Faculty Bibliography

Fabry disease is an X-linked inborn error of metabolism resulting from deficient activity of alpha-galactosidase A. Although several case reports have suggested an association between Fabry disease and airway obstruction, this has not been investigated in a large series of patients. We studied 25 unselected, consecutive, enzymatically diagnosed men referred to a General Clinical Research Center for evaluation. Thirty-six percent complained of dyspnea, and 24% had cough and/or wheezing. Symptoms were similar in smokers and nonsmokers. Nine (36%) had airway obstruction on spirometry; this finding was associated with age > or = 26 yr (p < 0.05) and dyspnea or wheezing (p < 0.005), but only weakly with smoking (p = 0.062). Five of eight patients responded to bronchodilators, but all 10 methacholine challenges were negative. Chest radiographs revealed normal lung fields in 24 patients and streaky bibasilar densities in one. No pulmonary uptake occurred on 67Ga citrate scans (18 patients) and 111In-tagged leukocyte scans (16 patients). Specific alpha-galactosidase A mutations were identified in 17 patients; all three patients with frameshift mutations and both subjects with the D264V missense mutation had obstructive impairment. We conclude that airway obstruction commonly occurs in patients with Fabry disease regardless of smoking history, and it increases with age. The presence of obstruction may be associated with certain mutations and most likely results from fixed narrowing of the airways by accumulated glycosphingolipid

Patients with sarcoidosis are known to have histologic pulmonary abnormalities despite normal lung fields or conventional pulmonary function or both. These patients permit a useful assessment of the alleged greater sensitivity of the various measurements made during incremental cardiorespiratory exercise testing. Abnormal responses on such testing may provide insight into such complaints as dyspnea in these patients. Incremental exercise testing was performed on 30 patients with biopsy-proven sarcoidosis who had normal spirometry; 13 had clear lung fields radiographically. Of these patients, the 21 who had normal single-breath diffusing capacity for carbon monoxide (Dsb; [group A]) were compared with the 9 who had decreased Dsb (group B). Half of the group A patients had excessive ventilation and 38% had increased dead space to tidal volume ratio (Vd/Vt), but frequencies of these abnormalities were greater in group B, 89 and 78%, respectively. Ventilatory response, as minute ventilation to oxygen consumption ratios ventilatory equivalents, and deadspace to tidal volume ratio (Vd/Vt) ratios were higher in group B. Widened alveolar-arterial oxygen pressure differences were seen in 7 of 9 group B patients but only 1 of 17 group A patients. This study supports the clinical impression that occult pulmonary impairment may be present in patients (in this case, sarcoidosis patients) with normal pulmonary function, and corroborates the utility of exercise testing in demonstrating such impairment. Reduction in Dsb predicted greater frequency of abnormal exercise responses, especially in oxygenation

The physiologic dead space/tidal volume ratio (VD/VT) at rest and during exercise is a sensitive measurement of gas exchange that reflects matching of ventilation to perfusion, but requires an invasive measurement for its calculation. Determining VD/VT noninvasively uses estimations of arterial PCO2 based on the end-tidal PCO2. To further standardize incremental cardiopulmonary exercise testing, we compared actual VD/VT with estimated VD/VT values in 35 patients referred for evaluation of dyspnea. Estimates of VD/VT used the Jones' equation (VD/VT[J]) derived from healthy subjects during steady-state exercise or PETCO2 alone (VD/VT[ET]) to approximate PaCO2. At rest, mean values for VD/VT(J) and actual VD/VT were not different: 0.372 +/- 0.08 vs 0.376 +/- 0.09, p = not significant (NS). Each method identified 61 percent of values > or = to 0.36. In 26 subjects who achieved higher work rates, the mean difference between actual VD/VT and VD/VT(J) increased from 0.009 +/- 0.04 (NS) at low work rate (VO2 = 28.3 percent pred max) to 0.040 +/- 0.06 at high work rate (VO2 = 54.7 percent pred max), p = 0.006. Actual VD/VT identified 18 (69 percent) patients as abnormal vs 13 (50 percent) so identified by VD/VT(J). With exercise, VD/VT(J) was no better than VD/VT(ET). We conclude that during incremental exercise in a patient population, methods for estimating VD/VT progressively underestimate this measurement; and therefore, 'normal' estimated VD/VT values may fail to identify underlying pulmonary and/or pulmonary vascular impairment

An increasing number of patients with asbestos exposure are being identified with pleural thickening (PT) alone, with little or no impairment in standard tests of lung function despite their frequent complaint of dyspnea. We have employed incremental cardiorespiratory exercise testing to evaluate the types and mechanisms of impairment in 23 such patients. All had normal lung fields on radiographic examinations and normal (group 1, n = 12) or minimally reduced (group 2A slight restriction, n = 5, group 2B, slight obstruction, n = 6), lung function. Excessive ventilation was common in all groups, but especially in group 2B. Abnormal dead space ventilation (VD/VT) was more frequent in groups 2A (4/5) and 2B (4/6) than in group 1 (3/12). It was associated with O2 desaturation in three patients in groups 2A and B. Cardiovascular abnormalities were rare (1/23). Excessive ventilation and dead space provide a basis for the symptom of dyspnea in these patients