76-Year-Old Woman With Hemoptysis

A 76-year-old woman presented with 2 years of hemoptysis that had been increasing in frequency until it was happening on a daily basis. She had also experienced new hypoxia, exertional dyspnea, fatigue, and weight loss. Her past medical history was pertinent for severe scoliosis, remote myocardial infarction, heart failure with preserved ejection fraction (HFpEF), mild aortic stenosis, hypertension, and chronic kidney disease stage IV. She had no history of atrial fibrillation. Her medications included aspirin, high-intensity atorvastatin, furosemide, metoprolol tartrate, and lisinopril. She denied smoking tobacco or recent travel outside the United States. Vital signs showed heart rate of 84 beats per minute, blood pressure of 106/67 mm Hg, respiratory rate of 27, temperature of 37.1°C, and she was saturating well on 2 liters of oxygen via nasal cannula. Physical examination was pertinent for thin habitus, right lower-lobe crackles, loud P2 sound, elevated jugular venous pressure, trace bilateral lower extremity edema, and no abdominal distension or tenderness. Laboratory testing showed the following (reference ranges provided parenthetically): hemoglobin 8.2 g/dL (11.6 to 15.0 g/dL); platelet count 151 × 109/L (157 to 371 x109/L); international normalized ratio (INR) 1.0 (0.9 to 1.1); and activated partial thromboplastin time (aPTT) 31 seconds (25 to 37 seconds).1.Which of the following would be the least likely cause of this patient’s presentation?a)Necrotizing pneumoniab)Lung cancerc)Granulomatosis with polyangiitisd)Pulmonary arteriovenous malformatione)Tuberculosis Necrotizing pneumonia usually presents with prominent fevers and chills as well as purulent sputum, making it the least likely explanation for this patient’s symptoms. Lung cancer can present with constitutional symptoms, dyspnea, and worsening hemoptysis. Although it most commonly presents in patients with history of smoking tobacco, approximately 25% of patients with lung cancer are never-smokers, with the most common primary lung cancer in this population being adenocarcinoma of the lung.1Parkin D.M. Bray F. Ferley J. Pisani P. Global cancer statistics, 2002.CA Cancer J Clin. 2005; 55: 74-108Crossref PubMed Scopus (17400) Google Scholar Patients with granulomatosis with polyangiitis (GPA) affecting the lung usually present with nonspecific constitutional symptoms over weeks to months. These patients may complain of cough, dyspnea, wheezing, or hemoptysis, and chest-imaging findings vary. Pulmonary manifestations of GPA may include interstitial lung disease or pulmonary arterial hypertension.2Gómez-Puerta J.A. Hernández-Rodríguez J. López-Soto A. Bosch X. Antineutrophil cytoplasmic antibody-associated vasculitides and respiratory disease.Chest. 2009; 136: 1101-1111Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar The disease can also present with diffuse alveolar hemorrhage (DAH) and hemoptysis. Pulmonary arteriovenous malformations are abnormal connections between pulmonary arteries and veins. They can lead to dyspnea and hypoxia caused by the associated right-to-left shunting and can also present with hemoptysis. Tuberculosis presents with constitutional symptoms and worsening hemoptysis although it is more common in patients with risk factors such as recent travelers to endemic areas, prisoners, the immunosuppressed, and residents of homeless shelters. Previous pulmonary function testing (PFTs), done 2 years before presentation, showed severe restriction, air trapping, and severely reduced diffusing capacity for carbon monoxide (DLCO).2.Which of the following would not be expected to contribute to the decreased DLCO in this patient at the time of the test?a)Pulmonary hypertensionb)Anemiac)Pulmonary hemorrhaged)Interstitial lung diseasee)Pulmonary edema DLCO reflects the ability of the lungs to transfer oxygen to the blood and is tested using carbon monoxide. Specifically, this is assessed using a single breath hold after maximal inhalation of a gas mixture containing low concentrations of carbon monoxide, with a sample taken afterward of exhaled alveolar breath to calculate the extent of diffusion. Pulmonary vascular diseases, including pulmonary hypertension (PH) and pulmonary emboli, lead to decreased DLCO; therefore, they would not be the correct answers. Anemia, with decreased red blood cell counts and hemoglobin in the blood, also leads to decreased ability to transfer oxygen between the lungs and blood and decreased DLCO and would not be the correct answer. Pulmonary hemorrhage, on the other hand, results in increased DLCO owing to the presence of blood in alveolar spaces, facilitating diffusion of oxygen and is, therefore, the most appropriate answer. Interstitial lung disease results in a decreased DLCO caused by the presence of fibrous tissues around alveoli, blood vessels, and airways