met to make a diagnosis of POPH: (1) evidence of portal hypertension; (2) MPAP ≥ 35 mm Hg; (3) PVR ≥ 240 dynes/s/cm⁵; (4) pulmonary capillary wedge pressure ≤ 15 mm Hg; and (5) TPG > 12 mm Hg. Individuals with POPH have worse outcomes compared to other forms of PAH, with a median survival of 6 months without medical therapy. The pathogenesis of POPH is unclear but may be related to a genetic predisposition since not all patients with portal hypertension develop POPH. Echocardiography is an excellent screening test for POPH, but a right heart catheterization must be performed to confirm the diagnosis.

Pulmonary arterial hypertension (PAH) is a rare disease that is associated with high mortality and is characterized by pulmonary vascular remodeling. Portopulmonary hypertension (POPH) is a form of PAH that occurs in patients with portal hypertension where no alternative cause of PAH can be identified. POPH is documented in approximately 4.5% to 8.5% of liver transplant candidates,^1,2 but there is no relationship between the existence or severity of POPH and the severity of liver dysfunction.³ Mantz and Craig described the first case of POPH in a 53-year-old woman with enlarged pulmonary arteries that exhibited forceful pulsations more characteristic of the aorta than a low-pressure pulmonary trunk.⁴ Autopsy revealed findings of chronic liver disease including a stenotic portal vein, portocaval shunt, and esophageal varices. In both PAH and POPH, pre-capillary pulmonary arteries have characteristic lesions, such as intimal thickening, endothelial proliferation, and thrombotic changes. This 2-part article reviews the diagnosis and treatment of patients with POPH. Here, we review the epidemiology, prognosis, pathogenesis, and diagnosis of POPH; current treatment options for POPH are reviewed in a separate article.

Definition

The term POPH was first used by Yoshida et al in 1993 to describe the first successful liver transplant in a patient with POPH, a 39-year-old man with chronic hepatitis.⁵ The World Health Organization (WHO) classifies POPH as a form of Group 1 PAH.⁶ The criteria that must be met to make a diagnosis of POPH are shown in the Table 1.⁷

Moderate POPH is defined as a mean pulmonary artery pressure (MPAP) between 35 mm Hg and < 45 mm Hg, whereas severe POPH is MPAP ≥ 45 mm Hg. Moderate and severe POPH are considered contraindications to liver transplant because of high perioperative and postoperative mortality rates.⁸ In 2000, the Mayo Clinic retrospectively reviewed 43 patients with POPH who underwent attempted liver transplantation.⁹ The cardiopulmonary-related mortality rate in patients with a MPAP of 35 to < 50 mm Hg was 50% and 100% for those with MPAP > 50 mm Hg. No mortality was noted in patients with a pre-liver transplant MPAP of < 35 mm Hg and transpulmonary gradient (TPG) < 15 mm Hg.

Epidemiology

In 1983, a series of 17,901 autopsied patients showed a primary pulmonary hypertension prevalence of 0.13% and a prevalence of 0.73% in patients with cirrhosis.¹⁰ In 1987, Rich et al published data from the National Institutes of Health’s national registry of primary pulmonary hypertension.¹¹ The registry included data from 187 patients from 32 centers. Further analyses by Groves et al concluded that 8.3% of the patients likely had POPH.¹² Humbert et al published data on the French pulmonary hypertension registry experience in 2006.¹³ The French registry included 674 patients from 17 university hospitals; 10.4% of these patients had POPH. The largest prospective study was published by Hadengue et al in 1991.¹⁴ In this study, 507 patients hospitalized with portal hypertension but without known pulmonary hypertension underwent cardiac catheterization; 10 patients (2%) had pulmonary hypertension and more than half were clinically asymptomatic. Finally, the Registry to Evaluate Early And Long-term pulmonary arterial hypertension disease management (REVEAL registry) documented a 5.3% frequency of POPH (174 of 3525) in the United States.¹⁵

Prognosis

Individuals with POPH have worse outcomes compared to other forms of PAH. Median survival prior to the introduction of vasodilator therapy was a dismal 6 months and mean survival was 15 months.¹⁶ The cause of death in patients with POPH is equally distributed between right heart failure from POPH and direct complications of chronic liver disease.¹ Le Pavec et al retrospectively analyzed all patients referred to the French Referral Center with POPH between 1984 and 2004 (154 patients).¹ Approximately 50% of the patients were Child-Turcotte-Pugh class B or C, and 60% were classified as New York Health Association (NYHA) class III or IV. In these patients, 1-, 3-, and 5-year survival rates were 88%, 75%, and 68%, respectively. Major independent prognostic risk factors were presence and severity of cirrhosis and preservation of right ventricular function. Interestingly, NYHA functional class was not related to survival in this study, although it has clearly been identified as a strong prognostic factor in idiopathic PAH.

Krowka et al evaluated 174 patients with POPH enrolled in the REVEAL Registry,¹⁵ a multicenter, observational, US-based study comprised of more than 3500 patients with PAH. Despite having better hemodynamic parameters at diagnosis, patients with POPH had significantly poorer survival and all-cause hospitalization compared with patients with idiopathic PAH (IPAH) or hereditary PAH (HPAH). Two-year survival from enrollment was 67% in POPH versus 85% in those with IPAH/HPAH (P < 0.001). Five-year survival from time of diagnosis was 40% versus 64% (P < 0.001). Additionally, patients with POPH were less likely to be on PAH-specific therapy at enrollment, with only 25% on treatment at the time of entry. These findings were replicated in 2005 when Kawut et al retrospectively compared 13 patients with POPH with 33 patients with IPAH.¹⁷ Despite having a higher cardiac index and lower pulmonary vascular resistance than patients with IPAH, patients with POPH had a higher risk of death (hazard ratio, 2.8, P = 0.04), likely reflecting the combination of 2 serious diseases.

In 2008 the Mayo Clinic published their retrospective analysis of patients with POPH to determine the natural history of POPH.¹⁸ Patients were categorized into 3 groups: (1) no medical therapy for POPH and no liver transplant; (2) medical therapy for POPH alone; (3) medical therapy for POPH followed by liver transplant. The study included 74 patients between 1994 through 2007; 19 patients who did not receive treatment for POPH or liver transplant truly represented the natural history of POPH. Their 5-year survival was only 14%, and over half were deceased 1 year after diagnosis. The largest group consisted of patients who received therapy for POPH but no liver transplant. This group did remarkably better than those who received no therapy at all, with a 5-year survival of 45%. However, the patients with the overall best survival were those who received a combination of treatment for POPH followed by liver transplant. Their 5-year survival was 67%. Survival at 5 years was only 25% for the small group of patients who received transplant without PAH therapy. Once again, mortality did not correlate with the severity of hepatic dysfunction or baseline hemodynamic data.

Pathogenesis

The pathogenesis of POPH is unclear. Multiple studies have shown that there is minimal, if any, association with pulmonary hypertension and the severity of liver disease or portal hypertension.^19,20 Portal hypertension is the result of an increase in intrahepatic resistance and an increase in blood flow into the portal circulation. Collateral vessels develop and blood from the splanchnic circulation is allowed directly into the systemic venous circulation, bypassing the liver. One of the most widely accepted theories is that a humoral substance, that would otherwise be metabolized by the liver, is able to reach the pulmonary circulation through collaterals, resulting in POPH.²¹ Pelicelli et al evaluated the possible role of endothelin-1, interleukin-6, interleukin 1β, and tumor necrosis factor in the pathogenesis of POPH.²² Plasma concentrations of these cytokines were compared between patients with POPH and patients with cirrhosis but no POPH. Patients with POPH had higher concentrations of endothelin-1 and interleukin-6, suggesting antagonists for these cytokines may have a role in the treatment of POPH. The role of endothelin-1 was further supported by Kamath et al in 2000²³ when they determined the pulmonary vascular bed is exposed to increased levels of circulating endothelin-1a in the setting of cirrhosis. Endothelin-1 is a potent vasoconstrictor and facilitator of smooth muscle proliferation.

In addition to collateral circulation allowing mediators to reach the pulmonary arterial bed in portal hypertension, high flow may trigger a vasoproliferative process in the pulmonary vascular bed. Patients with advanced liver disease have a low systemic vascular resistance, with a compensatory increase in cardiac output. An increase in cardiac output can lead to shear stress of the pulmonary vascular endothelial layer. Although the resistance of the pulmonary vasculature may decrease rapidly to help normalize pulmonary pressures, persistent circulatory overload could result in irreversible vascular changes. Autopsy and lung explant studies show that POPH is characterized by obstructive and remodeling changes in the pulmonary arterial bed.²⁴ Initially, medial hypertrophy with smooth muscle proliferation is present. As the disease advances, platelet aggregates, in situ thrombosis, and intimal fibrosis develop. Finally, web-like lesions involving the entire pulmonary wall develop with recanalization for the passage of pulmonary arterial flow. These changes are identical to the changes observed in patients with other forms of PAH.

Not all patients with portal hypertension develop POPH, suggesting that genetic predisposition may play a role in POPH development. The Pulmonary Vascular Complications of Liver Study Group published a multicenter case-control study that attempted to identify genetic risk factors for POPH in patients with advanced liver disease.²⁵ More than 1000 common single nucleotide polymorphisms (SNPs) in 93 candidate genes were genotyped in each patient. When compared to controls, multiple SNPs in the genes coding for estrogen receptor 1, aromatase, phosphodiesterase 5, angiopoietin 1, and calcium binding protein A4 were associated with an increased risk of POPH. One year earlier, the same study group concluded that female sex (adjusted odds ratio [OR], 2.90) and autoimmune hepatitis (adjusted OR, 4.02) were associated with a higher risk for POPH, whereas hepatitis C was associated with a decreased risk.²⁰

Clinical Presentation

Clinical presentation is variable in POPH. Patients referred to a pulmonologist will usually present with symptoms similar to patients with other forms of PAH. In a retrospective analysis of patients referred to the French Referral Center for Pulmonary Hypertension, 60% of the patients belonged to NYHA functional class III or IV.¹ In a series of 78 patients with POPH, the most common presenting pulmonary symptom was dyspnea on exertion (81%), followed by syncope, chest pain, and fatigue (< 33%).¹⁶ Symptoms such as syncope and chest pain are usually markers of severe POPH.³ Stigmata of portal hypertension, such as ascites, spider angiomata, and palmar erythema, may be present on exam. An accentuated pulmonary component of the second heart sound can be seen in 82% of patients and a systolic murmur caused by tricuspid regurgitation in 69% of patients.¹⁶ Patients with severe POPH may have jugular vein distention, peripheral edema, and a third heart sound.

Diagnostic Evaluation

Chest x-rays may show prominent pulmonary arteries and cardiomegaly in patients with POPH, whereas electrocardiogram can suggest right ventricular hypertrophy and right axis deviation. The best screening test for POPH in patients with portal hypertension is echocardiography. Routine screening for POPH is recommended during liver transplant evaluation in the practice guidelines from the American Association for the Study of Liver Disease.²⁶ Right-sided cardiac chamber enlargement and right ventricular pressure or volume overload can be assessed on echocardiography. Colle et al followed 165 patients evaluated for liver transplantation who underwent transthoracic Doppler echocardiography and right heart catheterization.²⁷ Seventeen patients met the criteria for POPH on echocardiography (presence of tricuspid regurgitation and calculated systolic pulmonary artery pressure over 30 mm Hg) and right heart catheterization confirmed the diagnosis in 10 patients. Right ventricular systolic pressure (RVSP) estimate of ≤ 30 mm Hg on 2-dimensional echo had a 100% sensitivity and negative predictive value. Positive predictive value was poor at 59%, reiterating the need for right heart catheterization in the diagnosis of POPH. When Kim et al used a RVSP threshold of 50 mm Hg, 72% had at least moderate pulmonary hypertension, including 30% with severe pulmonary hypertension.²⁸ Raevens et al analyzed data from 152 patients who underwent pretransplant echocardiography and catheterization.² Their data show a RVSP threshold of greater than 38 mm Hg by echocardiography had a specificity of 82% and sensitivity and negative predictive value of 100%. The European Respiratory Society recommendations state that PAH should be considered unlikely if echocardiography estimates a RVSP ≤36 mm Hg and likely if the RVSP is estimated at > 50 mm Hg.²⁹ We recommend repeating echocardiography every 6 to 12 months in patients listed for liver transplantation, as pulmonary hemodynamics may change over time.

Computed tomography (CT) may have a complementary role in the future for the noninvasive detection of POPH. In a study published in 2014, 49 patients referred for liver transplantation were retrospectively reviewed.³⁰ Measured CT signs included the main pulmonary artery/ascending aorta diameter ratio, the mean left and right main pulmonary artery diameter, and the enlargement of the pulmonary artery compared to the ascending aorta. Compared to the transthoracic echocardiography alone, an algorithm incorporating CT and echocardiography improved the detection of POPH (area under curve = 0.8, P < 0.0001).

