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Correlation of Bronchoalveolar Lavage Findings to Severity of Pneumocystis carinii Pneumonia in AIDS
Correlation of Bronchoalveolar Lavage Findings to Severity of Pneumocysfis carinii Pneumonia in AIDS* Evi~ence Permeabi~ity
for the Development of HighPulmonary Edema ~
Hamid Sadaghdar, M.D., F.C.C.R;t Zheng-Bo Huang, M.D.; and Edward Eden, M.D.
We correlated bronchoalveolar lavage 6ndings with the clinical course and outcome of Pneumocystis pneumonia. Forty-eight patients with AIDS and a coo6rmed diagnosis of P oo"';"ii pneumonia were studied. Patients with additional pulmonary infections were excluded. On the basis of lIAL findings, they were ~vided into those with a low neutrophil count (<5 percent) and those with a high neutrophil count (~5 percent). Sixteen patients with AIDS but' without PCP served as a control group. All BAL ftuid samples from the control group showed a low neutrophil count. The group with PCP and a high neutrophil count
carinii pneumonia (PCP) continues to P. beneumocystis a major source of morbidity and mortality in
patients with AIDS. Bronchoalveolar lavage with or without biopsy has been the cornerstone of diagnoSiS. I ,2
Previous studies of cell differential counts in BAL fluid (BALF) showed an increase in total cells, lymphocytes, and occasionally neutrophils and eosinophils compared to normal.P" Elevated neutrophil counts have been reported to correlate with the severity and mortality ofPCE6,7 However, prior studies have failed to exclude patients with PCP and a concomitant bacterial or viral pulmonary infection, which could independently increase the percentage of neutrophils in BALF. In addition, it was unclear how an elevated neutrophil count contributed to the increased mortali~ Biopsy analysis failed to show differences in pathologic severity between those with and those without BAL neutrophilia. 7 Because of these discrepancies, we studied the relationship between BAL neutrophilia, protein concentration, morbidity, and mortality in PCE We were careful to exclude those patients with concomitant pulmonary infections. We find that an increase in the number of BA~ neutrophils is associated with an *From the Department of Medicine, St. LukeslRoosevelt Hospital Center, College of Physicians and Surgeons, Columbia University, New York. tCurrently in the Division of Critical Care Medicine, University of California, Irvine. Manuscript received July 8; revision accepted October 10. Reprint requests: Dr. Eden, 126 wm 60th Street, New York City
10023
had more severe respiratory compromise and greater morbidity than the group with PCP and a low neutrophil count. Mortality rate was not different. The group showing a high BALF neutrophil count also showed a higher HALF protein concentration, a higher ratio of BALF protein concentration to plasma protein concentration, and the presence of as-globulins compared with other groups. The'se findings suggest that increased alveoJar..capillary permeability occurs during severe PCP. (Chat 1992; 102:63-69)
I
DS = dyspnea score
I
increased total alveolar protein and the presence of high-molecular-weight proteins. These changes correlate with the severity of disease and suggest the development of high alveolar epithelial permeability in some patients with severe PCE PATIENTS AND METHODS
Subjects
Between June 1989 and March 1990, 72 patients with risk factors for or known HIV infection whose pulmonary diagnosis was not apparent by clinical or other means underwent fiberoptic bronchoscop~
The diagnosis of PCP was made in 48 patients. Of these, five were excluded for improper mixing of lavage aliquots and two were excluded because of cytologic evidence for pulmonary cytomegalovirus (CMV) infection. The remaining 41 patients were divided into two groups based on the number of neutrophils (see below). At the time of bronchoscopy, 40 of 41 patients were receiving therapy or prophylaxis for PC}! No patients had clinical evidence of sepsis. Twenty-four patients did not have PC}! Of these, seven were excluded for the following reasons: presence of gross blood in BALF, lavage in segments other than right middle lobe or lingula, improper mixing of lavage returns, or positive bacterial cultures. One died of acute respiratory failure, and autopsy showed Toxoplasma and Staphylococcus aureus pneumonia without PC~ Of the 16 patients remaining after exclusion (group 1), four were diagnosed with pulmonary Kaposi's sarcoma and one with pulmonary lymphoma. No specific diagnosis was made in the 11 others. Bronchoscopy with BAL was also performed in a group of eight healthy, nonsmoking HIV-negative volunteers as part of an approved study. The severity of dyspnea on initial evaluation was determined and a dyspnea score (DS) was assigned: 0, no dyspnea; 1, dyspnea on exercise (climbing stairs, fast walk); 2, dyspnea with minimal exertion (dressing, shaving); 3, dyspnea at rest. Initial gasexchange was evaluated by admission arterial blood gas analysis performed CHEST I 102 I 1 I JUL'Y. 1992
83
Table I-DGta on BAL Cell AntJlpia Patients*
Total Cells, x 100/ml
Macrophages, x 10't/ml (%)
Lymphocytes, x 10't/ml(If,)
Neutropbils, x ~()'t/ml (if,)
Eosinopbils, x 10't/ml(,.)
