40-Year-Old Woman With Breathlessness and Fatigue

Abstract

A 40-year-old woman presented to her primary physician with dyspnea on exertion, fatigue, and lower extremity swelling that had progressed over the preceding 3 months. Her dyspnea was present only with exertion such as climbing a flight of stairs or walking briskly, and she had no dyspnea at rest. She reported no weight change, fever, cough, chest pain, syncope, or orthopnea. She had no history of recent travel and did not have a sedentary lifestyle. Her medical history included scleroderma and hyperlipidemia. She was a lifelong nonsmoker and had no allergies to medications. She was not currently being treated for her scleroderma and was taking only simvastatin. Her surgical, family, and social histories were unremarkable. On physical examination, she appeared well nourished and was not in any distress. Her pulse rate was 70 beats/min, respiratory rate was 20 breaths/min, blood pressure was 100/70 mm Hg, and oxygen saturation was 94% while she breathed room air. Physical examination findings were notable for increased jugular venous distention and a normal carotid pulse. Cardiac examination revealed a loud P2, a holosystolic grade 2/6 murmur best heard at the apex, and a right ventricular heave. Her lungs were clear on auscultation, and pulses were normal in all 4 limbs. Lower extremity examination results were notable for 1+ edema up to the midtibia. Examination of the upper limbs was notable for thickened skin and digits with limited range of motion of the fingers and wrists bilaterally. No clubbing or cyanosis was present. Electrocardiography and chest radiography were performed. Electrocardiography recorded prominent R waves in leads V1 and V2, an isoelectric lead I, and an enlarged and widened P wave in lead II. Chest radiography revealed enlarged pulmonary vasculature in the hilum, normal cardiac silhouette, and no evidence of parenchymal lung disease.1.Which one of the following is the most appropriate diagnostic test for this patient?a.Echocardiographyb.Cardiac magnetic resonance imagingc.Computed tomographic angiographyd.Complete pulmonary function testinge.Six-minute walk test This patient's presentation of dyspnea on exertion, elevated jugular venous distention, and lower extremity edema elicits particular concern for heart failure. Her loss of functional capacity can be categorized according to the World Health Organization's functional capacity scale (WHO-FC). In class I, symptoms do not limit physical activity; in class II, dyspnea occurs only with activities more strenuous than everyday activities; in class III, patients have dyspnea and limitations with everyday mild activity; and in class IV, patients have dyspnea at rest and are unable to perform any activity without symptoms.1Galiè N. Humbert M. Vachiery J.L. et al.Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS)2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension.Eur Heart J. 2016; 37 ([published online ahead of print August 29, 2015]): 67-119Crossref PubMed Scopus (4016) Google Scholar Given her limitations on moderate exertion, our patient's condition would be categorized as WHO-FC class II. The initial screening test should be echocardiography to evaluate cardiac function and physiology. Although cardiac magnetic resonance imaging has a role in certain cardiac etiologies and can provide similar information regarding cardiac function and physiology, its cost and limited availability can be prohibitory. Therefore, it should not be considered over echocardiography.1Galiè N. Humbert M. Vachiery J.L. et al.Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS)2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension.Eur Heart J. 2016; 37 ([published online ahead of print August 29, 2015]): 67-119Crossref PubMed Scopus (4016) Google Scholar Computed tomographic angiography is a valuable tool for detection of acute pulmonary embolism (PE), which should be included in this patient's differential diagnosis. However, this patient's risk for acute PE is low. Pulmonary function testing should be utilized early in the work-up of exertional dyspnea and should be performed in this patient because it can help clarify distinctions between true pulmonary and cardiopulmonary disease. In this case, however, echocardiography would remain the initial diagnostic test. A 6-minute walk test provides valuable information regarding functional status for patients with cardiopulmonary disease.2Benza R.L. Miller D.P. Gomberg-Maitland M. et al.Predicting survival in pulmonary arterial hypertension: insights from the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL).Circulation. 