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Cystic fibrosis is an autosomal recessive genetic disorder linked to chromosome 7q in all families studied. Expression of the disease varies, but the genetic basis for clinical heterogeneity is unknown. We describe an extended consanguineous family with pulmonary disease and the sweat gland phenotype of cystic fibrosis. In the members of this family, clinical expression of the disease was mild, as manifested by the absence of severe childhood lung disease and increased longevity with better functional status than that expected for age. The degree of pancreatic exocrine insufficiency varied (4/10), but the older patients had normal pancreatic function. The pedigree suggested the likelihood of common ancestry, and eight of the ten affected persons were clearly related. At least three of the family members with the mildest clinical disease had consanguineous parents and may therefore have been homozygous for a variant cystic fibrosis gene. The mild expression of cystic fibrosis in this family provides evidence for a form of cystic fibrosis that is intrinsically less debilitating than the classic form.

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Eleven human subjects were studied during steady state, controlled mild hypercapnia with resistive loading of either inspiration (RI) or expiration (RE). Minute ventilation and frequency were significantly reduced by RI (P = less than 0.01) and even more so by RE (P = less than 0.001). Tidal volume was unchanged. Both RI and RE reduced mean flow in the loaded phase - an effect relatively greater with RE. Neither RI nor RE altered mean flow in the unloaded phase. Although mean inspiratory flow was unchanged with RE, mouth occlusion pressure (P0.1) was increased (P = less than 0.01). Functional residual capacity (seven subjects) was increased with RE, but not with RI (P = less than 0.05). Five additional subjects were similarly studied with and without RE in whom transdiaphragmatic pressure (PDi) and peak diaphragmatic EMG (EMGDi) were examined. Changes in ventilation, breathing pattern and P0.1 were similar to those described above. Neither PDi nor EMGDi were significantly altered by RE, but with RE, diaphragmatic EMG activity began 50-190 ms before inspiratory flow. In conclusion, ventilation is reduced more by RE than by RI due to greater respiratory phase time. Moderately heavy RE does not augment inspiratory drive as reflected by mean flow, PDi or EMGDi. With RE and increased FRC, P0.1 does not accurately reflect inspiratory drive because of dissociation between EMG and flow.

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Three patients had diffuse reticulonodular shadowing on chest roentgenogram, dyspnea, cough, purulent sputum, airways obstruction, variable fever, and leukocytosis. Lung tissue from two showed inflammatory exudate in bronchioles and peribronchiolar alveoli; all had multiple isolates of either Haemophilus influenzae or Streptococcus pneumoniae from sputum or lung tissue. When examined in the context of similar syndromes reported by others under different labels in the past, these observations suggest that this is a specific clinical entity, which is both uncommon and serious. Despite initial misdiagnosis in all three cases, the two patients in whom the true nature of the disease was promptly recognized had complete recovery after the institution of appropriate antibacterial therapy. The most accurate and appropriate term for this entity is diffuse bacterial bronchiolitis with bronchiolar pneumonia.

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Steady-state responses to hyperoxic hypercapnia and eucapnic hypoxia were measured both as minute ventilation (VE) and as inspiratory mouth occlusion pressure (P0.1) with and without 25 cm H2O/I/s added resistance (R). Reduction in slope of the ventilatory response to CO2 with R was highly significant in all 3 subjects whereas the response to hypoxia was barely significantly reduced in 1 subject and not significantly decreased in two. Although P0.1 was higher with than without R under all conditions, the slope of the P0.1 response to CO2 with R was not increased in two subjects and only slightly increased in the third. The slope of the P0.1 response to hypoxia was significantly greater in all subjects with R. Expiratory reserve volume was increased with R but the change was the same with hypoxia and hypercapnia. We conclude that ventilation is better maintained with resistive loading during hypoxia than during hypercapnia and that this results from a greater force output of inspiratory muscles as reflected by a higher P0.1. This suggests a greater neural output to these muscles.

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Quantification of the major plasma protease inhibitors and genetic typing of alpha1-antirypsin were done in 107 patients with chronic obstructive pulmonary disease and in 91 control subjects with normal ventilatory function who were similar with respect to age, race, and sex. There was a significant increase in frequency of the PiZ gene and the Pi MZ phenotype of alpha1-antitrypsin among the patients when compared with the control subjects. No evidence for a primary deficiency of any other antiprotease was found; however, the mean concentration of inter-alpha-trypsin inhibitor was significantly lower in the patients than the control subjects, and moderate deficiency of alpha1-antichymotrypsin was noted in a few patients. These data indicate an increased risk of developing chronic obstructive pulmonary disease in persons with the Pi MZ phenotype of alpha1-antirypsin and suggest a possible relationship between these diseases and low serum concentrations of inter-alpha-trypsin inhibitor.

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