John A. Milberg

Survival with the acquired immunodeficiency syndrome. Experience with 5833 cases in New York City.

In a cohort of 5833 subjects in whom the acquired immunodeficiency syndrome (AIDS) was diagnosed in New York City before 1986, the cumulative probability of survival (mean +/- SE) was 48.8 +/- 0.7 percent at one year and 15.2 +/- 1.8 percent at five years. The group with the most favorable survival rate--white homosexual men 30 to 34 years old who presented with Kaposis sarcoma only--had a one-year cumulative probability of survival of 80.5 percent; that group was used as the reference group in assessing the effect of five variables: sex, race or ethnic background, age, probable route of acquiring AIDS (risk group), and manifestations of AIDS at diagnosis. The range in the mortality rate was greater than threefold, depending on these variables. Black women who acquired the disease through intravenous drug abuse, for example, had a particularly poor prognosis. The manifestations of disease at diagnosis had the most influence on survival, accounting on average for 56.3 percent of the excess risk. This variable was followed in importance by age (12.2 percent), race or ethnicity (10.6 percent), risk group (8.4 percent), and sex (8.0 percent), with 4.5 percent of the risk attributable to interactions between variables. When we compared subcohorts based on the year of diagnosis (1981 through 1985), we found a significant improvement in the one-year cumulative probability of survival among subjects with Pneumocystis carinii pneumonia, but not among subjects without P. carinii pneumonia.

Type III Procollagen Peptide in the Adult Respiratory Distress Syndrome: Association of Increased Peptide Levels in Bronchoalveolar Lavage Fluid with Increased Risk for Death