2010; 122: 164-172Crossref PubMed Scopus (1182) Google Scholar However, it does not provide diagnostic information. In this patient, a diagnosis has not been established. Echocardiography revealed normal left ventricular function, elevated right ventricular (RV) systolic pressure of 100 mm Hg (systolic blood pressure was 155 mm Hg), and measured estimated mean pulmonary arterial pressure (mPAP) of 60 mm Hg. The patient had an enlarged RV with RV end-diastolic volume of 150 mL and moderately reduced RV systolic function. Pulmonary function testing identified no obstructive or restrictive disease. The patient's forced vital capacity (FVC) was 110% of predicted, the diffusing capacity of the lung for carbon monoxide (DLCO) corrected for hemoglobin was 65% of predicted, and the FVC:DLCO ratio was 1.69.2.At this time, which one of the following is the most appropriate next step?a.Treatment with an endothelin receptor antagonistb.Right-sided heart catheterization (RHC)c.Left-sided heart catheterizationd.Pulmonary computed tomographic angiographye.Thoracic surgical consultation for pulmonary artery endarterectomy In view of the echocardiographic data, the patient likely has severe pulmonary hypertension (PH) of unknown classification (ie, precapillary vs postcapillary PH). Endothelin receptor antagonists are used for treatment of PH, but echocardiography is not a confirmatory test for PH, and RHC is indicated to confirm the diagnosis and help define the diagnostic PH classification before treatment is initiated. Left-sided heart catheterization would not be indicated in this patient. Although the patient has evidence of RV dysfunction on echocardiography, it is more likely a reflection of elevated pulmonary artery pressures and less likely ischemic in etiology. Computed tomographic angiography would help diagnose acute PE, which could be the cause of this patient's suspected PH. However, a ventilation-perfusion (V˙/Q˙) scan is the preferred method to screen for chronic thromboembolic PH (CTEPH). This patient should undergo V˙/Q˙ scan early in the evaluation of her suspected PH to help rule out CTEPH as a cause. This procedure could be performed before or after the RHC. Pulmonary artery endarterectomy is a surgical procedure for the treatment of CTEPH. This diagnosis has not been made, and surgical consultation would not be warranted at this time. Right-sided heart catheterization revealed a right atrial pressure of 12 mm Hg, RV systolic pressure of 96 mm Hg, mPAP of 65 mm Hg, pulmonary capillary wedge pressure (PCWP) of 8 mm Hg, and pulmonary vascular resistance of 7 Wood units. The oxygen saturation in the pulmonary artery was 65%. A vasoreactive challenge using inhaled nitric oxide revealed a reduction of the mPAP from 65 to 35 mm Hg without a change in cardiac output. The V˙/Q˙ scan identified no perfusion defects.3.Which one of the following is the most likely diagnosis?a.Associated pulmonary arterial hypertension (PAH)b.PH secondary to left ventricular dysfunctionc.CTEPHd.Patent foramen ovale with left-to-right stunte.Chronic fatigue syndrome The patient's clinical presentation and RHC results have established the diagnosis of associated pulmonary arterial hypertension (PAH). Any mPAP elevation of 25 mm Hg or higher on RHC (our patient's was 65 mm Hg) is consistent with PH, and but it must be further categorized as a particular diagnostic classification. A low PCWP of 15 mm Hg or less (our patient's was 8 mm Hg) defines precapillary PH. Precapillary PH includes several different diagnoses such as PAH, PH from chronic lung disease, CTEPH, and PH with multifactorial mechanisms. Pulmonary arterial hypertension by itself also includes idiopathic, heritable, drug- and toxin-induced, and associated types. Associated PAH (as in this case) further includes those with connective tissue disease, congenital heart disease, human immunodeficiency virus (HIV) infection, schistosomiasis, or portal hypertension. Our patient met criteria for precapillary PH, which given her history of scleroderma, is best categorized as associated PAH. Postcapillary PH would include patients with left-sided heart disease and also those with multifactorial conditions. The diagnosis of postcapillary PH requires a PCWP greater than 15 mm Hg, which was not seen in this patient. Therefore, PH secondary to left ventricular dysfunction would not be the correct diagnosis. Chronic thromboembolic PH is unlikely because the V˙/Q˙ scan detected no perfusion defects. The oxygen saturation in the pulmonary artery was 65% (normal, 65%-75%), making left-to-right shunting unlikely. Chronic fatigue syndrome is a controversial diagnosis that is characterized by profound fatigue affecting several aspects of the patient's life and presents with few objective findings.3Clayton E.W. Beyond myalgic encephalomyelitis/chronic fatigue syndrome: an IOM report on redefining