A diagnosis of POPH can only be confirmed when PAH exists in a patient with portal hypertension, as determined by right heart catheterization, and no other cause of PAH can be identified. MPAP should be 25 mm Hg or greater, PVR of 240 dynes/s/cm^–5, wedge pressure of 15 mm Hg or less, and TPG greater than 12 mm Hg. Krowka et al showed the value of right heart catheterization in their 10-year prospective, echocardiography-catheterization algorithm study.¹⁹ Of 1235 liver transplant candidates who underwent echocardiography, 104 patients had a RVSP exceeding 50 mm Hg. Almost all of these patients had a right heart catheterization. All cause pulmonary hypertension (MPAP > 25 mm Hg) was confirmed in 90% of the patients, and 35% had a PVR < 240 dynes/s/cm^–5 and pulmonary capillary wedge pressure (PCWP) > 15 mm Hg, suggesting fluid overload. Forty-one patients had significant POPH, with a PVR > 400 dynes/s/cm^–5, and 24% also had an elevated PCWP. TPG was > 12 mm Hg in all of these patients, confirming POPH. As demonstrated by this study, right heart catheterization is required to confirm the diagnosis of POPH because high flow and fluid overload can lead to elevated pulmonary artery pressures.

Patients with POPH have a unique clinical profile with characteristics common to patients with primary pulmonary hypertension and chronic liver disease. In a retrospective review that compared 30 patients with PAH, 30 patients with chronic liver disease only, and 30 patients with catheterization-proved POPH,³¹ patients with POPH had elevated MPAP similar to those with primary PAH, but they also had reduced SVR and elevated cardiac index similar to those with chronic liver disease alone.

Besides POPH, 2 other common causes can lead to increased pulmonary arterial blood flow in patients with portal hypertension. First is a high-flow condition caused by increased cardiac output but with a normal PVR and PCWP. Fluid overload can also lead to pulmonary venous hypertension with increased PCWP, normal cardiac output, and normal PVR. Up to 25% of patients with POPH may present with marked excess volume caused by fluid retention.³ There can be an increase in both PCWP and PVR depending on the presence and the degree of fluid retention. TPG (MPAP – PCWP) > 12 mm Hg was introduced to make such patients less confusing and to help correct for increased PCWP secondary to fluid overload. Obstruction to pulmonary arterial flow is manifest by an increased TPG (Table 2).

POPH should be distinguished from hepatopulmonary syndrome (HPS), which is another pulmonary vascular consequence of liver disease. Unlike POPH, HPS is characterized by a defect in arterial oxygenation induced by pulmonary vascular dilation.³² Similar to other patients with liver disease, patients with HPS have a normal PVR and increased cardiac output secondary to a high-flow state. HPS is diagnosed by confirmation of an intrapulmonary shunt by echocardiogram. Injection of agitated saline results in saline bubbles being visualized in the left atrium 3 or more cardiac cycles after they appear in the right atrium. Currently, there is no effective medical treatment for HPS and liver transplantation is the only successful treatment.

Conclusion

POPH is an uncommon complication of chronic liver disease. It is defined as PAH in a patient with portal hypertension excluding other causes of PAH. The following criteria must be met to make a diagnosis of POPH: (1) evidence of portal hypertension; (2) MPAP ≥ 35 mm Hg; (3) PVR ≥ 240 dynes/s/cm⁵; (4) pulmonary capillary wedge pressure ≤ 15 mm Hg; and (5) TPG > 12 mm Hg. Individuals with POPH have worse outcomes compared to other forms of PAH, with a median survival of 6 months without medical therapy. The pathogenesis of POPH is unclear but may be related to a genetic predisposition since not all patients with portal hypertension develop POPH. Echocardiography is an excellent screening test for POPH, but a right heart catheterization must be performed to confirm the diagnosis.

Pulmonary arterial hypertension (PAH) is a rare disease that is associated with high mortality and is characterized by pulmonary vascular remodeling. Portopulmonary hypertension (POPH) is a form of PAH that occurs in patients with portal hypertension where no alternative cause of PAH can be identified. POPH is documented in approximately 4.5% to 8.5% of liver transplant candidates,^1,2 but there is no relationship between the existence or severity of POPH and the severity of liver dysfunction.³ Mantz and Craig described the first case of POPH in a 53-year-old woman with enlarged pulmonary arteries that exhibited forceful pulsations more characteristic of the aorta than a low-pressure pulmonary trunk.⁴ Autopsy revealed findings of chronic liver disease including a stenotic portal vein, portocaval shunt, and esophageal varices. In both PAH and POPH, pre-capillary pulmonary arteries have characteristic lesions, such as intimal thickening, endothelial proliferation, and thrombotic changes. This 2-part article reviews the diagnosis and treatment of patients with POPH. Here, we review the epidemiology, prognosis, pathogenesis, and diagnosis of POPH; current treatment options for POPH are reviewed in a separate article.

Definition

The term POPH was first used by Yoshida et al in 1993 to describe the first successful liver transplant in a patient with POPH, a 39-year-old man with chronic hepatitis.⁵ The World Health Organization (WHO) classifies POPH as a form of Group 1 PAH.⁶ The criteria that must be met to make a diagnosis of POPH are shown in the Table 1.⁷

Moderate POPH is defined as a mean pulmonary artery pressure (MPAP) between 35 mm Hg and < 45 mm Hg, whereas severe POPH is MPAP ≥ 45 mm Hg. Moderate and severe POPH are considered contraindications to liver transplant because of high perioperative and postoperative mortality rates.⁸ In 2000, the Mayo Clinic retrospectively reviewed 43 patients with POPH who underwent attempted liver transplantation.⁹ The cardiopulmonary-related mortality rate in patients with a MPAP of 35 to < 50 mm Hg was 50% and 100% for those with MPAP > 50 mm Hg. No mortality was noted in patients with a pre-liver transplant MPAP of < 35 mm Hg and transpulmonary gradient (TPG) < 15 mm Hg.

Epidemiology

In 1983, a series of 17,901 autopsied patients showed a primary pulmonary hypertension prevalence of 0.13% and a prevalence of 0.73% in patients with cirrhosis.¹⁰ In 1987, Rich et al published data from the National Institutes of Health’s national registry of primary pulmonary hypertension.¹¹ The registry included data from 187 patients from 32 centers. Further analyses by Groves et al concluded that 8.3% of the patients likely had POPH.¹² Humbert et al published data on the French pulmonary hypertension registry experience in 2006.¹³ The French registry included 674 patients from 17 university hospitals; 10.4% of these patients had POPH. The largest prospective study was published by Hadengue et al in 1991.¹⁴ In this study, 507 patients hospitalized with portal hypertension but without known pulmonary hypertension underwent cardiac catheterization; 10 patients (2%) had pulmonary hypertension and more than half were clinically asymptomatic. Finally, the Registry to Evaluate Early And Long-term pulmonary arterial hypertension disease management (REVEAL registry) documented a 5.3% frequency of POPH (174 of 3525) in the United States.¹⁵

Prognosis

Individuals with POPH have worse outcomes compared to other forms of PAH. Median survival prior to the introduction of vasodilator therapy was a dismal 6 months and mean survival was 15 months.¹⁶ The cause of death in patients with POPH is equally distributed between right heart failure from POPH and direct complications of chronic liver disease.¹ Le Pavec et al retrospectively analyzed all patients referred to the French Referral Center with POPH between 1984 and 2004 (154 patients).¹ Approximately 50% of the patients were Child-Turcotte-Pugh class B or C, and 60% were classified as New York Health Association (NYHA) class III or IV. In these patients, 1-, 3-, and 5-year survival rates were 88%, 75%, and 68%, respectively. Major independent prognostic risk factors were presence and severity of cirrhosis and preservation of right ventricular function. Interestingly, NYHA functional class was not related to survival in this study, although it has clearly been identified as a strong prognostic factor in idiopathic PAH.

Krowka et al evaluated 174 patients with POPH enrolled in the REVEAL Registry,¹⁵ a multicenter, observational, US-based study comprised of more than 3500 patients with PAH. Despite having better hemodynamic parameters at diagnosis, patients with POPH had significantly poorer survival and all-cause hospitalization compared with patients with idiopathic PAH (IPAH) or hereditary PAH (HPAH). Two-year survival from enrollment was 67% in POPH versus 85% in those with IPAH/HPAH (P < 0.001). Five-year survival from time of diagnosis was 40% versus 64% (P < 0.001). Additionally, patients with POPH were less likely to be on PAH-specific therapy at enrollment, with only 25% on treatment at the time of entry. These findings were replicated in 2005 when Kawut et al retrospectively compared 13 patients with POPH with 33 patients with IPAH.¹⁷ Despite having a higher cardiac index and lower pulmonary vascular resistance than patients with IPAH, patients with POPH had a higher risk of death (hazard ratio, 2.8, P = 0.04), likely reflecting the combination of 2 serious diseases.

In 2008 the Mayo Clinic published their retrospective analysis of patients with POPH to determine the natural history of POPH.¹⁸ Patients were categorized into 3 groups: (1) no medical therapy for POPH and no liver transplant; (2) medical therapy for POPH alone; (3) medical therapy for POPH followed by liver transplant. The study included 74 patients between 1994 through 2007; 19 patients who did not receive treatment for POPH or liver transplant truly represented the natural history of POPH. Their 5-year survival was only 14%, and over half were deceased 1 year after diagnosis. The largest group consisted of patients who received therapy for POPH but no liver transplant. This group did remarkably better than those who received no therapy at all, with a 5-year survival of 45%. However, the patients with the overall best survival were those who received a combination of treatment for POPH followed by liver transplant. Their 5-year survival was 67%. Survival at 5 years was only 25% for the small group of patients who received transplant without PAH therapy. Once again, mortality did not correlate with the severity of hepatic dysfunction or baseline hemodynamic data.

Pathogenesis

The pathogenesis of POPH is unclear. Multiple studies have shown that there is minimal, if any, association with pulmonary hypertension and the severity of liver disease or portal hypertension.^19,20 Portal hypertension is the result of an increase in intrahepatic resistance and an increase in blood flow into the portal circulation. Collateral vessels develop and blood from the splanchnic circulation is allowed directly into the systemic venous circulation, bypassing the liver. One of the most widely accepted theories is that a humoral substance, that would otherwise be metabolized by the liver, is able to reach the pulmonary circulation through collaterals, resulting in POPH.²¹ Pelicelli et al evaluated the possible role of endothelin-1, interleukin-6, interleukin 1β, and tumor necrosis factor in the pathogenesis of POPH.²² Plasma concentrations of these cytokines were compared between patients with POPH and patients with cirrhosis but no POPH. Patients with POPH had higher concentrations of endothelin-1 and interleukin-6, suggesting antagonists for these cytokines may have a role in the treatment of POPH. The role of endothelin-1 was further supported by Kamath et al in 2000²³ when they determined the pulmonary vascular bed is exposed to increased levels of circulating endothelin-1a in the setting of cirrhosis. Endothelin-1 is a potent vasoconstrictor and facilitator of smooth muscle proliferation.

In addition to collateral circulation allowing mediators to reach the pulmonary arterial bed in portal hypertension, high flow may trigger a vasoproliferative process in the pulmonary vascular bed. Patients with advanced liver disease have a low systemic vascular resistance, with a compensatory increase in cardiac output. An increase in cardiac output can lead to shear stress of the pulmonary vascular endothelial layer. Although the resistance of the pulmonary vasculature may decrease rapidly to help normalize pulmonary pressures, persistent circulatory overload could result in irreversible vascular changes. Autopsy and lung explant studies show that POPH is characterized by obstructive and remodeling changes in the pulmonary arterial bed.²⁴ Initially, medial hypertrophy with smooth muscle proliferation is present. As the disease advances, platelet aggregates, in situ thrombosis, and intimal fibrosis develop. Finally, web-like lesions involving the entire pulmonary wall develop with recanalization for the passage of pulmonary arterial flow. These changes are identical to the changes observed in patients with other forms of PAH.

Not all patients with portal hypertension develop POPH, suggesting that genetic predisposition may play a role in POPH development. The Pulmonary Vascular Complications of Liver Study Group published a multicenter case-control study that attempted to identify genetic risk factors for POPH in patients with advanced liver disease.²⁵ More than 1000 common single nucleotide polymorphisms (SNPs) in 93 candidate genes were genotyped in each patient. When compared to controls, multiple SNPs in the genes coding for estrogen receptor 1, aromatase, phosphodiesterase 5, angiopoietin 1, and calcium binding protein A4 were associated with an increased risk of POPH. One year earlier, the same study group concluded that female sex (adjusted odds ratio [OR], 2.90) and autoimmune hepatitis (adjusted OR, 4.02) were associated with a higher risk for POPH, whereas hepatitis C was associated with a decreased risk.²⁰

Clinical Presentation

Clinical presentation is variable in POPH. Patients referred to a pulmonologist will usually present with symptoms similar to patients with other forms of PAH. In a retrospective analysis of patients referred to the French Referral Center for Pulmonary Hypertension, 60% of the patients belonged to NYHA functional class III or IV.¹ In a series of 78 patients with POPH, the most common presenting pulmonary symptom was dyspnea on exertion (81%), followed by syncope, chest pain, and fatigue (< 33%).¹⁶ Symptoms such as syncope and chest pain are usually markers of severe POPH.³ Stigmata of portal hypertension, such as ascites, spider angiomata, and palmar erythema, may be present on exam. An accentuated pulmonary component of the second heart sound can be seen in 82% of patients and a systolic murmur caused by tricuspid regurgitation in 69% of patients.¹⁶ Patients with severe POPH may have jugular vein distention, peripheral edema, and a third heart sound.