The adult respiratory distress syndrome frequently results in a fibroproliferative response and excessive lung extracellular matrix accumulation that may preclude recovery [1, 2]. An analysis of lung tissue from patients who died of the adult respiratory distress syndrome provided biochemical evidence that collagen, the major extracellular matrix component of lung, was greatly increased [3]. Immunohistologic evaluation of lung tissue from patients with the adult respiratory distress syndrome showed an abundance of type I and type III collagen, with type III collagen predominating earlier in the disease course [4]. Collagen accumulation in the adult respiratory distress syndrome results, at least in part, from increased procollagen synthesis, a mechanism that has been shown in numerous animal models of acute lung injury [5, 6]. Further, excessive lung collagen synthesis and accumulation may contribute to the high fatality rates associated with the adult respiratory distress syndrome by promoting progressive respiratory dysfunction. Alternatively, excessive lung collagen synthesis might indirectly influence outcome by impeding resolution of respiratory failure and increasing the risk for subsequent fatal complications, including multiple organ dysfunction. The relation between collagen synthesis and clinical outcomes in the adult respiratory distress syndrome has been difficult to examine directly. However, the N-terminal peptide of type III procollagen (procollagen III), cleaved from the precursor procollagen molecule during synthesis, appears to be a useful marker of collagen synthesis. Increased levels of procollagen III have been detected in serum from patients with sarcoidosis [7], idiopathic pulmonary fibrosis [8-10], and the adult respiratory distress syndrome [11, 12], as well as other conditions involving tissue fibrosis, such as cirrhosis [13], wound healing [14], trauma [12], and myelofibrosis [15]. In patients with idiopathic pulmonary fibrosis, increased procollagen III concentrations in bronchoalveolar lavage fluid were strongly associated with indices of clinical disease severity [10]. Although increased levels of procollagen III have been detected in lavage fluid from a few patients with the adult respiratory distress syndrome [16], their association with clinical outcome has not been examined. We analyzed procollagen III levels from bronchoalveolar lavage fluid in patients with the adult respiratory distress syndrome and studied the relation of increased lavage procollagen III levels to fatality rates. Methods Patients All patients between the ages of 18 and 72 years who were admitted to intensive care units at Harborview Medical Center [Seattle, Washington] between September 1986 and April 1991 were screened prospectively for the onset of the adult respiratory distress syndrome. Patients were screened using the following criteria: 1) for critical hypoxemia with cutoff Pao 2/Fio 2 ratios of 150 mm Hg or less or of 200 mm Hg or less using 5 cm H2O or more of positive end-expiratory pressure; 2) for diffuse parenchymal infiltrates involving at least three quadrants on chest radiographs; 3) for pulmonary artery wedge pressure [when available] of 18 mm Hg or less or no clinical evidence of congestive heart failure; and 4) no other obvious explanation for these findings [17, 18]. Because of the possible risk for complications related to bronchoalveolar lavage, patients with the adult respiratory distress syndrome were excluded if they met any of the following criteria: 1) Pao 2 less than 80 mm Hg with Fio 2 of 1.0; 2) evidence of acute ischemic heart disease; 3) severe hypotension (systolic blood pressure < 90 mm Hg); 4) cardiac dysrhythmias (heart rate > 140 beats/min or complex ventricular ectopy); 5) sustained increased intracranial pressure greater than 20 mm Hg; and 6) endotracheal tube internal diameter less than 7.0 mm. Patients were not excluded because of high minute ventilation, high levels of positive end-expiratory pressure, or presence of barotrauma. Informed consent was obtained from either the patient or the legal surrogate. The study was approved by the University of Washington Human Review Committee. Before bronchoalveolar lavage was done, the following clinical data were obtained: levels of Fio 2 and Pao 2, static compliance, and level of positive end-expiratory pressure. These data were used to calculate a modified lung injury score for the adult respiratory distress syndrome, as described by Murray and colleagues [19], except that a chest radiograph score was not included. However, all patients had alveolar infiltrates in three or four quadrants. Thus, the Murray acute lung injury score would be 0.75 to 1.0 points greater than our modified score. Patients in our study with lung injury scores of 1.75 or more met Murray criteria for severe lung injury. Risk factors associated with development of the adult respiratory distress syndrome were defined as previously described [17]. These included the sepsis syndrome, trauma, aspiration of gastric contents, drug overdose, and multiple transfusions. Trauma risk was defined as the presence of multiple long bone or pelvic fractures, pulmonary contusion, or trauma-associated multiple transfusions ( 15 units in 24 hours of emergency resuscitation) [17]. For this analysis, we combined clinical risks for aspiration of gastric contents, drug overdose, and multiple transfusions without trauma into the category other risks. Risk factors were identified prospectively when the patient was entered into the study. The first 18 patients in the study had a single bronchoalveolar lavage. Subsequently, we attempted to do lavage serially at days 3, 7, and 14 after the onset of the adult respiratory distress syndrome unless the patient died, was extubated, or became too unstable to tolerate a lavage, as indicated by the criteria above. Patients were followed until death or hospital discharge. Survival was defined as discharge from hospital. Organ failure and cause of death, as defined by Montgomery and colleagues [18], were analyzed in a subset of patients enrolled during 1990. Bronchoalveolar Lavage and Analyses All patients were intubated at the time of lavage. They were ventilated with Fio 2 levels of 1.0 for 10 to 15 minutes before and during the procedure. An adaptor was placed on the patients endotracheal tube, and a fiberoptic bronchoscope was passed through the endotracheal tube into the lower airway and was wedged into a subsegment of either the right middle lobe or lingula. Five 30-mL aliquots of sterile pyrogen-free 0.9% NaCl at room temperature were instilled (150 mL total) and recovered by gentle suction. Six normal volunteers had lavage using a similar technique. Serum samples also were obtained from patients at the time of lavage and were stored at 70C. Lavage samples were transported immediately to the laboratory for analysis. The fluid was filtered through gauze moistened with 0.9% NaCl, and the total recovered volume was recorded. Total cell counts were done in a hemacytometer, and differential cell counts were done on cytospin preparations stained with Diff-Quick (American Scientific Products, McGaw Park, Illinois). Cell viability was measured by trypan blue exclusion. After an aliquot was taken for cellular analysis, the lavage fluid was centrifuged at 200 g for 15 minutes to pellet the cells. Aliquots of the supernatant lavage fluid were put into polypropylene tubes and stored at 70C. Total protein was measured on an aliquot of the supernatant using either the modified Lowry method [20] or the bicinchoninic acid method [21]. Type III Procollagen Peptide Analysis The concentration of procollagen III in bronchoalveolar lavage fluid specimens or serum was determined by radioimmunoassay (RIAgnost PAP, Behringwerke, Marburg, Germany) according to the manufacturers instructions using 20 L of lavage fluid or serum. The radioimmunoassay for procollagen III was linear over a range of 0.4 to 9.5 U/mL. Serum control samples provided by the manufacturer contained 1.6 to 1.7 U/mL. Samples in which the procollagen III concentration was greater than the standard detection range were diluted 1:4 in 0.9% NaCl. Samples in which procollagen III concentrations were less than the detection range were assigned a value of 0.4 U/mL for subsequent data analysis. To determine the variability of repeat determinations, five lavage samples were analyzed in triplicate. The variability of triplicate determinations of procollagen III concentration measured in five different lavage samples was 5% or less. In one analysis, an aliquot of the lavage sample was subjected to a total of three freeze-thaw cycles to determine stability of the peptide under these conditions. No increase in the variability of measured values was detected. Cross-sectional and Serial Analyses Lavage fluid procollagen III concentrations in survivors and nonsurvivors initially were compared using the nonparametric Wilcoxon rank-sum test [22]. We then calculated the relative risk (RR) for fatality in patients with a lavage fluid procollagen III level of 1.75 U/mL or more compared with those with values less than 1.75 U/mL; 95% CIs were determined using the method of Rothman [23]. We also did a stratified analysis to determine if the relation between procollagen III concentration and fatality differed by risk factor for the adult respiratory distress syndrome (sepsis, trauma, other) or degree of lung injury, using the lung injury score. The difference in RRs for death among risk groups for the adult respiratory distress syndrome and lung injury severity groups was assessed by the Breslow-Day test of homogeneity [24]. We did logistic regression analyses of data obtained on days 3, 7, and 14 after onset of the adult respiratory distress syndrome to measure the effect of procollagen III levels on the risk for death while controlling for the effect of demographic and physiologic variables that, independ