Group I Group 2 Group 3
0.6±0.3t 0.3±0.2 0.4±O.3
375±277t (64±22) 182±IOB (61±19) 170± 116 (45± 19)
187± 117 (34±21) 124±II0 (37±18) 126± 140 (30± 14)
4±6 (O.8± 1.4) 4±5 (1.2±1.0) 84±79§ (21.6± 15.7)
3±9 (O.5± 1.2) 3±3 (1.1±1.4) 14±45 (2.1±4.2)
*Group I, AIDS without PCP; group 2, AIDS with PCP and BAL neutrophil <5,.; group 3, AIDS ~th tCompared with group 2: p
pcp and BAL neutrophil ~5".
with the patient breathing room air. Patients with a Pa0l s55 mm Hg generally received adjuvant corticosteroid therapy, but the final decision was made by the primary physician and based on the clinical evaluation. Other measured values included serum lactate dehydrogenase, serum albumin, and total protein.
to plasma protein (BALF/plasma) was calculated for each patient and expressed as a ratio x 100.5 The concentration of particular protein classes in BALF was obtained indirectly by multiplying the BALF protein eoncentradon by the percentage of each protein class as resolved by electrophoresis,
BAL and CeU Analysis
Statistics
Fiberoptic bronchoscopy was performed after ob~ng informed consent. Transbronchial biopsy, if obtained, was performed after BAL. Bronchial inJlammation was estimated by visual inspection of the segmental and subsegmental airways for erythema, secretions, and edema by two of the authors. The appearance was assigned a score as follows: 0, normal; I, mild bronchitis; 2, moderate bronchitis; 3, severe bronchitis. The bronchoscope was then wedged in either the right middle lobe or lingular subsegmental bronchus. Next, 150 ml of normal saline solution was instilled, in 5O-ml aliquots, and immediately aspirated with a syringe. The first aliquot of lavage was discarded. Lavage 8uid from the second and third aliquots was mixed and divided into aliquots for cytologic, bacteriologic, mycobacteriologic, and mycologic examination. Samples of lavage 8uid sent for bacterial analysis were cultured in enrichment broth as well as being plated directly on chocolate agar, MacConkey, CNA, blood, and anaerobic plates. The presence and identity of any bacterial colonies were reported. Specimens submitted for mycobacterial and fungal culture were centrifuged and the cell pellet plated. Cultures for 'CM·V or other viruses were not performed routinely. An aliquot of lavage 8uid was filtered through a layer of surgical gauze. The cell concentration was measured, and the sample was centrifuged at 400 g for 10 min. The cell pellet was resuspended in Hanks balanced salt solution. The cytospin slides were stained, and differential cell counts were performed.
All data are expressed as mean ± SD. Analysis of variance and Kruskal-Wallis 'test were used to compare multiple groups of normally distributed data and nonparametrie data, respectivel~
BALF Protein Analysis The concentration of protein was determined by the Lowry method." Protein electrophoresis on 80 to 100 times concentrated BALF was performed by the gel electrophoresis method. The BALF total protein concentration and as-globulins representing intermediate- to high-molecular-weight proteins (100,000820,000 daltons) were used as an index ~f alveolar-capillary membrane protein permeability. A concentration ratio of BALF protein
Further comparisons between each two groups were subject to Bonferroni correction.· Correlation between two variables was evaluated by Pearson correlation coefficient. Categorical data were compared' with a chi-square test. Dyspnea index and bronchitis index were analyzed by a method for assigned scores. lO Differences were considered sign~cant when p
lbtient Groups On the basis of differential cell counts, patients with PCP were divided into those showing <5 percent neutrophils (group 2) and those showing ~5 percent neutrophils (group 3). Of the 41 patients with PC~ 20 showed a neutrophil count of <5 percent, and 21 showed a neutrophil count ~5 percent. Group 'I comprised those patients with AIDS and lung disease but without peE Results of BAL cell analysis are shown in Table I, All 16 patients without PCf (group 1) had a B~L neutrophil count of <5 percent. The total cell concentration in BALF was higher in group 1 compared to group 2. The only difference in cell counts between groups 2 and 3 was a higher neutrophil count in the latter. The eosinophil count and proportion were increased' in group 3 but not significantly so. There were no significant- differences for age, sex, race, risk factors for AIDS, smoking history, or previ-
Table 2-Epitlerniologic ClaartJClBridica ofthe Study Population.