and would not be the answer. Pulmonary edema with accumulation of fluid in the alveoli or the interstitium adds a barrier to oxygen transfer to the blood and leads to decreased DLCO and is therefore not the correct answer. Computed tomography (CT) of the chest without contrast showed new ground-glass opacities mainly involving the right lower lobe although there was some involvement of the left lower lobe as well as pulmonary artery enlargement. The CT scan also demonstrated previously detected interstitial thickening of the bilateral lower lobes.3.What would be the best next step in this patient’s work-up?a)Transthoracic echocardiographyb)Bronchoalveolar lavagec)Positron emission tomographyd)QuantiFERON testinge)Repeat pulmonary function testing Transthoracic echocardiography (TTE) would be indicated to evaluate for PH and progression of this patient’s heart failure, especially with the finding of enlarged pulmonary artery on CT scan, but it would not be the most appropriate next step. The appearance on CT scan of the chest of new ground-glass opacities mainly involving the right lower lobe is concerning for DAH. Therefore, the best next step would be to perform a flexible bronchoscopy with sequential bronchoalveolar lavage (BAL). The typical finding for DAH would be a progressively bloody return on each aliquot, with 3 to 5 aliquots often provided to obtain at least 20 to 30 milliliters of lavage sample for testing. Positron emission tomography (PET) may be considered if findings from BAL were concerning for malignancy. QuantiFERON testing would be indicated to test for active or latent tuberculosis. However, tuberculosis is less likely in this patient with no risk factors. Moreover, CT scan findings of active disease would include centrilobular nodules, branching linear opacities, cavitation, and patchy consolidation.3Im J.G. Itoh H. Lee K.S. Han M.C. CT-pathology correlation of pulmonary tuberculosis.Crit Rev Diagn Imaging. 1995; 36: 227-285PubMed Google Scholar Furthermore, a negative result on QuantiFERON testing does not exclude active tuberculosis.4Lewinsohn D.M. Leonard M.K. LoBue P.A. et al.Official American Thoracic Society/Infectious Diseases Society of America/Centers for Disease Control and Prevention Clinical Practice Guidelines: diagnosis of tuberculosis in adults and children.Clin Infect Dis. 2017; 64: e1-e33Crossref PubMed Scopus (249) Google Scholar The patient’s previous PFTs results of severe restriction are likely at least in part a reflection of her severe scoliosis. The decreased DLCO could be caused by a component of interstitial lung disease or in the setting of likely PH. There is likely not much benefit to repeating a PFT at this point. Because of concerns of DAH, the patient was admitted to the hospital and underwent flexible bronchoscopy with sequential BAL, which revealed a slightly pink return without a progressive bloody component, making DAH unlikely. Biopsies from the mediastinal lymph nodes were obtained during the bronchoscopy, but both these and the BAL testing were negative for malignancy or infection. Autoimmune work-up results, including antinuclear antibodies (ANA), antineutrophil cytoplasmic antibodies (ANCA), antiglomerular basement membrane (anti-GBM), and extractable nuclear antigen (ENA) panels were negative. Her urinalysis result was unremarkable. N-terminal pro-brain natriuretic peptide (NT-proBNP) was elevated at 6,000 pg/mL (<=230 pg/mL), and TTE showed a right ventricular systolic pressure (RVSP) of 87 mm Hg, grade 2 diastolic dysfunction, preserved ejection fraction, biatrial enlargement, interventricular septum thickening, and mild aortic stenosis.4.Which of the following tests would be of minimal benefit in the evaluation of this patient?a)Serum-free light chain quantification and serum and urine immunofixationb)Kidney biopsyc)Right heart catheterizationd)Technetium Tc 99m pyrophosphate scanninge)Cardiac magnetic resonance imaging The patient’s echocardiographic findings of thickened interventricular septum, biatrial enlargement, grade 2 diastolic dysfunction, aortic stenosis, and highly elevated NT-proBNP would be worrisome for cardiac amyloidosis. Therefore, testing for AL amyloidosis using serum free light chain quantification and serum and urine immunofixation would be important. Kidney biopsy would not be beneficial at this stage given the normal urinalysis with no proteinuria or hematuria and the negative results of the autoimmune work-up and BAL. Right heart catheterization (RHC) would be important despite the very high RVSP suggesting severe pulmonary hypertension (PH). This is because a mixed etiology of PH is highly likely (eg, severe restriction on the PFT, HFpEF). Technetium Tc 99m pyrophosphate scanning is another important test to evaluate for cardiac amyloidosis, transthyretin (ATTR) type. Cardiac magnetic resonance imaging is another