Diagnostic Evaluation

Chest x-rays may show prominent pulmonary arteries and cardiomegaly in patients with POPH, whereas electrocardiogram can suggest right ventricular hypertrophy and right axis deviation. The best screening test for POPH in patients with portal hypertension is echocardiography. Routine screening for POPH is recommended during liver transplant evaluation in the practice guidelines from the American Association for the Study of Liver Disease.²⁶ Right-sided cardiac chamber enlargement and right ventricular pressure or volume overload can be assessed on echocardiography. Colle et al followed 165 patients evaluated for liver transplantation who underwent transthoracic Doppler echocardiography and right heart catheterization.²⁷ Seventeen patients met the criteria for POPH on echocardiography (presence of tricuspid regurgitation and calculated systolic pulmonary artery pressure over 30 mm Hg) and right heart catheterization confirmed the diagnosis in 10 patients. Right ventricular systolic pressure (RVSP) estimate of ≤ 30 mm Hg on 2-dimensional echo had a 100% sensitivity and negative predictive value. Positive predictive value was poor at 59%, reiterating the need for right heart catheterization in the diagnosis of POPH. When Kim et al used a RVSP threshold of 50 mm Hg, 72% had at least moderate pulmonary hypertension, including 30% with severe pulmonary hypertension.²⁸ Raevens et al analyzed data from 152 patients who underwent pretransplant echocardiography and catheterization.² Their data show a RVSP threshold of greater than 38 mm Hg by echocardiography had a specificity of 82% and sensitivity and negative predictive value of 100%. The European Respiratory Society recommendations state that PAH should be considered unlikely if echocardiography estimates a RVSP ≤36 mm Hg and likely if the RVSP is estimated at > 50 mm Hg.²⁹ We recommend repeating echocardiography every 6 to 12 months in patients listed for liver transplantation, as pulmonary hemodynamics may change over time.

Computed tomography (CT) may have a complementary role in the future for the noninvasive detection of POPH. In a study published in 2014, 49 patients referred for liver transplantation were retrospectively reviewed.³⁰ Measured CT signs included the main pulmonary artery/ascending aorta diameter ratio, the mean left and right main pulmonary artery diameter, and the enlargement of the pulmonary artery compared to the ascending aorta. Compared to the transthoracic echocardiography alone, an algorithm incorporating CT and echocardiography improved the detection of POPH (area under curve = 0.8, P < 0.0001).

A diagnosis of POPH can only be confirmed when PAH exists in a patient with portal hypertension, as determined by right heart catheterization, and no other cause of PAH can be identified. MPAP should be 25 mm Hg or greater, PVR of 240 dynes/s/cm^–5, wedge pressure of 15 mm Hg or less, and TPG greater than 12 mm Hg. Krowka et al showed the value of right heart catheterization in their 10-year prospective, echocardiography-catheterization algorithm study.¹⁹ Of 1235 liver transplant candidates who underwent echocardiography, 104 patients had a RVSP exceeding 50 mm Hg. Almost all of these patients had a right heart catheterization. All cause pulmonary hypertension (MPAP > 25 mm Hg) was confirmed in 90% of the patients, and 35% had a PVR < 240 dynes/s/cm^–5 and pulmonary capillary wedge pressure (PCWP) > 15 mm Hg, suggesting fluid overload. Forty-one patients had significant POPH, with a PVR > 400 dynes/s/cm^–5, and 24% also had an elevated PCWP. TPG was > 12 mm Hg in all of these patients, confirming POPH. As demonstrated by this study, right heart catheterization is required to confirm the diagnosis of POPH because high flow and fluid overload can lead to elevated pulmonary artery pressures.

Patients with POPH have a unique clinical profile with characteristics common to patients with primary pulmonary hypertension and chronic liver disease. In a retrospective review that compared 30 patients with PAH, 30 patients with chronic liver disease only, and 30 patients with catheterization-proved POPH,³¹ patients with POPH had elevated MPAP similar to those with primary PAH, but they also had reduced SVR and elevated cardiac index similar to those with chronic liver disease alone.

Besides POPH, 2 other common causes can lead to increased pulmonary arterial blood flow in patients with portal hypertension. First is a high-flow condition caused by increased cardiac output but with a normal PVR and PCWP. Fluid overload can also lead to pulmonary venous hypertension with increased PCWP, normal cardiac output, and normal PVR. Up to 25% of patients with POPH may present with marked excess volume caused by fluid retention.³ There can be an increase in both PCWP and PVR depending on the presence and the degree of fluid retention. TPG (MPAP – PCWP) > 12 mm Hg was introduced to make such patients less confusing and to help correct for increased PCWP secondary to fluid overload. Obstruction to pulmonary arterial flow is manifest by an increased TPG (Table 2).

POPH should be distinguished from hepatopulmonary syndrome (HPS), which is another pulmonary vascular consequence of liver disease. Unlike POPH, HPS is characterized by a defect in arterial oxygenation induced by pulmonary vascular dilation.³² Similar to other patients with liver disease, patients with HPS have a normal PVR and increased cardiac output secondary to a high-flow state. HPS is diagnosed by confirmation of an intrapulmonary shunt by echocardiogram. Injection of agitated saline results in saline bubbles being visualized in the left atrium 3 or more cardiac cycles after they appear in the right atrium. Currently, there is no effective medical treatment for HPS and liver transplantation is the only successful treatment.

Conclusion

POPH is an uncommon complication of chronic liver disease. It is defined as PAH in a patient with portal hypertension excluding other causes of PAH. The following criteria must be met to make a diagnosis of POPH: (1) evidence of portal hypertension; (2) MPAP ≥ 35 mm Hg; (3) PVR ≥ 240 dynes/s/cm⁵; (4) pulmonary capillary wedge pressure ≤ 15 mm Hg; and (5) TPG > 12 mm Hg. Individuals with POPH have worse outcomes compared to other forms of PAH, with a median survival of 6 months without medical therapy. The pathogenesis of POPH is unclear but may be related to a genetic predisposition since not all patients with portal hypertension develop POPH. Echocardiography is an excellent screening test for POPH, but a right heart catheterization must be performed to confirm the diagnosis.

Reinforcing previous findings, a new study has determined that the next-generation corrector elexacaftor, in combination with tezacaftor and ivacaftor, can effectively treat patients with Phe508del-minimal function genotypes who did not respond to previous cystic fibrosis transmembrane conductance regulator (CFTR) modulator regimens.

“These results provide evidence that elexacaftor-tezacaftor-ivacaftor can modulate a single Phe508del allele in people with cystic fibrosis, thus addressing the underlying cause of disease in the large majority of patients,” wrote Peter G. Middleton, PhD, of the University of Sydney (Australia) and his coauthors. The study was published in the New England Journal of Medicine.

To further determine if the elexacaftor-tezacaftor-ivacaftor regimen was effective and safe, the researchers launched a randomized, placebo-controlled phase 3 trial of 403 cystic fibrosis patients age 12 or older who had a single Phe508del allele. Patients in the combination group (n = 200) received 200 mg of elexacaftor once daily, 100 mg of tezacaftor once daily, and 150 mg of ivacaftor every 12 hours for 24 weeks. Patients in the other group (n = 203) received matched placebos.

At 14 weeks, patients in the combination group had a change in percentage of predicted forced expiratory volume in 1 second (FEV₁) that was 13.8 points higher than the placebo group (95% confidence interval, 12.1-15.4, P less than .001). At 24 weeks, the combination group had a predicted FEV₁ difference that was 14.3 percentage points higher (95% confidence interval, 12.7-15.8, P less than .001). The rate of pulmonary exacerbations was 63% lower (rate ratio 0.37; 95% CI, 0.25-0.55, P less than .001) and sweat chloride concentration was 41.8 mmol/L lower (95% CI, –44.4 to –39.3, P less than .001) in the combination group through 24 weeks.

At least one adverse event occurred in 93.1% of patients in the combination group and 96% of patients in the placebo group. Serious adverse events occurred in 28 patients (13.9%) in the combination group and 42 patients (20.9%) in the placebo group. There were no deaths in either group.

The study was funded by Vertex Pharmaceuticals. The authors had disclosures, including receiving personal fees and grants from various pharmaceutical companies and being on the advisory board, owning stock, or being an employee of Vertex Pharmaceuticals.

SOURCE: Middleton PG et al. 2019 Oct 31. N Engl J Med. doi: 10.1056/NEJMoa1908639.

Reinforcing previous findings, a new study has determined that the next-generation corrector elexacaftor, in combination with tezacaftor and ivacaftor, can effectively treat patients with Phe508del-minimal function genotypes who did not respond to previous cystic fibrosis transmembrane conductance regulator (CFTR) modulator regimens.

“These results provide evidence that elexacaftor-tezacaftor-ivacaftor can modulate a single Phe508del allele in people with cystic fibrosis, thus addressing the underlying cause of disease in the large majority of patients,” wrote Peter G. Middleton, PhD, of the University of Sydney (Australia) and his coauthors. The study was published in the New England Journal of Medicine.

To further determine if the elexacaftor-tezacaftor-ivacaftor regimen was effective and safe, the researchers launched a randomized, placebo-controlled phase 3 trial of 403 cystic fibrosis patients age 12 or older who had a single Phe508del allele. Patients in the combination group (n = 200) received 200 mg of elexacaftor once daily, 100 mg of tezacaftor once daily, and 150 mg of ivacaftor every 12 hours for 24 weeks. Patients in the other group (n = 203) received matched placebos.

At 14 weeks, patients in the combination group had a change in percentage of predicted forced expiratory volume in 1 second (FEV₁) that was 13.8 points higher than the placebo group (95% confidence interval, 12.1-15.4, P less than .001). At 24 weeks, the combination group had a predicted FEV₁ difference that was 14.3 percentage points higher (95% confidence interval, 12.7-15.8, P less than .001). The rate of pulmonary exacerbations was 63% lower (rate ratio 0.37; 95% CI, 0.25-0.55, P less than .001) and sweat chloride concentration was 41.8 mmol/L lower (95% CI, –44.4 to –39.3, P less than .001) in the combination group through 24 weeks.

At least one adverse event occurred in 93.1% of patients in the combination group and 96% of patients in the placebo group. Serious adverse events occurred in 28 patients (13.9%) in the combination group and 42 patients (20.9%) in the placebo group. There were no deaths in either group.

The study was funded by Vertex Pharmaceuticals. The authors had disclosures, including receiving personal fees and grants from various pharmaceutical companies and being on the advisory board, owning stock, or being an employee of Vertex Pharmaceuticals.

SOURCE: Middleton PG et al. 2019 Oct 31. N Engl J Med. doi: 10.1056/NEJMoa1908639.

Reinforcing previous findings, a new study has determined that the next-generation corrector elexacaftor, in combination with tezacaftor and ivacaftor, can effectively treat patients with Phe508del-minimal function genotypes who did not respond to previous cystic fibrosis transmembrane conductance regulator (CFTR) modulator regimens.

“These results provide evidence that elexacaftor-tezacaftor-ivacaftor can modulate a single Phe508del allele in people with cystic fibrosis, thus addressing the underlying cause of disease in the large majority of patients,” wrote Peter G. Middleton, PhD, of the University of Sydney (Australia) and his coauthors. The study was published in the New England Journal of Medicine.

To further determine if the elexacaftor-tezacaftor-ivacaftor regimen was effective and safe, the researchers launched a randomized, placebo-controlled phase 3 trial of 403 cystic fibrosis patients age 12 or older who had a single Phe508del allele. Patients in the combination group (n = 200) received 200 mg of elexacaftor once daily, 100 mg of tezacaftor once daily, and 150 mg of ivacaftor every 12 hours for 24 weeks. Patients in the other group (n = 203) received matched placebos.

At 14 weeks, patients in the combination group had a change in percentage of predicted forced expiratory volume in 1 second (FEV₁) that was 13.8 points higher than the placebo group (95% confidence interval, 12.1-15.4, P less than .001). At 24 weeks, the combination group had a predicted FEV₁ difference that was 14.3 percentage points higher (95% confidence interval, 12.7-15.8, P less than .001). The rate of pulmonary exacerbations was 63% lower (rate ratio 0.37; 95% CI, 0.25-0.55, P less than .001) and sweat chloride concentration was 41.8 mmol/L lower (95% CI, –44.4 to –39.3, P less than .001) in the combination group through 24 weeks.

At least one adverse event occurred in 93.1% of patients in the combination group and 96% of patients in the placebo group. Serious adverse events occurred in 28 patients (13.9%) in the combination group and 42 patients (20.9%) in the placebo group. There were no deaths in either group.

The study was funded by Vertex Pharmaceuticals. The authors had disclosures, including receiving personal fees and grants from various pharmaceutical companies and being on the advisory board, owning stock, or being an employee of Vertex Pharmaceuticals.

SOURCE: Middleton PG et al. 2019 Oct 31. N Engl J Med. doi: 10.1056/NEJMoa1908639.

Vaping-associated lung injury cases have now reached 1,888, according to the latest update provided by the Centers for Disease Control and Prevention. Thirty-seven deaths have been confirmed.

Deaths have occurred in 24 states and the District of Columbia: Alabama, California (3), Connecticut, Delaware, Florida, Georgia (3), Illinois (2), Indiana (3), Kansas (2), Massachusetts, Michigan, Minnesota (3), Mississippi, Missouri, Montana, Nebraska, New Jersey, New York, Oregon (2), Pennsylvania, Tennessee (2), Texas, Utah, and Virginia. As on Oct. 28, the median age of deceased patients was 49 years and ranged from 17 to 75 years.

The CDC is now doing additional testing on available samples for chemical in the bronchoalveolar lavage fluid, blood, or urine, as well as lung biopsy or autopsy specimens. It also is validating methods for aerosol emission testing of case-associated product samples from vaping products and e-liquids.

