Jonathan E. Gottlieb

Infection with Mycobacterium avium complex in patients without predisposing conditions.

Pulmonary disease caused by Mycobacterium avium complex usually occurs in patients with chronic lung disease or deficient cellular immunity, and its prevalence is increasing. We describe 21 patients (mean age, 66 years) with such infection without the usual predisposing factors, representing 18 percent of the 119 patients surveyed. Seventeen women and 4 men were given a diagnosis of M. avium complex from 1978 to 1987, with a stable incidence over the decade, on the basis of pulmonary symptoms, abnormalities on chest films, positive cultures, and in 14, biopsy evidence of invasive disease. Most of the patients (86 percent) presented with persistent cough and purulent sputum, usually without fever or weight loss. The cough was present for a mean of 25 weeks before the correct diagnosis was made. Radiographic patterns of slowly progressive nodular opacities predominated (71 percent); only five patients had cavitary disease at presentation. All patients responded initially to antimycobacterial therapy, but eight eventually relapsed when it was stopped. Four patients died of progressive pulmonary infection caused by M. avium complex. The extent of the initial pulmonary involvement was greater in patients with progressive disease than in those whose condition improved. We conclude that pulmonary disease caused by the M. avium complex can affect persons without predisposing conditions, particularly elderly women, and that recognition of this disease is often delayed because of its indolent nature.

Randomized, placebo-controlled trial of lisofylline for early treatment of acute lung injury and acute respiratory distress syndrome

Objective To determine whether the administration of lisofylline (1-[5R-hydroxyhexyl]-3,7-dimethylxanthine) would decrease mortality in patients with acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). Design A prospective, randomized, double-blind, placebo-controlled, multicenter study. Setting Intensive care units at 21 hospitals at the ten centers constituting the ARDS Clinical Trials Network. Patients A total of 235 patients who met eligibility criteria were enrolled in the study (116 into the lisofylline group, 119 into the placebo group). Interventions Patients were randomized to receive either lisofylline or placebo. The dose of lisofylline was 3 mg/kg with a maximum dose of 300 mg intravenously every 6 hrs. The intravenous solution of study drug was administered over 10 mins every 6 hrs. Dosing was continued for 20 days or until the patient achieved 48 hrs of unassisted breathing. Measurements and Main Results The trial was stopped by the Data Safety Monitoring Board for futility at the first scheduled interim analysis. The patient groups had similar characteristics at enrollment. No significant safety concerns were associated with lisofylline therapy. There was no significant difference between groups in the number of patients who had died at 28 days (31.9% lisofylline vs. 24.7% placebo, p = .215). There was no significant difference between the lisofylline and placebo groups in terms of resolution of organ failures, ventilator-free days, infection-related deaths, or development of serious infection during the 28-day study period. The median number of organ failure–free days for the five nonpulmonary organ failures examined (cardiovascular, central nervous system, coagulation, hepatic, and renal) was not different between the lisofylline and placebo groups. Although lisofylline has been reported to decrease circulating free fatty acid levels, we did not find any such treatment effect compared with placebo. Conclusions In this study, there was no evidence that lisofylline had beneficial effects in the treatment of established ALI/ARDS.

Acquired renal insufficiency in critically ill patients

We undertook a study to determine the frequency, predisposing factors, and outcome in 315 patients admitted to a medical-surgical ICU, of whom 47 (14.9%) subsequently acquired renal insufficiency (ARI) during their stay in the unit. Four well-recognized risk factors for ARI were present alone or in combination in all episodes: hypotension, sepsis, aminoglycoside antibiotics, and radiocontrast dye. Hypotension was the most prevalent factor, present in 42 (85.8%) episodes, and was the sole factor present in 18 (36.7%). Patients with ARI but without hypotension all survived their ICU stay, while only 13 (33%) of 40 with hypotension survived (p less than .05). Neither initial, peak nor change in BUN or creatinine predicted mortality; oliguria was marginally associated with poor prognosis. Our findings indicate that: a) ARI was a frequent and important contributing factor to mortality in our critically ill patients, b) hypotension was the most common of well-recognized risk factors, and c) conditions that predisposed to ARI also predisposed to mortality, although mortality did not appear to depend on the severity of renal insufficiency.

