David P. Meeker

Pulmonary hypertension in type 1 Gaucher’s disease: genetic and epigenetic determinants of phenotype and response to therapy☆

Type 1 Gauchers disease (GD) is recognized for striking but unexplained phenotypic diversity. Rarely, severe pulmonary hypertension (PH) may occur in GD but its clinical spectrum, determinants or its response to enzyme replacement therapy (ERT)+/-vasodilators is not known. One hundred and thirty-four consecutive patients with Type 1 GD were screened to estimate right ventricular systolic pressure (RVSP) by Doppler echocardiography. Ninety-four patients were on ERT and 40 were untreated. Eight additional GD patients were studied that represented consecutive tertiary referrals with severe PH. Angiotensin converting enzyme (ACE) gene polymorphisms and acid beta-glucosidase gene (GBA) mutations were determined by DNA analysis. Mild, asymptomatic PH (RVSP>35<50 mmHg) was prevalent in Type 1 GD: 30% in untreated patients and 7.4% among patients receiving ERT (P<0.001). Splenectomy was strongly associated with severe, life-threatening PH: all patients with severe PH (RVSP 50-130 mmHg) were asplenic compared to only 31% of patients with RVSP<50 mmHg (Odds ratio [OR] 28.8, 95% CI 1.6-531.6, P<0.001). Other characteristics of patients presenting with severe PH were poor compliance to ERT (4/9 patients) or no ERT (5/9 patients), a family history of a sib with GD and PH (2/2 patients), an excess of ACE I allele (OR 2.3, 95% CI 1.1-4.9, P=0.034) and an excess of non-N370S GBA mutation (OR 6.0, 95% CI 1.1-33, P=0.003). Severe PH was ameliorated by ERT+/-vasodilators during 4.6+/-4.0 yr (range 1-12 yr) follow-up; three patients were initially considered for lung transplantation but improved such that they are no longer active transplant candidates. Our study reveals a remarkable predisposition for PH in type 1 GD. Progression to severe, life-threatening PH occurs in the presence of additional genetic factors (non-N370S GBA mutation, positive family history, and ACE I gene polymorphism) and epigenetic modifiers (i.e., asplenia and female sex). Splenectomy should be avoided and in high-risk patients, ERT+/-vasodilators/coumadin should be initiated.

The Diagnostic Utility of Bronchoscopic Biopsy and Tissue Culture in Lower Respiratory Infections

Our objectives were (a) to determine if routinely sending bronchoscopic biopsy (BB) for histopathology (HP) and tissue culture (CUL) increases the diagnostic yield over that obtained by bronchoalveolar lavage (BAD) and protected specimen brush (PSB), (b) to identify subsets of patients who benefit from BB (CUL), and (c) to assess the morbidity associated with BB for suspected lower respiratory infection. We used a prospective design in a single tertiary care center. Our study patients were consecutive (N = 45) inpatients or outpatients with presumed lower respiratory infection in whom a BAL. PSB, and BB were planned as the standard of care. BAL, PSB, and BB specimens were obtained from each patient by flexible bronchoscopy. The initial two BB pieces were sent for BB (CUL) and subsequent specimens (three to six) were sent for routine BB (HP) analysis. Infectious pneumonia was identified in 34 (76%) study patients. Pathogens identified were cytomegalovirus (10), bacterial (10), Pneumocystis carinii (9), mycobacterial (3), fungi (1), and respiratory syncytial virus (1). BB (CUL) solely identified only one additional pathogen. However, BB (HP) provided additional diagnostic information over BAL and PSB in 13 of 45 (29%) patients. The addition of BB (HP) to BAL and PSB significantly increased the yield for making a specific diagnosis (either infectious or noninfectious) compared to BAL and PSB alone (p < 0.004). BB (HP) increased the diagnostic yield among patients with diffuse pulmonary infiltrates (p = 0.03). Pneumothorax (N = 3) and mild bleeding (N = 3) were the complications of biopsy. Our conclusions were as follows: (a) BB (HP) in addition to BAL and PSB significantly increased the likelihood for making a specific diagnosis (infectious or noninfectious) compared to BAL and PSB alone, especially among patients with diffuse pulmonary infiltrates: (b) routine CUL of BB had a limited incremental yield; and (c) sending BB routinely for both CUL and HP may be associated with a slight increase in morbidity.