option that could show specific features related to cardiac amyloidosis with certain patterns of late gadolinium enhancement although it cannot distinguish between AL and ATTR types. The patient had negative cardiac amyloidosis work-up results, including serum free light chains, plasma and urine protein electrophoresis, Technetium Tc 99m pyrophosphate scanning, and endomyocardial biopsy. She then underwent RHC to characterize her PH, which showed mean pulmonary artery pressure (mPAP) of 39 mm Hg, pulmonary capillary wedge pressure (PCWP) of 20 mm Hg, and pulmonary vascular resistance (PVR) of 3.55 Wood units. Testing with nitroprusside or inhaled nitric oxide was not performed because of systolic blood pressure during RHC <100 mm Hg. As this patient had mPAP >20 mm Hg, she was confirmed to have PH.5Vachiéry J.L. Tedford R.J. Rosenkranz S. et al.Pulmonary hypertension due to left heart disease.Eur Respir J. 2019; 53: 1801897Crossref PubMed Scopus (308) Google Scholar Her PCWP was ≥15 mm Hg, consistent with PH caused by left heart disease (PH-LHD).5Vachiéry J.L. Tedford R.J. Rosenkranz S. et al.Pulmonary hypertension due to left heart disease.Eur Respir J. 2019; 53: 1801897Crossref PubMed Scopus (308) Google Scholar Her PVR was ≥3 Wood units, consistent with combined post- and precapillary PH (Cpc-PH).5Vachiéry J.L. Tedford R.J. Rosenkranz S. et al.Pulmonary hypertension due to left heart disease.Eur Respir J. 2019; 53: 1801897Crossref PubMed Scopus (308) Google Scholar The postcapillary component of our patient’s PH was the most likely explanation for her hemoptysis. Her severe PH was also the reason behind her new hypoxia. Her severe exertional dyspnea was caused by both the PH and HFpEF. The ground-glass opacities likely represented pulmonary edema, with the reason behind asymmetric involvement of right lower lung lobe being her severe scoliosis.5.Which of the following is the most appropriate initial treatment for this patient?a)Diuresisb)Diuresis and metoprolol succinatec)Epoprostenold)Bosentane)Riociguat The initial management in patients with PH-LHD is to optimize the underlying LHD.6Melenovsky V. Andersen M.J. Andress K. Reddy Y.N. Borlaug B.A. Lung congestion in chronic heart failure: haemodynamic, clinical, and prognostic implications.Eur J Heart Fail. 2015; 17: 1161-1171Crossref PubMed Scopus (95) Google Scholar In this patient, this seems to be HFpEF, and therefore the mainstay of treatment would be diuresis. Metoprolol succinate would be indicated in cases of HFrEF, which the patient does not have. PH-targeted therapy, including epoprostenol, bosentan, and riociguat, is not indicated for PH-LHD.5Vachiéry J.L. Tedford R.J. Rosenkranz S. et al.Pulmonary hypertension due to left heart disease.Eur Respir J. 2019; 53: 1801897Crossref PubMed Scopus (308) Google Scholar The patient was treated with diuresis and arranged to have a follow up with the PH clinic. Pulmonary hypertension is defined hemodynamically as mPAP exceeding 20 mm Hg.7Simonneau G. Montani D. Celermajer D.S. et al.Haemodynamic definitions and updated clinical classification of pulmonary hypertension.Eur Respir J. 2019; 53: 1801913Crossref PubMed Scopus (1979) Google Scholar Most patients with PH are identified by screening for clinical symptoms and noninvasive testing with TTE. Symptoms include exertional dyspnea, lethargy, and fatigue in the early stages, in addition to the symptoms of the underlying cause of PH (eg, symptoms of heart failure in the case of PH-LHD). When PH progresses to involve right ventricular (RV) failure, symptoms also include exertional chest pain, syncope, edema, anorexia, and abdominal swelling.8Runo J.R. Loyd J.E. Primary pulmonary hypertension.Lancet. 2003; 361: 1533-1544Abstract Full Text Full Text PDF PubMed Scopus (468) Google Scholar Physical examination findings include increased P2 heart sound at early stages. When RV failure ensues, signs also include increased jugular venous pressure, right-sided third or fourth heart sound, tricuspid regurgitation murmur, peripheral edema, and hepatomegaly.8Runo J.R. Loyd J.E. Primary pulmonary hypertension.Lancet. 2003; 361: 1533-1544Abstract Full Text Full Text PDF PubMed Scopus (468) Google Scholar Postcapillary PH leads to elevated pulmonary venous and capillary pressures and can result in hemoptysis when rupture occurs. This can be in the setting of mitral stenosis, significant left ventricular failure, congenital heart disease, pulmonary veno-occlusive disease, and fibrosing mediastinitis. The nonspecific nature of symptoms, especially early in the disease course, usually results in delayed diagnosis. Testing should start with TTE, which could give an estimation for pulmonary artery systolic pressure (PASP) using peak tricuspid regurgitation jet velocity and the derived RVSP.9McQuillan B.M. Picard M.H. Leavitt M. Weyman A.E. Clinical correlates and reference intervals for pulmonary artery systolic pressure among echocardiographically normal subjects.Circulation. 