For more information and resources visit For the Public, For Healthcare Providers, and For State and Local Health Departments pages, as well as the CDC’s Publications and Resources page.

[email protected]

Vaping-associated lung injury cases have now reached 1,888, according to the latest update provided by the Centers for Disease Control and Prevention. Thirty-seven deaths have been confirmed.

Deaths have occurred in 24 states and the District of Columbia: Alabama, California (3), Connecticut, Delaware, Florida, Georgia (3), Illinois (2), Indiana (3), Kansas (2), Massachusetts, Michigan, Minnesota (3), Mississippi, Missouri, Montana, Nebraska, New Jersey, New York, Oregon (2), Pennsylvania, Tennessee (2), Texas, Utah, and Virginia. As on Oct. 28, the median age of deceased patients was 49 years and ranged from 17 to 75 years.

The CDC is now doing additional testing on available samples for chemical in the bronchoalveolar lavage fluid, blood, or urine, as well as lung biopsy or autopsy specimens. It also is validating methods for aerosol emission testing of case-associated product samples from vaping products and e-liquids.

For more information and resources visit For the Public, For Healthcare Providers, and For State and Local Health Departments pages, as well as the CDC’s Publications and Resources page.

[email protected]

Vaping-associated lung injury cases have now reached 1,888, according to the latest update provided by the Centers for Disease Control and Prevention. Thirty-seven deaths have been confirmed.

Deaths have occurred in 24 states and the District of Columbia: Alabama, California (3), Connecticut, Delaware, Florida, Georgia (3), Illinois (2), Indiana (3), Kansas (2), Massachusetts, Michigan, Minnesota (3), Mississippi, Missouri, Montana, Nebraska, New Jersey, New York, Oregon (2), Pennsylvania, Tennessee (2), Texas, Utah, and Virginia. As on Oct. 28, the median age of deceased patients was 49 years and ranged from 17 to 75 years.

The CDC is now doing additional testing on available samples for chemical in the bronchoalveolar lavage fluid, blood, or urine, as well as lung biopsy or autopsy specimens. It also is validating methods for aerosol emission testing of case-associated product samples from vaping products and e-liquids.

For more information and resources visit For the Public, For Healthcare Providers, and For State and Local Health Departments pages, as well as the CDC’s Publications and Resources page.

[email protected]

NEW ORLEANS – Real-world data support the use of macitentan to treat pulmonary arterial hypertension (PAH) associated with connective tissue disease, according to a speaker at the annual meeting of the American College of Chest Physicians.

Jen Smith/MDedge News

Outcomes of macitentan (Opsumit) treatment were similar in patients who had PAH associated with systemic sclerosis (PAH-SSc) and patients who had idiopathic PAH (IPAH) or heritable PAH (HPAH), Vallerie McLaughlin, MD, of the University of Michigan, Ann Arbor, said at the meeting.

“Within the limits of a real-world registry, these data add to the growing body of evidence supporting the use of macitentan for treatment in patients with CTD [connective tissue disease],” Dr. McLaughlin said.

She and her colleagues evaluated data from the prospective OPUS registry (NCT02126943) and the retrospective OrPHeUS study (NCT03197688), both of which included patients who were newly started on macitentan.

Dr. McLaughlin presented data on 2,311 patients with IPAH/HPAH and 668 patients with PAH-SSc. She also presented data on patients with PAH-systemic lupus erythematosus and PAH-mixed CTD, but numbers in these groups were small, and outcomes were similar to those in the PAH-SSc group.

Demographic and disease characteristics at the start of macitentan were similar between the IPAH/HPAH and PAH-SSc groups. The median age was 64 years in both groups. The median time from PAH diagnosis was 7.6 months in the IPAH/HPAH group and 8.5 months in the PAH-SSc group.

The median duration of macitentan exposure was 13.4 months in the IPAH/HPAH group and 14.4 months in the PAH-SSc group. The proportion of patients receiving macitentan in combination with other therapies (double or triple combinations) increased from baseline to 6 months in both groups.

Hepatic adverse events occurred in 7.4% of IPAH/HPAH patients and 7.9% of PAH-SSc patients. The most common adverse events among the IPAH/HPAH and PAH-SSc groups in the OPUS registry alone were dyspnea (19% and 26.1%, respectively), peripheral edema (9.8% and 12.4%), fatigue (6.8% and 11.7%), anemia (6.7% and 11.7%), headache (10.2% and 11%), and dizziness (6.7% and 10.7%).

About 39% of patients in both groups discontinued macitentan. Similar proportions in each group discontinued because of adverse events (17% in the IPAH/HPAH group and 18.3% in the PAH-SSc group) and hepatic adverse events (0.2% and 0.7%, respectively).

The proportion of patients with at least one hospitalization was 36.2% in the IPAH/HPAH group and 40.1% in the PAH-SSc group.

The 12-month Kaplan-Meier survival estimate was 92.9% in the IPAH/HPAH group and 91.3% in the PAH-SSc group. The 24-month estimated survival rate was 85.6% and 82.1%, respectively.

The OPUS registry and OrPHeUS study are sponsored by Actelion. Dr. McLaughlin disclosed relationships with Actelion, Acceleron, Bayer, Caremark, CiVi Biopharma, Reata, Sonovie, and United Therapeutics.

[email protected]

SOURCE: McLaughlin V et al. CHEST 2019. Abstract, doi: 10.1016/j.chest.2019.08.827.

NEW ORLEANS – Real-world data support the use of macitentan to treat pulmonary arterial hypertension (PAH) associated with connective tissue disease, according to a speaker at the annual meeting of the American College of Chest Physicians.

Jen Smith/MDedge News

Outcomes of macitentan (Opsumit) treatment were similar in patients who had PAH associated with systemic sclerosis (PAH-SSc) and patients who had idiopathic PAH (IPAH) or heritable PAH (HPAH), Vallerie McLaughlin, MD, of the University of Michigan, Ann Arbor, said at the meeting.

“Within the limits of a real-world registry, these data add to the growing body of evidence supporting the use of macitentan for treatment in patients with CTD [connective tissue disease],” Dr. McLaughlin said.

She and her colleagues evaluated data from the prospective OPUS registry (NCT02126943) and the retrospective OrPHeUS study (NCT03197688), both of which included patients who were newly started on macitentan.

Dr. McLaughlin presented data on 2,311 patients with IPAH/HPAH and 668 patients with PAH-SSc. She also presented data on patients with PAH-systemic lupus erythematosus and PAH-mixed CTD, but numbers in these groups were small, and outcomes were similar to those in the PAH-SSc group.

Demographic and disease characteristics at the start of macitentan were similar between the IPAH/HPAH and PAH-SSc groups. The median age was 64 years in both groups. The median time from PAH diagnosis was 7.6 months in the IPAH/HPAH group and 8.5 months in the PAH-SSc group.

The median duration of macitentan exposure was 13.4 months in the IPAH/HPAH group and 14.4 months in the PAH-SSc group. The proportion of patients receiving macitentan in combination with other therapies (double or triple combinations) increased from baseline to 6 months in both groups.

Hepatic adverse events occurred in 7.4% of IPAH/HPAH patients and 7.9% of PAH-SSc patients. The most common adverse events among the IPAH/HPAH and PAH-SSc groups in the OPUS registry alone were dyspnea (19% and 26.1%, respectively), peripheral edema (9.8% and 12.4%), fatigue (6.8% and 11.7%), anemia (6.7% and 11.7%), headache (10.2% and 11%), and dizziness (6.7% and 10.7%).

About 39% of patients in both groups discontinued macitentan. Similar proportions in each group discontinued because of adverse events (17% in the IPAH/HPAH group and 18.3% in the PAH-SSc group) and hepatic adverse events (0.2% and 0.7%, respectively).

The proportion of patients with at least one hospitalization was 36.2% in the IPAH/HPAH group and 40.1% in the PAH-SSc group.

The 12-month Kaplan-Meier survival estimate was 92.9% in the IPAH/HPAH group and 91.3% in the PAH-SSc group. The 24-month estimated survival rate was 85.6% and 82.1%, respectively.

The OPUS registry and OrPHeUS study are sponsored by Actelion. Dr. McLaughlin disclosed relationships with Actelion, Acceleron, Bayer, Caremark, CiVi Biopharma, Reata, Sonovie, and United Therapeutics.

[email protected]

SOURCE: McLaughlin V et al. CHEST 2019. Abstract, doi: 10.1016/j.chest.2019.08.827.

NEW ORLEANS – Real-world data support the use of macitentan to treat pulmonary arterial hypertension (PAH) associated with connective tissue disease, according to a speaker at the annual meeting of the American College of Chest Physicians.

Jen Smith/MDedge News

Outcomes of macitentan (Opsumit) treatment were similar in patients who had PAH associated with systemic sclerosis (PAH-SSc) and patients who had idiopathic PAH (IPAH) or heritable PAH (HPAH), Vallerie McLaughlin, MD, of the University of Michigan, Ann Arbor, said at the meeting.

“Within the limits of a real-world registry, these data add to the growing body of evidence supporting the use of macitentan for treatment in patients with CTD [connective tissue disease],” Dr. McLaughlin said.

She and her colleagues evaluated data from the prospective OPUS registry (NCT02126943) and the retrospective OrPHeUS study (NCT03197688), both of which included patients who were newly started on macitentan.

Dr. McLaughlin presented data on 2,311 patients with IPAH/HPAH and 668 patients with PAH-SSc. She also presented data on patients with PAH-systemic lupus erythematosus and PAH-mixed CTD, but numbers in these groups were small, and outcomes were similar to those in the PAH-SSc group.

Demographic and disease characteristics at the start of macitentan were similar between the IPAH/HPAH and PAH-SSc groups. The median age was 64 years in both groups. The median time from PAH diagnosis was 7.6 months in the IPAH/HPAH group and 8.5 months in the PAH-SSc group.

The median duration of macitentan exposure was 13.4 months in the IPAH/HPAH group and 14.4 months in the PAH-SSc group. The proportion of patients receiving macitentan in combination with other therapies (double or triple combinations) increased from baseline to 6 months in both groups.

Hepatic adverse events occurred in 7.4% of IPAH/HPAH patients and 7.9% of PAH-SSc patients. The most common adverse events among the IPAH/HPAH and PAH-SSc groups in the OPUS registry alone were dyspnea (19% and 26.1%, respectively), peripheral edema (9.8% and 12.4%), fatigue (6.8% and 11.7%), anemia (6.7% and 11.7%), headache (10.2% and 11%), and dizziness (6.7% and 10.7%).

About 39% of patients in both groups discontinued macitentan. Similar proportions in each group discontinued because of adverse events (17% in the IPAH/HPAH group and 18.3% in the PAH-SSc group) and hepatic adverse events (0.2% and 0.7%, respectively).

The proportion of patients with at least one hospitalization was 36.2% in the IPAH/HPAH group and 40.1% in the PAH-SSc group.

The 12-month Kaplan-Meier survival estimate was 92.9% in the IPAH/HPAH group and 91.3% in the PAH-SSc group. The 24-month estimated survival rate was 85.6% and 82.1%, respectively.

The OPUS registry and OrPHeUS study are sponsored by Actelion. Dr. McLaughlin disclosed relationships with Actelion, Acceleron, Bayer, Caremark, CiVi Biopharma, Reata, Sonovie, and United Therapeutics.

[email protected]

SOURCE: McLaughlin V et al. CHEST 2019. Abstract, doi: 10.1016/j.chest.2019.08.827.

WASHINGTON – Influenza vaccine continues to cut not just the incidence of flu but also mitigates infection severity in both children and adults, according to recent U.S. experience collected by the Centers for Disease Control and Prevention.

During recent U.S. flu seasons, children and adults who contracted influenza despite vaccination had significantly fewer severe infections and infection complications, compared with unimmunized people, according to two separate reports from CDC researchers presented at an annual scientific meeting on infectious diseases.

One of the reports tracked the impact of flu vaccine in children using data that the CDC collected at seven medical centers that participated in the agency’s New Vaccine Surveillance Network, which provided information on children aged 6 months to 17 years who were hospitalized for an acute respiratory illness, including more than 1,700 children during the 2016-2017 flu season and more than 1,900 during the 2017-2018 season. Roughly 10% of these children tested positive for influenza, and the subsequent analysis focused on these cases and compared incidence rates among children who had been vaccinated during the index season and those who had remained unvaccinated.

Combined data from both seasons showed that vaccinated children were 50% less likely to have been hospitalized for an acute influenza infection, compared with unvaccinated kids, a pattern consistently seen both in children aged 6 months to 8 years and in those aged 9-17 years. The pattern of vaccine effectiveness also held regardless of which flu strain caused the infections, reported Angela P. Campbell, MD, a CDC medical officer.

“We saw a nice benefit from vaccination, both in previously healthy children and in those with an underlying medical condition,” a finding that adds to existing evidence of vaccine effectiveness, Dr. Campbell said in a video interview. The results confirmed that flu vaccination does not just prevent infections but also cuts the rate of more severe infections that lead to hospitalization, she explained.

Another CDC study looked at data collected by the agency’s Influenza Hospitalization Surveillance Network from adults at least 18 years old who were hospitalized for a laboratory-confirmed influenza infection during five flu seasons, 2013-2014 through 2017-18. The data, which came from more than 250 acute-care hospitals in 13 states, included more than 43,000 people hospitalized for an identified influenza strain and with a known vaccination history who were not institutionalized and had not received any antiviral treatment.