Biochemical analysis of the activation of adherent neutrophils in vitro

The role played by neutrophil oxidative responses in host defense and injury is an area of active investigation. In order to study neutrophil responses in vitro, methods are required for cell purification, enumeration, and quantification of activation responses, which mimic the in vivo situation as closely as possible. In this communication (and its companion paper, Albertine et al., 1988) improved methods for all of these tasks are described and applied to investigate neutrophil structure-function relationships in vitro and in vivo. Human neutrophils were purified by using a series of platelet-poor plasma-Percoll gradients (51, 62, 76 and 80% in Percoll). This modification of previously published procedures results in consistently successful neutrophil purification and has allowed us to purify neutrophils from bronchoalveolar lavage fluid as well as blood. Activation of human and sheep neutrophils (superoxide anion production) was quantitated by the reduction of ferricytochrome c using a microtiter plate reader to measure the increase in absorbance at 550 nm from adherent neutrophils. Adherence of neutrophils was quantitated by measurement of LDH in cells lysed with Triton X-100 using a new method which uses readily available commercial reagents and can quantitate the LDH content of as few as 5000 neutrophils (or the LDH released from 5% of 100,000 neutrophils). Assay conditions for superoxide anion were optimized, limitations both in assay design and instruments used to measure OD were explored and enumerated, and these methods were used to quantitate sheep and human neutrophil activation responses. Using methods described in Albertine et al. (1988) for fixing neutrophils in microtiter wells after assay of their functional capacity, we have studied the same cells functionally and morphologically. We have used these techniques to study blood and alveolar neutrophils from a patient with acute respiratory failure. His alveolar neutrophils displayed 67% of the activation response as peripheral neutrophils (4.31 +/- 0.12 nmol superoxide released per 250,000 neutrophils at 60 min vs. 6.38 +/- 0.18 in blood, P less than 0.01) and structural changes which suggested previous activation in vivo. These studies demonstrate that similar morphological changes are observed in neutrophils activated with phorbol myristate acetate in vitro, as are observed in cells which have been activated by pathophysiologic processes in vivo.

Prolonged Exposure of Neutrophils to Saline or Bronchoalveolar Lavage Fluid Does Not Alter Superoxide Anion Generation

The role played by neutrophils (PMNs) in the genesis of lung injury in diverse clinical situations, such as bronchial asthma, idiopathic pulmonary fibrosis, and the adult respiratory distress syndrome, is an area of intensive investigation. Functional studies of PMNs, particularly those obtained from the alveoli by bronchoalveolar lavage, should shed light on their contribution to lung injury. However, it has not been demonstrated whether procedures used to harvest cells from the lung (bronchoalveolar lavage), particularly the potentially prolonged exposure to saline, commonly used to perform lavage, and other components of lavage fluid, can alter the functional characteristics of PMNs. In this report we demonstrate that a 2- to 3-hour exposure of neutrophils to saline from both humans and sheep in vitro does not alter the functional characteristics of PMNs as determined by superoxide anion generation after activation with phorbol myristate acetate (PMA; 6.96 +/- 0.44 vs. 7.60 +/- 0.32 nmol O2-/250,000 PMNs for control and saline-treated human cells, respectively, after a 45-min incubation with 10(-7) M PMA, and 4.73 +/- 0.30 vs. 4.50 +/- 0.42 nmol O2-/250,000 PMNs for control and saline-treated sheep cells). In a second series of experiments, we studied the effect of exposure of human PMNs to bronchoalveolar lavage fluid supernatants obtained from normal volunteers on superoxide anion generation by neutrophils.(ABSTRACT TRUNCATED AT 250 WORDS)