2001; 104: 2797-2802Crossref PubMed Scopus (526) Google Scholar This was shown to have a sensitivity of 87%, specificity of 79%, positive predictive value of 91%, and negative predictive value of 70%, with overall accuracy of 85%, when compared with PH diagnosis using invasive RHC.10Greiner S. Jud A. Aurich M. et al.Reliability of noninvasive assessment of systolic pulmonary artery pressure by Doppler echocardiography compared to right heart catheterization: analysis in a large patient population.J Am Heart Assoc. 2014; 3e001103Crossref PubMed Scopus (138) Google Scholar Values exceeding 35 mm Hg in younger adults or 40 mm Hg in older adults are considered elevated, especially if symptoms are present.9McQuillan B.M. Picard M.H. Leavitt M. Weyman A.E. Clinical correlates and reference intervals for pulmonary artery systolic pressure among echocardiographically normal subjects.Circulation. 2001; 104: 2797-2802Crossref PubMed Scopus (526) Google Scholar Sometimes TTE will also be able to estimate left atrial pressure and whether an increased PCWP is likely (ie, grades II and III diastolic dysfunction). In patients with estimated PASP >35 mm Hg, assessment of hemodynamics by RHC is indicated if there is evidence of RV dysfunction, the cause of PH is unclear, multiple causes of PH are suspected, or if advanced therapies for HF are being considered.11Krishnan U. Horn E. Pulmonary hypertension due to left heart disease (group 2 pulmonary hypertension) in adults.in: Post T.W. UpToDate. Waltham, MA. 2021Google Scholar In our patient, increased RVSP and diastolic dysfunction grade indicated the presence of PH-LHD. However, with this severe degree of RVSP elevation and the presence of severely reduced DLCO, it was not possible to exclude other potential causes of PH definitely. Indeed, RHC testing demonstrated the presence of Cpc-PH. As explained previously, PCWP >15 mm Hg refers to the presence of PH-LHD. PVR is then used to determine isolated post-capillary PH (Ipc-PH;PVR <3 Wood units) or Cpc-PH (PVR ≥3 Wood units). PH is classified into 5 categories, depending on the mechanism involved:7Simonneau G. Montani D. Celermajer D.S. et al.Haemodynamic definitions and updated clinical classification of pulmonary hypertension.Eur Respir J. 2019; 53: 1801913Crossref PubMed Scopus (1979) Google Scholar1.Group 1 is referred to as pulmonary arterial hypertension and is diagnosed with mPAP ≥20 mm Hg, PVR ≥3 Wood units, and PCWP ≤15, which excludes PH-LHD; PH should not be explained by chronic lung diseases, other causes of hypoxemia, or venous thromboembolic disease. Systemic diseases involved in Group 5 PH (as follows) should also be absent.2.Group 2 is caused by left heart disease (ie, PH-LHD) and is most commonly caused by HFpEF, HFrEF, valvular heart disease, and other structural heart diseases. The group is subclassified into Ipc-PH and Cpc-PH.3.Group 3 is caused by chronic lung disease or hypoxemia, which is usually evident clinically.4.Group 4 is caused by pulmonary artery obstructions: most commonly, recurrent pulmonary emboli.5.Group 5 is multifactorial and could be caused by hematologic disorders (eg, chronic hemolytic anemia, myeloproliferative disorders), systemic diseases (eg, sarcoidosis), congenital heart disease with left-to-right shunting, among others. Treatment of PH-LHD usually involves managing the underlying heart disease with diuresis. Guideline-directed medical treatment with or without cardiac synchronization therapy is indicated in the case of HFrEF. In the case of ischemic or valvular heart disease, surgical or transcatheter interventions can be indicated.11Krishnan U. Horn E. Pulmonary hypertension due to left heart disease (group 2 pulmonary hypertension) in adults.in: Post T.W. UpToDate. Waltham, MA. 2021Google Scholar This applies to both patients with Ipc- and Cpc-PH. Systemic vasodilator challenge during RHC can be used to identify the subset of patients with Cpc-PH who have reversible precapillary components, which could be caused by vasoconstriction rather than pulmonary vascular remodeling and fibrosis.11Krishnan U. Horn E. Pulmonary hypertension due to left heart disease (group 2 pulmonary hypertension) in adults.in: Post T.W. UpToDate. Waltham, MA. 2021Google Scholar However, such reversibility is not an indication to use calcium channel blockers as a pulmonary vasodilator in Cpc-PH, compared with patients with group 1 PH and reversibility on RHC.11Krishnan U. Horn E. Pulmonary hypertension due to left heart disease (group 2 pulmonary hypertension) in adults.in: Post T.W. UpToDate. Waltham, MA. 2021Google Scholar Nonetheless, this reversibility may be beneficial to demonstrate in patients undergoing evaluation for heart transplantation. The authors report no competing interests.