After propensity-weighted adjustment to create better parity between the vaccinated and unvaccinated patients, the results showed that people 18-64 years old with vaccination had statistically significant decreases in mortality of a relative 36%, need for mechanical ventilation of 34%, pneumonia of 20%, and need for ICU admission of a relative 19%, as well as an 18% drop in average ICU length of stay, Shikha Garg, MD, said at the meeting. The propensity-weighted analysis of data from people at least 65 years old showed statistically significant relative reductions linked with vaccination: 46% reduction in the need for mechanical ventilation, 28% reduction in ICU admissions, and 9% reduction in hospitalized length of stay.

Further analysis of these outcomes by the strains that caused these influenza infections showed that the statistically significant benefits from vaccination were seen only in patients infected with an H1N1 strain. Statistically significant effects on these severe outcomes were not apparent among people infected with the H3N2 or B strains, said Dr. Garg, a medical epidemiologist at the CDC.

“All adults should receive an annual flu vaccination as it can improve outcomes among those who develop influenza despite vaccination,” she concluded.

Results from a third CDC study reported at the meeting examined the importance of two vaccine doses (administered at least 4 weeks apart) given to children aged 6 months to 8 years for the first season they receive flu vaccination, which is the immunization approach for flu recommended by the CDC. The findings from a total of more than 7,500 children immunized during the 2014-2018 seasons showed a clear increment in vaccine protection among kids who received two doses during their first season vaccinated, especially in children who were 2 years old or younger. In that age group, administration of two doses produced vaccine effectiveness of 53% versus a 23% vaccine effectiveness after a single vaccine dose, reported Jessie Chung, a CDC epidemiologist.

[email protected]

WASHINGTON – Influenza vaccine continues to cut not just the incidence of flu but also mitigates infection severity in both children and adults, according to recent U.S. experience collected by the Centers for Disease Control and Prevention.

During recent U.S. flu seasons, children and adults who contracted influenza despite vaccination had significantly fewer severe infections and infection complications, compared with unimmunized people, according to two separate reports from CDC researchers presented at an annual scientific meeting on infectious diseases.

One of the reports tracked the impact of flu vaccine in children using data that the CDC collected at seven medical centers that participated in the agency’s New Vaccine Surveillance Network, which provided information on children aged 6 months to 17 years who were hospitalized for an acute respiratory illness, including more than 1,700 children during the 2016-2017 flu season and more than 1,900 during the 2017-2018 season. Roughly 10% of these children tested positive for influenza, and the subsequent analysis focused on these cases and compared incidence rates among children who had been vaccinated during the index season and those who had remained unvaccinated.

Combined data from both seasons showed that vaccinated children were 50% less likely to have been hospitalized for an acute influenza infection, compared with unvaccinated kids, a pattern consistently seen both in children aged 6 months to 8 years and in those aged 9-17 years. The pattern of vaccine effectiveness also held regardless of which flu strain caused the infections, reported Angela P. Campbell, MD, a CDC medical officer.

“We saw a nice benefit from vaccination, both in previously healthy children and in those with an underlying medical condition,” a finding that adds to existing evidence of vaccine effectiveness, Dr. Campbell said in a video interview. The results confirmed that flu vaccination does not just prevent infections but also cuts the rate of more severe infections that lead to hospitalization, she explained.

Another CDC study looked at data collected by the agency’s Influenza Hospitalization Surveillance Network from adults at least 18 years old who were hospitalized for a laboratory-confirmed influenza infection during five flu seasons, 2013-2014 through 2017-18. The data, which came from more than 250 acute-care hospitals in 13 states, included more than 43,000 people hospitalized for an identified influenza strain and with a known vaccination history who were not institutionalized and had not received any antiviral treatment.

After propensity-weighted adjustment to create better parity between the vaccinated and unvaccinated patients, the results showed that people 18-64 years old with vaccination had statistically significant decreases in mortality of a relative 36%, need for mechanical ventilation of 34%, pneumonia of 20%, and need for ICU admission of a relative 19%, as well as an 18% drop in average ICU length of stay, Shikha Garg, MD, said at the meeting. The propensity-weighted analysis of data from people at least 65 years old showed statistically significant relative reductions linked with vaccination: 46% reduction in the need for mechanical ventilation, 28% reduction in ICU admissions, and 9% reduction in hospitalized length of stay.

Further analysis of these outcomes by the strains that caused these influenza infections showed that the statistically significant benefits from vaccination were seen only in patients infected with an H1N1 strain. Statistically significant effects on these severe outcomes were not apparent among people infected with the H3N2 or B strains, said Dr. Garg, a medical epidemiologist at the CDC.

“All adults should receive an annual flu vaccination as it can improve outcomes among those who develop influenza despite vaccination,” she concluded.

Results from a third CDC study reported at the meeting examined the importance of two vaccine doses (administered at least 4 weeks apart) given to children aged 6 months to 8 years for the first season they receive flu vaccination, which is the immunization approach for flu recommended by the CDC. The findings from a total of more than 7,500 children immunized during the 2014-2018 seasons showed a clear increment in vaccine protection among kids who received two doses during their first season vaccinated, especially in children who were 2 years old or younger. In that age group, administration of two doses produced vaccine effectiveness of 53% versus a 23% vaccine effectiveness after a single vaccine dose, reported Jessie Chung, a CDC epidemiologist.

[email protected]

WASHINGTON – Influenza vaccine continues to cut not just the incidence of flu but also mitigates infection severity in both children and adults, according to recent U.S. experience collected by the Centers for Disease Control and Prevention.

During recent U.S. flu seasons, children and adults who contracted influenza despite vaccination had significantly fewer severe infections and infection complications, compared with unimmunized people, according to two separate reports from CDC researchers presented at an annual scientific meeting on infectious diseases.

One of the reports tracked the impact of flu vaccine in children using data that the CDC collected at seven medical centers that participated in the agency’s New Vaccine Surveillance Network, which provided information on children aged 6 months to 17 years who were hospitalized for an acute respiratory illness, including more than 1,700 children during the 2016-2017 flu season and more than 1,900 during the 2017-2018 season. Roughly 10% of these children tested positive for influenza, and the subsequent analysis focused on these cases and compared incidence rates among children who had been vaccinated during the index season and those who had remained unvaccinated.

Combined data from both seasons showed that vaccinated children were 50% less likely to have been hospitalized for an acute influenza infection, compared with unvaccinated kids, a pattern consistently seen both in children aged 6 months to 8 years and in those aged 9-17 years. The pattern of vaccine effectiveness also held regardless of which flu strain caused the infections, reported Angela P. Campbell, MD, a CDC medical officer.

“We saw a nice benefit from vaccination, both in previously healthy children and in those with an underlying medical condition,” a finding that adds to existing evidence of vaccine effectiveness, Dr. Campbell said in a video interview. The results confirmed that flu vaccination does not just prevent infections but also cuts the rate of more severe infections that lead to hospitalization, she explained.

Another CDC study looked at data collected by the agency’s Influenza Hospitalization Surveillance Network from adults at least 18 years old who were hospitalized for a laboratory-confirmed influenza infection during five flu seasons, 2013-2014 through 2017-18. The data, which came from more than 250 acute-care hospitals in 13 states, included more than 43,000 people hospitalized for an identified influenza strain and with a known vaccination history who were not institutionalized and had not received any antiviral treatment.

After propensity-weighted adjustment to create better parity between the vaccinated and unvaccinated patients, the results showed that people 18-64 years old with vaccination had statistically significant decreases in mortality of a relative 36%, need for mechanical ventilation of 34%, pneumonia of 20%, and need for ICU admission of a relative 19%, as well as an 18% drop in average ICU length of stay, Shikha Garg, MD, said at the meeting. The propensity-weighted analysis of data from people at least 65 years old showed statistically significant relative reductions linked with vaccination: 46% reduction in the need for mechanical ventilation, 28% reduction in ICU admissions, and 9% reduction in hospitalized length of stay.

Further analysis of these outcomes by the strains that caused these influenza infections showed that the statistically significant benefits from vaccination were seen only in patients infected with an H1N1 strain. Statistically significant effects on these severe outcomes were not apparent among people infected with the H3N2 or B strains, said Dr. Garg, a medical epidemiologist at the CDC.

“All adults should receive an annual flu vaccination as it can improve outcomes among those who develop influenza despite vaccination,” she concluded.

Results from a third CDC study reported at the meeting examined the importance of two vaccine doses (administered at least 4 weeks apart) given to children aged 6 months to 8 years for the first season they receive flu vaccination, which is the immunization approach for flu recommended by the CDC. The findings from a total of more than 7,500 children immunized during the 2014-2018 seasons showed a clear increment in vaccine protection among kids who received two doses during their first season vaccinated, especially in children who were 2 years old or younger. In that age group, administration of two doses produced vaccine effectiveness of 53% versus a 23% vaccine effectiveness after a single vaccine dose, reported Jessie Chung, a CDC epidemiologist.

[email protected]

AUSTIN, TEX. – Patients with chronic inflammatory demyelinating polyneuropathy (CIDP) who receive intravenous immunoglobulin (IVIg) appear to have an increased risk of thromboembolic events if it is administered with a central venous access device (CVAD) when compared against those without a CVAD, according to a recent study.

Although CVADs can reliably deliver IVIg, they also represent an established risk factor for thromboembolic events, Ami Patel, PhD, a senior epidemiologist at CSL Behring, and colleagues noted on their poster at the annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine.

The results suggest a need for physicians to be vigilant about patients’ potential risk factors for thromboembolic events, Dr. Patel said in an interview. Further research is planned, however, because the current study did not control for other risk factors or explore other possible confounding, she said.

Dr. Patel and her associates analyzed U.S. claims data (IBM/Truven MarketScan) from 2006 to 2018 and included all patients with a CIDP diagnosis claim and a postdiagnosis code for IVIg. A code for CVAD up to 2 months before CIDP diagnosis without removal before IVIg treatment ended determined those with CVAD exposure, and thromboembolic events included any codes related to arterial, venous, or vascular prostheses.

The researchers then compared patients in a case-control fashion, matching each one with a CVAD to five patients of similar demographics without a CVAD. Characteristics used for matching included medical insurance type, prescription data availability, sex, age, geographic region, and years enrolled in the database.

Among 7,447 patients with at least one IVIg claim, 11.8% (n = 882) had CVAD exposure and 88.2% (n = 6,565) did not. Of those without a CVAD, 3,642 patients were matched to patients with CVAD. A quarter (25.4%) of patients with a CVAD had a thromboembolic event, compared with 11.2% of matched patients without CVADs (P less than .0001).

In the year leading up to IVIg therapy, 16.9% of those with a CVAD and 10.9% of matched patients without one had a previous thromboembolic event (P less than .0001). Patients with a CVAD also had significantly higher rates of hypertension (51.9% vs. 45.0% with placebo; P less than .001) and anticoagulation therapy (7.0% vs. 5.2% with placebo; P less than .05). Differences between the groups were not significant for diabetes (26.9% vs. 24.2%) and hyperlipidemia (19.1% vs. 17.8%).

Occlusion and stenosis of the carotid artery was the most common arterial thromboembolic outcome, occurring in 5.3% of those with a CVAD and in 2.8% of those without a CVAD. The most common venous thromboembolic event was acute venous embolism and thrombosis of lower-extremity deep vessels, which occurred in 7% of those with a CVAD and in 1.8% of those without.

The researchers also compared inpatient admissions and emergency department visits among those with and without a CVAD; both rates were higher in patients with a CVAD. Visits to the emergency department occurred at a rate of 0.14 events per month for those with a CVAD (2.01 distinct months with a claim) and 0.09 events per month for those without a CVAD (0.65 distinct months with a claim). Patients with a CVAD had 1.44 months with an inpatient admissions claim, in comparison with 0.41 months among matched patients without a CVAD. Inpatient admission frequency per month was 0.14 for those with a CVAD and 0.08 for those without.

The research was funded by CSL Behring. Dr. Patel and two of the other five authors are employees of CSL Behring.

SOURCE: Patel A et al. AANEM 2019, Abstract 94.

AUSTIN, TEX. – Patients with chronic inflammatory demyelinating polyneuropathy (CIDP) who receive intravenous immunoglobulin (IVIg) appear to have an increased risk of thromboembolic events if it is administered with a central venous access device (CVAD) when compared against those without a CVAD, according to a recent study.

Although CVADs can reliably deliver IVIg, they also represent an established risk factor for thromboembolic events, Ami Patel, PhD, a senior epidemiologist at CSL Behring, and colleagues noted on their poster at the annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine.

The results suggest a need for physicians to be vigilant about patients’ potential risk factors for thromboembolic events, Dr. Patel said in an interview. Further research is planned, however, because the current study did not control for other risk factors or explore other possible confounding, she said.

Dr. Patel and her associates analyzed U.S. claims data (IBM/Truven MarketScan) from 2006 to 2018 and included all patients with a CIDP diagnosis claim and a postdiagnosis code for IVIg. A code for CVAD up to 2 months before CIDP diagnosis without removal before IVIg treatment ended determined those with CVAD exposure, and thromboembolic events included any codes related to arterial, venous, or vascular prostheses.

The researchers then compared patients in a case-control fashion, matching each one with a CVAD to five patients of similar demographics without a CVAD. Characteristics used for matching included medical insurance type, prescription data availability, sex, age, geographic region, and years enrolled in the database.

