A 44-year-old man comes to the office for evaluation of lower extremity swelling and exertional dyspnea for 3 months. The patient has homozygous sickle cell disease and a history of multiple vasoocclusive episodes and acute chest syndrome. He has required frequent blood transfusions. Medications include hydroxyurea and folic acid. The patient does not use tobacco, alcohol, or illicit drugs. Temperature is 37 C (98.6 F), blood pressure is 130/80 mm Hg, heart rate is 94/min, and respirations are 22/min. BMI is 24 kg/m². Examination shows clear lungs. The second heart sound is loud. The point of maximal impulse is at the left fifth intercostal space in the midclavicular line. The liver is palpable 2 cm below the right costal margin. There is 2+ pedal edema bilaterally. Laboratory studies show a hemoglobin of 9.8 g/dL and 2% reticulocytes. Diffusing capacity for carbon monoxide is normal. Which of the following is the most likely cause of this patient's symptoms?

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11ec25c8_d4cb_41e8_bc81_33292bcf24ff_MD0003_00 This patient with sickle cell disease (SCD) has chronic exertional dyspnea and signs of right heart failure. These findings are most likely due to pulmonary hypertension (PH), a potentially severe complication of SCD associated with increased mortality. Pathogenesis of PH in SCD is multifactorial. Intravascular hemolysis, leading to chronic inflammation and endothelial dysfunction, causes hyperplasia and hypertrophy of small pulmonary vessels (ie, vascular remodeling) and increased pulmonary vascular resistance (PVR). Increased PVR leads to decreased right ventricular (RV) output and left ventricular filling. As a result, cardiac output is unable to sufficiently increase during exercise. Therefore, initial presentation of PH can include exertional dyspnea and fatigue. Signs of right heart failure (eg, hepatomegaly, edema) then develop. Elevated right-sided heart pressures can increase the intensity of the pulmonic component of the second heart sound (S2) (ie, loud S2). right heart failure (Choice A) Bronchiolitis obliterans is due to injury and narrowing of small airways caused by infectious or toxic exposures. It presents with dyspnea, nonreversible airflow limitation, and a normal chest x-ray. Although this condition can lead to PH, additional pulmonary manifestations (eg, cough, crackles, wheezing) would be expected, and diffusing capacity for carbon monoxide (DLCO) is often low. (Choice B) Left-sided heart failure with decreased left ventricular ejection fraction can cause dyspnea and lower extremity edema and lead to PH. However, examination typically reveals crackles due to pulmonary edema and may show a laterally displaced point of maximal impulse due to left ventricular enlargement. Left-sided heart failure (Choice D) Pulmonary fibrosis is a potential complication of SCD (eg, following recurrent episodes of acute chest syndrome and pulmonary infarction) characterized by restrictive lung disease due to parenchymal scarring. It can cause exertional dyspnea. However, crackles are typical (particularly if significant enough to cause PH), lower extremity edema is not a classic early finding, and DLCO would be low. (Choice E) RV infarction can lead to lower extremity edema with clear lungs, but a significant RV infarct is likely to have presented acutely with chest pain and hypotension and would not typically lead to chronic dyspnea or a loud S2. Educational objective: The risk of pulmonary hypertension is increased in patients with sickle cell disease due to chronic intravascular hemolysis causing pulmonary vascular remodeling. Symptoms include exertional dyspnea and signs of right-sided heart failure (eg, hepatomegaly, edema). References: Chronic pulmonary complications of sickle cell disease. (http://www.ncbi.nlm.nih.gov/pubmed/26836905) Pulmonary hypertension in sickle cell disease. (http://www.ncbi.nlm.nih.gov/pubmed/25423000)

A 44-Year-Old Man Comes to the Office for Evaluation of Lower