Pulmonary hypertension (PH) associated with Whipple’s disease (WD) is extremely rare. Only five cases have been reported to date.
A 23-year-old Caucasian male was evaluated for exertional dyspnea and decreased appetite. He was diagnosed with PH by right heart catheterization six months prior to admission. Pulmonary artery pressure (PAP) at diagnosis was 102/47 mmHg (mean 66 mmHg), pulmonary capillary wedge pressure was 5 mmHg, cardiac output was 5.5 L/minute, and pulmonary vascular resistance was 11 Wood units. Interestingly, the patient demonstrated a positive vasodilator response after nitric oxide challenge (40 ppm), with a decrease in PAP to 47/19 mmHg (mean 27 mmHg). Cardiac output increased to 6.9 L/minute. Other causes for PH were excluded, and the patient was started on nifedipine (30 mg/day) in addition to sildenafil (20 mg three times/day) with moderate improvement in dyspnea. Six months later, the patient was admitted with worsening dyspnea, chronic diarrhea, malnutrition and marked iron deficiency anemia. He was also found to have diffuse thoracic and abdominal lymphadenopathy, bilateral uveitis and unilateral optic neuritis. Chest CT revealed a massively enlarged pulmonary artery (diameter 4.6 cm) with moderate pulmonary edema, bilateral small pleural effusions and a small pericardial effusion (Figure 1). Echocardiography revealed right atrial dilatation, right ventricular dilatation, and right ventricular hypertrophy. The estimated right ventricular systolic pressure was 55 mmHg. Left ventricular dysfunction was excluded. Esophagogastroduodenoscopy demonstrated diffuse inflammation and granularity in the stomach and duodenum. Biopsies revealed periodic acid-Schiff (PAS)-positive macrophages (Figure 2), which were also found on a conjunctival biopsy. WD was further confirmed by positive polymerase chain reaction (PCR) for Tropheryma Whipplei in the peripheral blood. The patient was started on ceftriaxone followed by trimethoprim/sulfamethoxazole with mild improvement in symptoms. A repeat right heart catherization is pending.
WD is caused by Tropheryma Whipplei, a gram-positive bacillus related to Actinomycetes. Infection with T. Whipplei results in extensive macrophage recruitment with subsequent engulfment of bacteria and production of pro-inflammatory cytokines (e.g. IL-16 and IL-1). This process stimulates the production of additional pro-inflammatory cytokines, such as TNF-α, IL-6, and IL-15. Apoptosis of recruited macrophages results in further bacterial dissemination. The association between WD and PH is only poorly understood. The following pathophysiological mechanisms have been proposed: 1) PH as a consequence of a pro-inflammatory state with cytokine activation, 2) direct infiltration of the pulmonary vasculature by T. whipplei, 3) endocarditis and/or valvulopathy, 4) pulmonary emboli with PAS-positive cells. The presence of pulmonary edema with normal cardiac function in our patient suggests a concomitant component of pulmonary venous involvement. Alternatively, this may be explained by capillary leak due to cytokine activation. The diagnosis of Whipple’s disease is usually made by PAS staining of duodenal biopsies along with positive PCR of tissue or peripheral blood. Treatment consists of parenteral ceftriaxone or penicillin G in conjunction with streptomycin for two weeks followed by trimethoprim/sulfamethoxazole for one to two years. One previous report demonstrated improvement of PH following antibiotics, while other cases failed to show improvement. Of note, several cases, including ours, demonstrated a dramatic response to vasodilator challenge despite high baseline PAP, potentially indicating a favorable diagnosis of the disease when adequately treated. The role of PAH-specific therapy in this patient population remains to be determined.
WD as a cause of PH though rare should be considered in the differential since it is potentially treatable.
Salah Najm, Grant monies (from sources other than industry) Dr. Tim Lahm has a research grant from Pfizer, $16.000, to investigate selective endothelin receptor antagonists in an animal model of endotoxemia; No Product/Research Disclosure Information