Among 7,447 patients with at least one IVIg claim, 11.8% (n = 882) had CVAD exposure and 88.2% (n = 6,565) did not. Of those without a CVAD, 3,642 patients were matched to patients with CVAD. A quarter (25.4%) of patients with a CVAD had a thromboembolic event, compared with 11.2% of matched patients without CVADs (P less than .0001).

In the year leading up to IVIg therapy, 16.9% of those with a CVAD and 10.9% of matched patients without one had a previous thromboembolic event (P less than .0001). Patients with a CVAD also had significantly higher rates of hypertension (51.9% vs. 45.0% with placebo; P less than .001) and anticoagulation therapy (7.0% vs. 5.2% with placebo; P less than .05). Differences between the groups were not significant for diabetes (26.9% vs. 24.2%) and hyperlipidemia (19.1% vs. 17.8%).

Occlusion and stenosis of the carotid artery was the most common arterial thromboembolic outcome, occurring in 5.3% of those with a CVAD and in 2.8% of those without a CVAD. The most common venous thromboembolic event was acute venous embolism and thrombosis of lower-extremity deep vessels, which occurred in 7% of those with a CVAD and in 1.8% of those without.

The researchers also compared inpatient admissions and emergency department visits among those with and without a CVAD; both rates were higher in patients with a CVAD. Visits to the emergency department occurred at a rate of 0.14 events per month for those with a CVAD (2.01 distinct months with a claim) and 0.09 events per month for those without a CVAD (0.65 distinct months with a claim). Patients with a CVAD had 1.44 months with an inpatient admissions claim, in comparison with 0.41 months among matched patients without a CVAD. Inpatient admission frequency per month was 0.14 for those with a CVAD and 0.08 for those without.

The research was funded by CSL Behring. Dr. Patel and two of the other five authors are employees of CSL Behring.

SOURCE: Patel A et al. AANEM 2019, Abstract 94.

AUSTIN, TEX. – Patients with chronic inflammatory demyelinating polyneuropathy (CIDP) who receive intravenous immunoglobulin (IVIg) appear to have an increased risk of thromboembolic events if it is administered with a central venous access device (CVAD) when compared against those without a CVAD, according to a recent study.

Although CVADs can reliably deliver IVIg, they also represent an established risk factor for thromboembolic events, Ami Patel, PhD, a senior epidemiologist at CSL Behring, and colleagues noted on their poster at the annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine.

The results suggest a need for physicians to be vigilant about patients’ potential risk factors for thromboembolic events, Dr. Patel said in an interview. Further research is planned, however, because the current study did not control for other risk factors or explore other possible confounding, she said.

Dr. Patel and her associates analyzed U.S. claims data (IBM/Truven MarketScan) from 2006 to 2018 and included all patients with a CIDP diagnosis claim and a postdiagnosis code for IVIg. A code for CVAD up to 2 months before CIDP diagnosis without removal before IVIg treatment ended determined those with CVAD exposure, and thromboembolic events included any codes related to arterial, venous, or vascular prostheses.

The researchers then compared patients in a case-control fashion, matching each one with a CVAD to five patients of similar demographics without a CVAD. Characteristics used for matching included medical insurance type, prescription data availability, sex, age, geographic region, and years enrolled in the database.

Among 7,447 patients with at least one IVIg claim, 11.8% (n = 882) had CVAD exposure and 88.2% (n = 6,565) did not. Of those without a CVAD, 3,642 patients were matched to patients with CVAD. A quarter (25.4%) of patients with a CVAD had a thromboembolic event, compared with 11.2% of matched patients without CVADs (P less than .0001).

In the year leading up to IVIg therapy, 16.9% of those with a CVAD and 10.9% of matched patients without one had a previous thromboembolic event (P less than .0001). Patients with a CVAD also had significantly higher rates of hypertension (51.9% vs. 45.0% with placebo; P less than .001) and anticoagulation therapy (7.0% vs. 5.2% with placebo; P less than .05). Differences between the groups were not significant for diabetes (26.9% vs. 24.2%) and hyperlipidemia (19.1% vs. 17.8%).

Occlusion and stenosis of the carotid artery was the most common arterial thromboembolic outcome, occurring in 5.3% of those with a CVAD and in 2.8% of those without a CVAD. The most common venous thromboembolic event was acute venous embolism and thrombosis of lower-extremity deep vessels, which occurred in 7% of those with a CVAD and in 1.8% of those without.

The researchers also compared inpatient admissions and emergency department visits among those with and without a CVAD; both rates were higher in patients with a CVAD. Visits to the emergency department occurred at a rate of 0.14 events per month for those with a CVAD (2.01 distinct months with a claim) and 0.09 events per month for those without a CVAD (0.65 distinct months with a claim). Patients with a CVAD had 1.44 months with an inpatient admissions claim, in comparison with 0.41 months among matched patients without a CVAD. Inpatient admission frequency per month was 0.14 for those with a CVAD and 0.08 for those without.

The research was funded by CSL Behring. Dr. Patel and two of the other five authors are employees of CSL Behring.

SOURCE: Patel A et al. AANEM 2019, Abstract 94.

The national outbreak of vaping-associated lung injuries is ongoing and the number of cases and deaths continues to rise.

The Centers for Disease Control and Prevention is providing frequent updates of the wide-ranging and aggressive investigation of the cases and deaths linked to vaping, and although a definitive cause remains unknown, evidence is accumulating to implicate tetrahydrocannabinol (THC)-containing devices. The investigation is being conducted in concert with the Food and Drug Administration, many state and local health departments, and public health and clinical partners.

The acronym EVALI has been developed by CDC to refer to e-cigarette, or vaping products use–associated lung injury. In a report summarizing data up to Oct. 22, CDC reported 1,604 EVALI cases and 34 deaths. These cases have occurred in all U.S. states (except Alaska), the District of Columbia, and the U.S. Virgin Islands. The CDC also published a report in the Morbidity and Mortality Weekly report on characteristics of those patients who have died from EVALI-based symptoms as of Oct. 15, 2019.

With data available for more than 867 patients with EVALI, about 86% had a history of using e-cigarette or vaping products that contained THC in the previous 90 days; 64% reported using nicotine-containing products; 34% reported exclusive use of THC-containing products, and 11% reported exclusive use of nicotine-containing products; 52% reported use of both.

In a telebriefing on Oct. 25, Anne Schuchat, MD, CDC principal deputy director, said, “The data do continue to point towards THC-containing products as the source of the vast majority of individuals’ lung injury. There are continuing cases that do not report that history. But I’d like to stress that we don’t know what the risky material or substance is. THC may be a marker for a way that cartridges were prepared or the way that the devices are producing harm. Whether there are similar activities going on with cartridges that don’t contain THC, for instance, remains to be seen. So, I think we are seeing the THC as a marker for products that are risky.”

EVALI deaths

Among the 29 deaths reported as of Oct. 15, 59% (17) were male; the median age was 45 years (range, 17-75 years), 55 years (range, 17-71 years) among males, and 43 years (range, 27-75 years) among females; the age difference between males and females was not statistically significant. Patients who died tended to be older than patients who survived. Among 19 EVALI patients who died and for whom data on substance use was available, the use of any THC-containing products was reported by patients or proxies for 84% (16), including 63% (12) who exclusively used THC-containing products. Use of any nicotine-containing products was reported for 37% (7), including 16% (3) who exclusively used nicotine-containing products. Use of both THC- and nicotine-containing products was reported in four of those who died.

Investigation update

Mitch Zeller, JD, director, Center for Tobacco Products at the Food and Drug Administration, participated in the telebriefing and provided an update on the ongoing investigation. “State of the art methods are being used to assess the presence of a broad range of chemicals including nicotine, THC, and other cannabinoids, opioids, additives, pesticides, poisons and toxins,” he said. “FDA has received or collected over 900 samples from 25 states to date. Those numbers continue to increase. The samples [were] collected directly from consumers, hospitals, and from state offices include vaping devices and products that contain liquid as well as packaging and some nearly empty containers.” He cautioned that identifying the substance is “but one piece of the puzzle and will not necessarily answer questions about causality.” He also noted that the self-reports of THC and/or nicotine could mean that there is misreported data, because reports in many cases are coming from teens and from jurisdictions in which THC is not legal.

vchal/Getty Images

The issue of whether EVALI has been seen in recent years but not recognized or whether EVALI is a new phenomenon was raised by a caller at the telebriefing. Dr. Schuchat responded, “We are aware of older cases that look similar to what we are seeing now. But we do not believe that this outbreak or surge in cases is due to better recognition.” She suggested that some evidence points to cutting agents being introduced to increase profits of e-cigarettes and that risky and unknown substances have been introduced into the supply chain.

A “handful” of cases of readmission have been reported, and the CDC is currently investigating whether these cases included patients who took up vaping again or had some other possible contributing factor. Dr. Schuchat cautioned recovering patients not to resume vaping because of the risk of readmission and the probability that their lungs will remain in a weakened state.

Clinical guidance update

The CDC provided detailed interim clinical guidance on evaluating and caring for patients with EVALI. The recommendations focus on patient history, lab testing, criteria for hospitalization, and follow-up for these patients.

Obtaining a detailed history of patients presenting with suspected EVALI is especially important for this patient population, given the many unknowns surrounding this condition, according to the CDC. The updated guidance states, “All health care providers evaluating patients for EVALI should ask about the use of e-cigarette or vaping products, and ideally should ask about types of substances used (e.g.,THC, cannabis [oil, dabs], nicotine, modified products or the addition of substances not intended by the manufacturer); product source, specific product brand and name; duration and frequency of use, time of last use; product delivery system and method of use (aerosolization, dabbing, or dripping).” The approach recommended for soliciting accurate information is “empathetic, nonjudgmental” and, the guidelines say, patients should be questioned in private regarding sensitive information to assure confidentiality.

A respiratory virus panel is recommended for all suspected EVALI patients, although at this time, these tests cannot be used to distinguish EVALI from infectious etiologies. All patients should be considered for urine toxicology testing, including testing for THC.

Imaging guidance for suspected EVALI patients includes chest x-ray, with additional CT scan when the x-ray result does not correlate with clinical findings or to evaluate severe or worsening disease.

Recommended criteria for hospitalization of patients with suspected EVALI are those patients with decreased O₂ saturation (less than 95%) on room air, in respiratory distress, or with comorbidities that compromise pulmonary reserve. As of Oct. 8, 96% of patients with suspected EVALI reported to the CDC have been hospitalized.

As for medical treatment of these patients, corticosteroids have been found to be helpful. The statement noted, “Among 140 cases reported nationally to CDC that received corticosteroids, 82% of patients improved.”

The natural progression of this injury is not known, however, and it is possible that patients might recover without corticosteroids. Given the unknown etiology of the disease and “because the diagnosis remains one of exclusion, aggressive empiric therapy with corticosteroids, antimicrobial, and antiviral therapy might be warranted for patients with severe illness. A range of corticosteroid doses, durations, and taper plans might be considered on a case-by-case basis.”

The report concluded with a strong recommendation that patients hospitalized with EVALI are followed closely with a visit 1-2 weeks after discharge and again with additional testing 1-2 months later. Health care providers are also advised to consult medical specialists, in particular pulmonologists, who can offer further evaluation, recommend empiric treatment, and review indications for bronchoscopy.

CPT coding for EVALI

CDC has issued coding guidance to help track EVALI. The document was posted on the CDC website. The coding guidance is consistent with current clinical knowledge about EVALI-related disorders and is intended for use in conjunction with current ICD-10-CM classifications.

The following conditions associated with EVALI are covered in the new coding guidance:

• Bronchitis and pneumonitis caused by chemicals, gases, and fumes; including chemical pneumonitis; J68.0.
• Pneumonitis caused by inhalation of oils and essences; including lipoid pneumonia; J69.1.
• Acute respiratory distress syndrome; J80.
• Pulmonary eosinophilia, not elsewhere classified; J82.
• Acute interstitial pneumonitis; J84.114.

The document notes that the coding guidance has been approved by the National Center for Health Statistics, the American Health Information Management Association, the American Hospital Association, and the Centers for Medicare & Medicaid Services.

Investigation continues

Mr. Zeller cautioned that this investigation will not be concluded in the near future. He noted, “We are committed to working to [solve the mystery] just as quickly as we can, but we also recognize that it will likely take some time. Importantly, the diversity of the patients and the products or substances they have reported using and the samples being tested may mean ultimately that there are multiple causes of these injuries.”

[email protected]

Richard Franki and Gregory Twachtman contributed to this story.

The national outbreak of vaping-associated lung injuries is ongoing and the number of cases and deaths continues to rise.

The Centers for Disease Control and Prevention is providing frequent updates of the wide-ranging and aggressive investigation of the cases and deaths linked to vaping, and although a definitive cause remains unknown, evidence is accumulating to implicate tetrahydrocannabinol (THC)-containing devices. The investigation is being conducted in concert with the Food and Drug Administration, many state and local health departments, and public health and clinical partners.

The acronym EVALI has been developed by CDC to refer to e-cigarette, or vaping products use–associated lung injury. In a report summarizing data up to Oct. 22, CDC reported 1,604 EVALI cases and 34 deaths. These cases have occurred in all U.S. states (except Alaska), the District of Columbia, and the U.S. Virgin Islands. The CDC also published a report in the Morbidity and Mortality Weekly report on characteristics of those patients who have died from EVALI-based symptoms as of Oct. 15, 2019.