an illness.JAMA. 2015; 313: 1101-1102Crossref PubMed Scopus (156) Google Scholar Based on the diagnostic test results, associated PAH was diagnosed. The patient was referred to the pulmonary hypertension clinic to discuss further management and treatment.4.In view of the patient's RHC results, which one of the following is the most appropriate initial treatment?a.Epoprostenolb.Iloprostc.Sildenafild.Bosentane.Nifedipine This patient with associated PAH and WHO-FC class II requires treatment. All of the choices provided are approved treatments for PAH. The first steps in determining the proper initial treatment requires knowledge of the patient's WHO-FC class, the results of nitric oxide vasoreactive testing, and the severity of the RV dysfunction. A positive vasoreactive response is defined as reduction of mPAP of more than 10 mm Hg that reaches an absolute mPAP below 40 mm Hg without reduction in cardiac output.1Galiè N. Humbert M. Vachiery J.L. et al.Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS)2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension.Eur Heart J. 2016; 37 ([published online ahead of print August 29, 2015]): 67-119Crossref PubMed Scopus (4016) Google Scholar A positive vasoreactive response is not common, occurring in only about 10% of patients.1Galiè N. Humbert M. Vachiery J.L. et al.Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS)2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension.Eur Heart J. 2016; 37 ([published online ahead of print August 29, 2015]): 67-119Crossref PubMed Scopus (4016) Google Scholar This test remains important because patients with a positive response have a favorable prognosis. Any patient with a positive vasoreactive response and WHO-FC class I-III should be considered for an initial trial of calcium channel blocker therapy. Epoprostenol and iloprost are synthetic prostacyclins used as first-line treatments only for patients who are not vasoreactive and who have WHO-FC class III-IV. Sildenafil is a phosphodiesterase type 5 inhibitor (PDE5I) and can be used as initial therapy in nonvasoreactive patients who have WHO-FC class II. Bosentan is an endothelin receptor antagonist and should be considered as first-line therapy in nonvasoreactive patients with WHO-FC class II-III. Given that this patient has mild loss of functional capacity (WHO-FC class II) and positive results on nitric oxide vasoactive study, nifedipine would be the most appropriate initial treatment.1Galiè N. Humbert M. Vachiery J.L. et al.Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS)2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension.Eur Heart J. 2016; 37 ([published online ahead of print August 29, 2015]): 67-119Crossref PubMed Scopus (4016) Google Scholar Treatment with nifedipine was initiated on the basis of the results of the inhaled nitric oxide stimulation test. The patient noted marked improvement in her symptoms at 3 months. Her functional capacity, right-sided heart function, and pulmonary hypertension also improved. Therapy was continued with close follow-up.5.In this patient, which one of the following is considered a strong contraindication?a.Regular exercise routineb.Anticoagulationc.Diet high in folated.23-Valent pneumococcal vaccinatione.Pregnancy Several randomized trials have evaluated rehabilitation and exercise training in patients with PAH and found a decrease in fatigue and improvement in both functional status and quality of life. Exercise training and rehabilitation should be offered to patients with PAH.1Galiè N. Humbert M. Vachiery J.L. et al.Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS)2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension.Eur Heart J. 2016; 37 ([published online ahead of print August 29, 2015]): 67-119Crossref PubMed Scopus (4016) Google Scholar Anticoagulation can be considered for supportive therapy in patients with PAH, particularly those with hereditary or idiopathic PAH or those in whom there is concern about PAH secondary to weight loss medications. Although its role in therapy continues to be debated, it is not contraindicated unless an individual has substantial bleeding risks. Currently, anticoagulation has a class IIb recommendation for patients with associated PAH.1Galiè N. Humbert M. Vachiery J.L. et al.Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS)2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension.Eur Heart J. 2016; 37 ([published online ahead of print August 29, 2015]): 67-119Crossref PubMed Scopus (4016) Google Scholar Caution is recommended in patients with scleroderma who may have a higher risk of gastrointestinal bleeding. Folate plays no role in the pathogenesis of PAH, and thus there are no restrictions on dietary folate for patients with PAH. The 23-valent pneumococcal vaccine is recommended in adults over 65 years of age and in those with certain comorbidities, particularly in patients with pulmonary diseases, including PH. Despite our patient's age, she should receive a 23-valent vaccine.4Mirsaeidi M. Ebrahimi G. Allen M.B. Aliberti S. Pneumococcal vaccine and patients with pulmonary diseases.Am J Med. 2014; 127: 886.e1-886.e8Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar Because of the physiologic changes associated with pregnancy, there is substantial risk for mortality in patients with PAH, and avoidance of pregnancy is considered a class I, level C recommendation in patients with PAH.1Galiè N. Humbert M. Vachiery J.L. et al.Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS)2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension.Eur Heart J. 2016; 37 ([published online ahead of print August 29, 2015]): 67-119Crossref PubMed Scopus (4016) Google Scholar The patient was counseled regarding the risks of pregnancy, and she decided to undergo placement of an intrauterine device as well as continue barrier contraceptive use. Pulmonary hypertension includes a variety of conditions that cause elevated pulmonary pressures (mPAP ≥25 mm Hg). The initial clinical presentation is often nonspecific, with symptoms including dyspnea, edema, and fatigue. Clinicians must have a high clinical suspicion for PH, particularly in high-risk groups including patients with scleroderma, a strong family history of PAH, or HIV. Exertional syncope is an ominous sign and should alert clinicians to PH. Physical examination in advanced PH cases may yield findings of a prominent P2, loud tricuspid regurgitation murmur, RV heave, ankle edema, jugular venous distention, hepatomegaly, and ascites. These findings are often specific but poorly sensitive, and these patients require comprehensive testing to establish the diagnosis. The World Health Organization has established 5 distinct diagnostic classifications to define and categorize the different etiologies and pathophysiology of PH. Each classification requires different diagnostic testing for confirmation. Our patient has group 1 PH, also known as PAH, which is characterized by precapillary PH (mPAP ≥25 mm Hg and PCWP <15 mm Hg). It involves mainly the pulmonary arterial system (eg, increased PA stiffness). The incidence of PAH may be as high as 15 cases per million persons.1Galiè N. Humbert M. Vachiery J.L. et al.Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS)2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension.Eur Heart J. 2016; 37 ([published online ahead of print August 29, 2015]): 67-119Crossref PubMed Scopus (4016) Google Scholar Different diagnostic subcategories exist in PAH. The largest proportion is classified as idiopathic. Other subclasses include heritable genetic mutations (including the BMPR2 and ACVRL1 [activin receptor-like kinase 1] mutations) and associated PAH. Associated PAH encompasses PAH associated with connective tissue disease, HIV, portal hypertension, congenital heart disease, and schistosomiasis. The pathophysiology reflects a complex interaction of abnormalities including vascular thrombosis, vasoconstriction, and vascular wall remodeling.5Tuder R.M. Archer S.L. Dorfmüller P. et al.Relevant issues in the pathology and pathobiology of pulmonary hypertension.J Am Coll Cardiol. 2013; 62: D4-D12Crossref PubMed Scopus (422) Google Scholar Group 2 PH refers to patients in whom disease develops as a result of elevated left-sided heart pressures. These patients have postcapillary PH with an mPAP of 25 mm Hg or higher and PCWP of 15 mm Hg or higher. Pulmonary hypertension is often a result of left ventricular diastolic or systolic dysfunction, left-sided valvular disease, and certain congenital cardiomyopathies. Patients with group 3 PH have an intrinsic pulmonary disorder often leading to chronic hypoxia, which contributes to chronic hypoxic vasoconstriction and elevated pulmonary arterial pressures. Chronic obstructive pulmonary disease, interstitial lung disease, pulmonary fibrosis, and sleep-disordered breathing are common examples of group 3 PH. Group 4 PH is due to chronic thromboembolic occlusion of the pulmonary vasculature. Prognosis is generally poor unless patients are able to undergo pulmonary thromboendarterectomy. Newer PH medications targeting CTEPH have become available in addition to standard anticoagulation. Group 5 PH generally includes patients with unclear multifactorial mechanisms. Various etiologies include systemic disorders such as sarcoidosis, myeloproliferative disorders, hemolytic anemia, sickle cell disease, and chronic kidney disease.1Galiè N. Humbert M. Vachiery J.L. et al.Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS)2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension.Eur Heart J. 2016; 37 ([published online ahead of print August 29, 2015]): 67-119Crossref PubMed Scopus (4016) Google Scholar Along with a detailed history and physical examination, echocardiography is considered the first screening test used in suspected PH. Echocardiography allows for estimation of pulmonary pressures using Doppler ultrasound, assessment of ventricular morphology and function, and corroboration of physical examination findings of valvular heart disease. Ultimately, RHC is the standard and required confirmatory test used in PH. To help characterize etiology, comprehensive testing is often performed that may be tailored on the basis of the patient's clinical presentation. For example, pulmonary function testing, high-resolution computed tomography, and arterial blood gas measurements can assist in the diagnosis of chronic lung disease leading to chronic hypoxia. Pulmonary function tests have also been suggested for the diagnosis of PAH, particularly the use of the FVC:DLCO ratio as a screening tool. A ratio exceeding 2 is highly suggestive of PAH.6Gupta R. Pulmonary function test as screening test for pulmonary artery hypertension in scleroderma patients.Rheumatology (Oxford). 2004; 43 ([letter]): 1315Crossref PubMed Scopus (5) Google Scholar Ventilation-perfusion scans are essential in the screening and diagnosis of CTEPH and should be performed before any diagnosis of PH is considered. In addition, it is imperative to perform other studies to help exclude causes of PH, including laboratory tests for connective tissue disease, exposures to toxins and infectious agents, and at times gene mutations.1Galiè N. Humbert M. Vachiery J.L. et al.Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS)2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension.Eur Heart J. 2016; 37 ([published online ahead of print August 29, 2015]): 67-119Crossref PubMed Scopus (4016) Google Scholar Treatment depends on the diagnostic classification, WHO-FC class, and whether there is a positive vasoreactive response in patients with PAH. Patients who are vasoreactive positive and have WHO-FC class I-III should undergo an initial trial of calcium channel blocker therapy. For patients who are considered nonresponders, initial treatment options are based on WHO-FC class. Patients with WHO-FC class II may be prescribed a PDE5I, endothelin receptor antagonist, or riociguat, a soluble guanylate cyclase stimulator. Patients with WHO-FC class III are often treated with a PDE5I or inhaled or intravenous prostanoid. Those with WHO-FC class IV require an intravenous prostanoid. Combination therapy is typically reserved for patients who do not receive maximum benefit from single therapy. However, there is recent data that recommends the use of initial dual therapy.1Galiè N. Humbert M. Vachiery J.L. et al.Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS)2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension.Eur Heart J. 2016; 37 ([published online ahead of print August 29, 2015]): 67-119Crossref PubMed Scopus (4016) Google Scholar Patients with group 2 PH do not typically meet criteria for PH-specific therapies, and their treatment focuses on the underlying cause. Those with systolic heart failure merit treatment focusing on reverse remodeling and appropriate diuresis. Patients who have heart failure with preserved ejection fraction often require antihypertensive therapy, diuresis, and appropriate treatment of comorbidities including atrial fibrillation. Those with left-sided valvular heart disease may require specific surgical therapies targeting valvular regurgitation or stenosis. Patients with group 3 PH are most appropriately treated by optimizing the treatments for their underlying pulmonary disease or hypoxia. This may include supplemental oxygen, nocturnal noninvasive positive pressure ventilation, and/or medication changes. Patients with group 4 PH have limited options for treatment. Pulmonary thromboendarterectomy is the first-line treatment, and patients should be referred to a tertiary referral center. Riociguat has been found to be beneficial, particularly if surgical intervention is not feasible or as a bridge to surgery. In all patients, referral to a PH center is strongly suggested. In patients who do not respond to conventional PH-specific therapies, lung transplant may be a rare but potential option. After the diagnosis of PH is established, follow-up at a designated PH center or by a physician specifically trained in PH is imperative. Several prognostic indicators such as WHO-FC class, right ventricular function, brain natriuretic peptide level, and 6-minute walk test results are monitored for treatment response and medical management decision making.