With data available for more than 867 patients with EVALI, about 86% had a history of using e-cigarette or vaping products that contained THC in the previous 90 days; 64% reported using nicotine-containing products; 34% reported exclusive use of THC-containing products, and 11% reported exclusive use of nicotine-containing products; 52% reported use of both.

In a telebriefing on Oct. 25, Anne Schuchat, MD, CDC principal deputy director, said, “The data do continue to point towards THC-containing products as the source of the vast majority of individuals’ lung injury. There are continuing cases that do not report that history. But I’d like to stress that we don’t know what the risky material or substance is. THC may be a marker for a way that cartridges were prepared or the way that the devices are producing harm. Whether there are similar activities going on with cartridges that don’t contain THC, for instance, remains to be seen. So, I think we are seeing the THC as a marker for products that are risky.”

EVALI deaths

Among the 29 deaths reported as of Oct. 15, 59% (17) were male; the median age was 45 years (range, 17-75 years), 55 years (range, 17-71 years) among males, and 43 years (range, 27-75 years) among females; the age difference between males and females was not statistically significant. Patients who died tended to be older than patients who survived. Among 19 EVALI patients who died and for whom data on substance use was available, the use of any THC-containing products was reported by patients or proxies for 84% (16), including 63% (12) who exclusively used THC-containing products. Use of any nicotine-containing products was reported for 37% (7), including 16% (3) who exclusively used nicotine-containing products. Use of both THC- and nicotine-containing products was reported in four of those who died.

Investigation update

Mitch Zeller, JD, director, Center for Tobacco Products at the Food and Drug Administration, participated in the telebriefing and provided an update on the ongoing investigation. “State of the art methods are being used to assess the presence of a broad range of chemicals including nicotine, THC, and other cannabinoids, opioids, additives, pesticides, poisons and toxins,” he said. “FDA has received or collected over 900 samples from 25 states to date. Those numbers continue to increase. The samples [were] collected directly from consumers, hospitals, and from state offices include vaping devices and products that contain liquid as well as packaging and some nearly empty containers.” He cautioned that identifying the substance is “but one piece of the puzzle and will not necessarily answer questions about causality.” He also noted that the self-reports of THC and/or nicotine could mean that there is misreported data, because reports in many cases are coming from teens and from jurisdictions in which THC is not legal.

vchal/Getty Images

The issue of whether EVALI has been seen in recent years but not recognized or whether EVALI is a new phenomenon was raised by a caller at the telebriefing. Dr. Schuchat responded, “We are aware of older cases that look similar to what we are seeing now. But we do not believe that this outbreak or surge in cases is due to better recognition.” She suggested that some evidence points to cutting agents being introduced to increase profits of e-cigarettes and that risky and unknown substances have been introduced into the supply chain.

A “handful” of cases of readmission have been reported, and the CDC is currently investigating whether these cases included patients who took up vaping again or had some other possible contributing factor. Dr. Schuchat cautioned recovering patients not to resume vaping because of the risk of readmission and the probability that their lungs will remain in a weakened state.

Clinical guidance update

The CDC provided detailed interim clinical guidance on evaluating and caring for patients with EVALI. The recommendations focus on patient history, lab testing, criteria for hospitalization, and follow-up for these patients.

Obtaining a detailed history of patients presenting with suspected EVALI is especially important for this patient population, given the many unknowns surrounding this condition, according to the CDC. The updated guidance states, “All health care providers evaluating patients for EVALI should ask about the use of e-cigarette or vaping products, and ideally should ask about types of substances used (e.g.,THC, cannabis [oil, dabs], nicotine, modified products or the addition of substances not intended by the manufacturer); product source, specific product brand and name; duration and frequency of use, time of last use; product delivery system and method of use (aerosolization, dabbing, or dripping).” The approach recommended for soliciting accurate information is “empathetic, nonjudgmental” and, the guidelines say, patients should be questioned in private regarding sensitive information to assure confidentiality.

A respiratory virus panel is recommended for all suspected EVALI patients, although at this time, these tests cannot be used to distinguish EVALI from infectious etiologies. All patients should be considered for urine toxicology testing, including testing for THC.

Imaging guidance for suspected EVALI patients includes chest x-ray, with additional CT scan when the x-ray result does not correlate with clinical findings or to evaluate severe or worsening disease.

Recommended criteria for hospitalization of patients with suspected EVALI are those patients with decreased O₂ saturation (less than 95%) on room air, in respiratory distress, or with comorbidities that compromise pulmonary reserve. As of Oct. 8, 96% of patients with suspected EVALI reported to the CDC have been hospitalized.

As for medical treatment of these patients, corticosteroids have been found to be helpful. The statement noted, “Among 140 cases reported nationally to CDC that received corticosteroids, 82% of patients improved.”

The natural progression of this injury is not known, however, and it is possible that patients might recover without corticosteroids. Given the unknown etiology of the disease and “because the diagnosis remains one of exclusion, aggressive empiric therapy with corticosteroids, antimicrobial, and antiviral therapy might be warranted for patients with severe illness. A range of corticosteroid doses, durations, and taper plans might be considered on a case-by-case basis.”

The report concluded with a strong recommendation that patients hospitalized with EVALI are followed closely with a visit 1-2 weeks after discharge and again with additional testing 1-2 months later. Health care providers are also advised to consult medical specialists, in particular pulmonologists, who can offer further evaluation, recommend empiric treatment, and review indications for bronchoscopy.

CPT coding for EVALI

CDC has issued coding guidance to help track EVALI. The document was posted on the CDC website. The coding guidance is consistent with current clinical knowledge about EVALI-related disorders and is intended for use in conjunction with current ICD-10-CM classifications.

The following conditions associated with EVALI are covered in the new coding guidance:

• Bronchitis and pneumonitis caused by chemicals, gases, and fumes; including chemical pneumonitis; J68.0.
• Pneumonitis caused by inhalation of oils and essences; including lipoid pneumonia; J69.1.
• Acute respiratory distress syndrome; J80.
• Pulmonary eosinophilia, not elsewhere classified; J82.
• Acute interstitial pneumonitis; J84.114.

The document notes that the coding guidance has been approved by the National Center for Health Statistics, the American Health Information Management Association, the American Hospital Association, and the Centers for Medicare & Medicaid Services.

Investigation continues

Mr. Zeller cautioned that this investigation will not be concluded in the near future. He noted, “We are committed to working to [solve the mystery] just as quickly as we can, but we also recognize that it will likely take some time. Importantly, the diversity of the patients and the products or substances they have reported using and the samples being tested may mean ultimately that there are multiple causes of these injuries.”

[email protected]

Richard Franki and Gregory Twachtman contributed to this story.

The national outbreak of vaping-associated lung injuries is ongoing and the number of cases and deaths continues to rise.

The Centers for Disease Control and Prevention is providing frequent updates of the wide-ranging and aggressive investigation of the cases and deaths linked to vaping, and although a definitive cause remains unknown, evidence is accumulating to implicate tetrahydrocannabinol (THC)-containing devices. The investigation is being conducted in concert with the Food and Drug Administration, many state and local health departments, and public health and clinical partners.

The acronym EVALI has been developed by CDC to refer to e-cigarette, or vaping products use–associated lung injury. In a report summarizing data up to Oct. 22, CDC reported 1,604 EVALI cases and 34 deaths. These cases have occurred in all U.S. states (except Alaska), the District of Columbia, and the U.S. Virgin Islands. The CDC also published a report in the Morbidity and Mortality Weekly report on characteristics of those patients who have died from EVALI-based symptoms as of Oct. 15, 2019.

With data available for more than 867 patients with EVALI, about 86% had a history of using e-cigarette or vaping products that contained THC in the previous 90 days; 64% reported using nicotine-containing products; 34% reported exclusive use of THC-containing products, and 11% reported exclusive use of nicotine-containing products; 52% reported use of both.

In a telebriefing on Oct. 25, Anne Schuchat, MD, CDC principal deputy director, said, “The data do continue to point towards THC-containing products as the source of the vast majority of individuals’ lung injury. There are continuing cases that do not report that history. But I’d like to stress that we don’t know what the risky material or substance is. THC may be a marker for a way that cartridges were prepared or the way that the devices are producing harm. Whether there are similar activities going on with cartridges that don’t contain THC, for instance, remains to be seen. So, I think we are seeing the THC as a marker for products that are risky.”

EVALI deaths

Among the 29 deaths reported as of Oct. 15, 59% (17) were male; the median age was 45 years (range, 17-75 years), 55 years (range, 17-71 years) among males, and 43 years (range, 27-75 years) among females; the age difference between males and females was not statistically significant. Patients who died tended to be older than patients who survived. Among 19 EVALI patients who died and for whom data on substance use was available, the use of any THC-containing products was reported by patients or proxies for 84% (16), including 63% (12) who exclusively used THC-containing products. Use of any nicotine-containing products was reported for 37% (7), including 16% (3) who exclusively used nicotine-containing products. Use of both THC- and nicotine-containing products was reported in four of those who died.

Investigation update

Mitch Zeller, JD, director, Center for Tobacco Products at the Food and Drug Administration, participated in the telebriefing and provided an update on the ongoing investigation. “State of the art methods are being used to assess the presence of a broad range of chemicals including nicotine, THC, and other cannabinoids, opioids, additives, pesticides, poisons and toxins,” he said. “FDA has received or collected over 900 samples from 25 states to date. Those numbers continue to increase. The samples [were] collected directly from consumers, hospitals, and from state offices include vaping devices and products that contain liquid as well as packaging and some nearly empty containers.” He cautioned that identifying the substance is “but one piece of the puzzle and will not necessarily answer questions about causality.” He also noted that the self-reports of THC and/or nicotine could mean that there is misreported data, because reports in many cases are coming from teens and from jurisdictions in which THC is not legal.

vchal/Getty Images

The issue of whether EVALI has been seen in recent years but not recognized or whether EVALI is a new phenomenon was raised by a caller at the telebriefing. Dr. Schuchat responded, “We are aware of older cases that look similar to what we are seeing now. But we do not believe that this outbreak or surge in cases is due to better recognition.” She suggested that some evidence points to cutting agents being introduced to increase profits of e-cigarettes and that risky and unknown substances have been introduced into the supply chain.

A “handful” of cases of readmission have been reported, and the CDC is currently investigating whether these cases included patients who took up vaping again or had some other possible contributing factor. Dr. Schuchat cautioned recovering patients not to resume vaping because of the risk of readmission and the probability that their lungs will remain in a weakened state.

Clinical guidance update

The CDC provided detailed interim clinical guidance on evaluating and caring for patients with EVALI. The recommendations focus on patient history, lab testing, criteria for hospitalization, and follow-up for these patients.

Obtaining a detailed history of patients presenting with suspected EVALI is especially important for this patient population, given the many unknowns surrounding this condition, according to the CDC. The updated guidance states, “All health care providers evaluating patients for EVALI should ask about the use of e-cigarette or vaping products, and ideally should ask about types of substances used (e.g.,THC, cannabis [oil, dabs], nicotine, modified products or the addition of substances not intended by the manufacturer); product source, specific product brand and name; duration and frequency of use, time of last use; product delivery system and method of use (aerosolization, dabbing, or dripping).” The approach recommended for soliciting accurate information is “empathetic, nonjudgmental” and, the guidelines say, patients should be questioned in private regarding sensitive information to assure confidentiality.

A respiratory virus panel is recommended for all suspected EVALI patients, although at this time, these tests cannot be used to distinguish EVALI from infectious etiologies. All patients should be considered for urine toxicology testing, including testing for THC.

Imaging guidance for suspected EVALI patients includes chest x-ray, with additional CT scan when the x-ray result does not correlate with clinical findings or to evaluate severe or worsening disease.

Recommended criteria for hospitalization of patients with suspected EVALI are those patients with decreased O₂ saturation (less than 95%) on room air, in respiratory distress, or with comorbidities that compromise pulmonary reserve. As of Oct. 8, 96% of patients with suspected EVALI reported to the CDC have been hospitalized.

As for medical treatment of these patients, corticosteroids have been found to be helpful. The statement noted, “Among 140 cases reported nationally to CDC that received corticosteroids, 82% of patients improved.”

The natural progression of this injury is not known, however, and it is possible that patients might recover without corticosteroids. Given the unknown etiology of the disease and “because the diagnosis remains one of exclusion, aggressive empiric therapy with corticosteroids, antimicrobial, and antiviral therapy might be warranted for patients with severe illness. A range of corticosteroid doses, durations, and taper plans might be considered on a case-by-case basis.”

The report concluded with a strong recommendation that patients hospitalized with EVALI are followed closely with a visit 1-2 weeks after discharge and again with additional testing 1-2 months later. Health care providers are also advised to consult medical specialists, in particular pulmonologists, who can offer further evaluation, recommend empiric treatment, and review indications for bronchoscopy.

CPT coding for EVALI

CDC has issued coding guidance to help track EVALI. The document was posted on the CDC website. The coding guidance is consistent with current clinical knowledge about EVALI-related disorders and is intended for use in conjunction with current ICD-10-CM classifications.

The following conditions associated with EVALI are covered in the new coding guidance:

• Bronchitis and pneumonitis caused by chemicals, gases, and fumes; including chemical pneumonitis; J68.0.
• Pneumonitis caused by inhalation of oils and essences; including lipoid pneumonia; J69.1.
• Acute respiratory distress syndrome; J80.
• Pulmonary eosinophilia, not elsewhere classified; J82.
• Acute interstitial pneumonitis; J84.114.

The document notes that the coding guidance has been approved by the National Center for Health Statistics, the American Health Information Management Association, the American Hospital Association, and the Centers for Medicare & Medicaid Services.

Investigation continues

Mr. Zeller cautioned that this investigation will not be concluded in the near future. He noted, “We are committed to working to [solve the mystery] just as quickly as we can, but we also recognize that it will likely take some time. Importantly, the diversity of the patients and the products or substances they have reported using and the samples being tested may mean ultimately that there are multiple causes of these injuries.”

[email protected]

Richard Franki and Gregory Twachtman contributed to this story.

Use of tetrahydrocannabinol-containing vaping products was reported by 86% of patients with e-cigarette, or vaping, product use–associated lung injury (EVALI), according to the Centers for Disease Control and Prevention.

In the largest analysis to date, exclusive use of THC-containing products was reported for 34% of the 1,378 patients with confirmed or probable EVALI as of Oct. 15, 2019. Among those who died, 63% had been using THC exclusively during the 3 months preceding symptom onset, Erin D. Moritz, PhD, and associates said Oct. 28 in the Morbidity and Mortality Weekly Report.

Almost two-thirds (64%) of all EVALI patients had used nicotine-containing products at some time in the 3 months before symptom onset, and nicotine use was exclusive for 11%. Any nicotine use was reported for 37% of EVALI-related deaths, with exclusive use at 16%, the investigators reported.

“The data presented here suggest that THC-containing products are playing an important role in this outbreak,” they wrote, but “to date, no single compound or ingredient has emerged as the cause of EVALI, and there might be more than one cause.”

Dr. Moritz and associates also noted that many “patients likely did not know the content of the e-cigarette, or vaping, products they used,” which may have led to misclassification of substances.

[email protected]

SOURCE: Moritz ED et al. MMWR. Morbidity and mortality weekly report 2019 Oct 28;68(early release):1-4.

Use of tetrahydrocannabinol-containing vaping products was reported by 86% of patients with e-cigarette, or vaping, product use–associated lung injury (EVALI), according to the Centers for Disease Control and Prevention.

In the largest analysis to date, exclusive use of THC-containing products was reported for 34% of the 1,378 patients with confirmed or probable EVALI as of Oct. 15, 2019. Among those who died, 63% had been using THC exclusively during the 3 months preceding symptom onset, Erin D. Moritz, PhD, and associates said Oct. 28 in the Morbidity and Mortality Weekly Report.

Almost two-thirds (64%) of all EVALI patients had used nicotine-containing products at some time in the 3 months before symptom onset, and nicotine use was exclusive for 11%. Any nicotine use was reported for 37% of EVALI-related deaths, with exclusive use at 16%, the investigators reported.

“The data presented here suggest that THC-containing products are playing an important role in this outbreak,” they wrote, but “to date, no single compound or ingredient has emerged as the cause of EVALI, and there might be more than one cause.”

Dr. Moritz and associates also noted that many “patients likely did not know the content of the e-cigarette, or vaping, products they used,” which may have led to misclassification of substances.

[email protected]

SOURCE: Moritz ED et al. MMWR. Morbidity and mortality weekly report 2019 Oct 28;68(early release):1-4.

Use of tetrahydrocannabinol-containing vaping products was reported by 86% of patients with e-cigarette, or vaping, product use–associated lung injury (EVALI), according to the Centers for Disease Control and Prevention.

In the largest analysis to date, exclusive use of THC-containing products was reported for 34% of the 1,378 patients with confirmed or probable EVALI as of Oct. 15, 2019. Among those who died, 63% had been using THC exclusively during the 3 months preceding symptom onset, Erin D. Moritz, PhD, and associates said Oct. 28 in the Morbidity and Mortality Weekly Report.

Almost two-thirds (64%) of all EVALI patients had used nicotine-containing products at some time in the 3 months before symptom onset, and nicotine use was exclusive for 11%. Any nicotine use was reported for 37% of EVALI-related deaths, with exclusive use at 16%, the investigators reported.

“The data presented here suggest that THC-containing products are playing an important role in this outbreak,” they wrote, but “to date, no single compound or ingredient has emerged as the cause of EVALI, and there might be more than one cause.”

Dr. Moritz and associates also noted that many “patients likely did not know the content of the e-cigarette, or vaping, products they used,” which may have led to misclassification of substances.

[email protected]

SOURCE: Moritz ED et al. MMWR. Morbidity and mortality weekly report 2019 Oct 28;68(early release):1-4.

The Centers for Disease Control and Prevention has issued coding guidance to help track e-cigarette, or vaping, product use–associated lung injury (EVALI).

mauro grigollo/Thinkstock

The purpose of the coding guidelines “is to provide official diagnosis coding guidance for healthcare encounters related to the 2019 health care encounters and deaths related to” EVALI, CDC stated in a document detailing the coding update. The document was posted on the CDC website. The guidance is consistent with current clinical knowledge about e-cigarette, or vaping, related disorders.

CDC noted in the document that the guidance “is intended to be used in conjunction with current ICD-10-CM classification,” and the codes provided “are intended to provide e-cigarette, or vaping, product use coding guidance only.”

The codes are intended to track a number of areas related to EVALI, including lung-related complications, poisoning and toxicity, and substance use, abuse, and dependence.

The following conditions associated with EVALI are covered in the new coding guidance:

• Bronchitis and pneumonitis caused by chemicals, gases, and fumes.
• Bronchitis and pneumonitis caused by chemicals, gases, fumes, and vapors; includes chemical pneumonitis.
• Pneumonitis caused by inhalation of oils and essences; includes lipoid pneumonia.
• Acute respiratory distress syndrome.
• Pulmonary eosinophilia, not elsewhere classified.
• Acute interstitial pneumonitis.

The document notes that the coding guidance has been approved by the National Center for Health Statistics, the American Health Information Management Association, the American Hospital Association, and the Centers for Medicare & Medicaid Services.

[email protected]

The Centers for Disease Control and Prevention has issued coding guidance to help track e-cigarette, or vaping, product use–associated lung injury (EVALI).

mauro grigollo/Thinkstock

The purpose of the coding guidelines “is to provide official diagnosis coding guidance for healthcare encounters related to the 2019 health care encounters and deaths related to” EVALI, CDC stated in a document detailing the coding update. The document was posted on the CDC website. The guidance is consistent with current clinical knowledge about e-cigarette, or vaping, related disorders.

CDC noted in the document that the guidance “is intended to be used in conjunction with current ICD-10-CM classification,” and the codes provided “are intended to provide e-cigarette, or vaping, product use coding guidance only.”

The codes are intended to track a number of areas related to EVALI, including lung-related complications, poisoning and toxicity, and substance use, abuse, and dependence.

The following conditions associated with EVALI are covered in the new coding guidance:

• Bronchitis and pneumonitis caused by chemicals, gases, and fumes.
• Bronchitis and pneumonitis caused by chemicals, gases, fumes, and vapors; includes chemical pneumonitis.
• Pneumonitis caused by inhalation of oils and essences; includes lipoid pneumonia.
• Acute respiratory distress syndrome.
• Pulmonary eosinophilia, not elsewhere classified.
• Acute interstitial pneumonitis.

The document notes that the coding guidance has been approved by the National Center for Health Statistics, the American Health Information Management Association, the American Hospital Association, and the Centers for Medicare & Medicaid Services.

[email protected]

The Centers for Disease Control and Prevention has issued coding guidance to help track e-cigarette, or vaping, product use–associated lung injury (EVALI).

mauro grigollo/Thinkstock

The purpose of the coding guidelines “is to provide official diagnosis coding guidance for healthcare encounters related to the 2019 health care encounters and deaths related to” EVALI, CDC stated in a document detailing the coding update. The document was posted on the CDC website. The guidance is consistent with current clinical knowledge about e-cigarette, or vaping, related disorders.

CDC noted in the document that the guidance “is intended to be used in conjunction with current ICD-10-CM classification,” and the codes provided “are intended to provide e-cigarette, or vaping, product use coding guidance only.”

The codes are intended to track a number of areas related to EVALI, including lung-related complications, poisoning and toxicity, and substance use, abuse, and dependence.

The following conditions associated with EVALI are covered in the new coding guidance:

• Bronchitis and pneumonitis caused by chemicals, gases, and fumes.
• Bronchitis and pneumonitis caused by chemicals, gases, fumes, and vapors; includes chemical pneumonitis.
• Pneumonitis caused by inhalation of oils and essences; includes lipoid pneumonia.
• Acute respiratory distress syndrome.
• Pulmonary eosinophilia, not elsewhere classified.
• Acute interstitial pneumonitis.

The document notes that the coding guidance has been approved by the National Center for Health Statistics, the American Health Information Management Association, the American Hospital Association, and the Centers for Medicare & Medicaid Services.

[email protected]

NEW ORLEANS – Reduction of readmission rates among individuals hospitalized for an acute exacerbation of COPD could reduce mortality and health care expenditures, results of a large, retrospective study suggest.

“This is not a small problem,” Dr. Krishnan said in a podium presentation at the annual meeting of the American College of Chest Physicians. “The amount of money that can be saved can be put into primary care for curbing COPD and better patient outcomes, basically, if you’re able to put in checkpoints to stop this problem.”

Bundled care interventions by interdisciplinary teams have thus far proven effective at improving quality of care and improving process measures in this setting, said Dr. Krishnan.

The retrospective cohort study by Dr. Krishnan and colleagues included 530,229 adult patients in the 2016 National Readmission Database who had a principal diagnosis of acute COPD exacerbation. The mean age of the patients was 68 years, and 58% were female.

The rates of readmission at 30 days after discharge were 16.3% for any cause and 5.4% specifically for COPD, the researchers found. Of note, the in-hospital mortality rate increased from 1.1% to 3.8% during readmission (P less than .01), Dr. Krishnan said.

Readmissions were linked to a cumulative length of stay of 458,677 days, with corresponding hospital costs of $0.97 billion and charges of $4.0 billion; the COPD-specific readmissions were associated with cumulative length of stay of 132,026 days, costs of $253 million, and charges of $1 billion, Dr. Krishnan reported.

Dr. Krishnan and coauthors disclosed no relationships relevant to their study.

SOURCE: Krishnan AM et al. CHEST 2019. Abstract, doi: 10.1016/j.chest.2019.08.229.

NEW ORLEANS – Reduction of readmission rates among individuals hospitalized for an acute exacerbation of COPD could reduce mortality and health care expenditures, results of a large, retrospective study suggest.

“This is not a small problem,” Dr. Krishnan said in a podium presentation at the annual meeting of the American College of Chest Physicians. “The amount of money that can be saved can be put into primary care for curbing COPD and better patient outcomes, basically, if you’re able to put in checkpoints to stop this problem.”

Bundled care interventions by interdisciplinary teams have thus far proven effective at improving quality of care and improving process measures in this setting, said Dr. Krishnan.

The retrospective cohort study by Dr. Krishnan and colleagues included 530,229 adult patients in the 2016 National Readmission Database who had a principal diagnosis of acute COPD exacerbation. The mean age of the patients was 68 years, and 58% were female.

The rates of readmission at 30 days after discharge were 16.3% for any cause and 5.4% specifically for COPD, the researchers found. Of note, the in-hospital mortality rate increased from 1.1% to 3.8% during readmission (P less than .01), Dr. Krishnan said.

Readmissions were linked to a cumulative length of stay of 458,677 days, with corresponding hospital costs of $0.97 billion and charges of $4.0 billion; the COPD-specific readmissions were associated with cumulative length of stay of 132,026 days, costs of $253 million, and charges of $1 billion, Dr. Krishnan reported.

Dr. Krishnan and coauthors disclosed no relationships relevant to their study.

SOURCE: Krishnan AM et al. CHEST 2019. Abstract, doi: 10.1016/j.chest.2019.08.229.

NEW ORLEANS – Reduction of readmission rates among individuals hospitalized for an acute exacerbation of COPD could reduce mortality and health care expenditures, results of a large, retrospective study suggest.

“This is not a small problem,” Dr. Krishnan said in a podium presentation at the annual meeting of the American College of Chest Physicians. “The amount of money that can be saved can be put into primary care for curbing COPD and better patient outcomes, basically, if you’re able to put in checkpoints to stop this problem.”

Bundled care interventions by interdisciplinary teams have thus far proven effective at improving quality of care and improving process measures in this setting, said Dr. Krishnan.

The retrospective cohort study by Dr. Krishnan and colleagues included 530,229 adult patients in the 2016 National Readmission Database who had a principal diagnosis of acute COPD exacerbation. The mean age of the patients was 68 years, and 58% were female.

The rates of readmission at 30 days after discharge were 16.3% for any cause and 5.4% specifically for COPD, the researchers found. Of note, the in-hospital mortality rate increased from 1.1% to 3.8% during readmission (P less than .01), Dr. Krishnan said.

Readmissions were linked to a cumulative length of stay of 458,677 days, with corresponding hospital costs of $0.97 billion and charges of $4.0 billion; the COPD-specific readmissions were associated with cumulative length of stay of 132,026 days, costs of $253 million, and charges of $1 billion, Dr. Krishnan reported.

Dr. Krishnan and coauthors disclosed no relationships relevant to their study.

SOURCE: Krishnan AM et al. CHEST 2019. Abstract, doi: 10.1016/j.chest.2019.08.229.