Group I (n = 16) Group 2 (n = 20) Group 3 (n = 21)
Age, yr
Sex, M:F (n)
Race, B:H:W (n)
37.8±8.2 35.3±6.6 38.3± 10.9
15:1 20:0 20:1
2:3:11 5:3:12 3:4:14
H:IVD:T (n)
Smolcing Status, C:E:N (n)
Prior pcp (n)
14:1:0 14:5:1 19:2:0
4:3:9 8:7:5 7:4:10
3 4 3
RF,
*B, black; H, Hispanic; ~ white; RF, risk factors; H, homosexual; IVD, intravenous drug user; T, transfusion; C, current smoker; E, exsmoker; and N, nonsmoker.
84
Con8IaIIon of ~ findings to 8eYertty of pcp
(Sadag~
Huang, Eden)
Table 3-RapirGtorfl MetJlUrementa No. of Patients with Dyspnea Scores Group 1 Group 2 Group 3
120
of 0:1:2:3
P(A-a)O., mmHg
PaO., mmHg
2:12:2:0 4:4:10:2 1:3:3:14*
35.3± 11.6 34.2± 19.2 54.6± 14.2*
83.0±14.6 77.7 ± 20.9 56.7±12.6*
*Compared with group 1 and 2: p
n=38
C;; J:
E
5 0
ous history of PCP among the three groups (Iable ~). More patients in group 1 were taking prophylaxis (nine cases), but no difference was found between groups 2 and 3 (five and four cases, respectively). In group 3, seven patients were receiving systemic corticosteroids in addition to standard therapy three to five days before bronchoscopy No patients in group 1 and only one in group 2 were treated With steroids. The BALli' neutrophilia or eosinophilia was not significantly different between the patients who received adjuvant corticosteroid therapy (17.9± 14.2 percent and 2.6 ± 6.3 percent, respectively) and those who did not (23.5 ± 16.6 percent and 2.0 ± 2.9 percent, respectively).
Clinical,- Laboratory, an4 Respiratory Data There were more cases with a higher DS in group 3 (lable 3). The PaO! was significantly lower, and the alveolar-arterial Po! gradient measured at air Flo! 0.21 was significantly higher in group 3 (Table 3). No difference was noted between groups 1 and 2. Serum total protein level was 6.6± 1.3, 7.1 ±O.9, and 6.4± 1.0 mwdl for the three groups, respectively Similarly, serum albumin value was 3.0 ± 0.7, 3.1±0.5, and 2.7±0.6 mg/ml, and serum lactate dehydrogenase level was 322 ± 122, 424 ± 250, and 514 ± 219 lUlL. There was' no significant difference between the three groups,
Bronchoscopic Data and Lavage CeU Population Because ofthe severity ofhypoxemia, bronchoscopy was performed later after admission in group 3 compared to group 1 (4.8±2.9 vs 2.6±2.6 days, p
r=-O.42 P
100
0
80
•
N
a...
60
• •• • •
40
• 20
• •
~-~_....L-_..-.I...._"""""'_---L_----I_----'
o
10
•
20
30
40
50
60
70
% of PMN in BALF FICURE 1. Correlation between PMN percentage in BALF and PaO. for AIDS patients with pcp (groups 2 and 3). PMN indicates polymorphonuclear cells (neutrophils + eosinopbils); BALF, bronehoalveolar lavage 8uid.
group 3 and group 2 (3.3 ± 2.5 days). The lavage recoveries among three groups (63 ± 6 percent, 56 ± 13 percent, and 52 ± 13 percent, p>O.05) were not significantly different. The number of cases assigned to a specific bronchitis index from 0 to 3 were 9:5:2:0 for group 1, 7:9:3:1 for group 2, and 4:13:3:0 for group 3. There was no significant difference among the three groups.
Protein Analysis in BALF The concentrations ofprotein and albumin in BALF and their ratios to concentrations in serum are shown in Table 4. Protein concentration in BALF of group 3 was significantly higher than in group 1 and group 2. There was no difference in albumin concentration among the three groups, so the proportion of albumin to total protein ill BALF fell in group 3. However, both protein and albumin concentrations in all three patient groups were higher than that of a normal population surveyed in o~ laboratory (Iable 4).
Table 4- Protein AntJlr/Bis of BALF*
Group 1 Group 2 Group 3 Normal (n =8)
BAL-[TP]
BAL-[Alb]
BAL-[TP], ..,glml
BAL-[Alb], ..,glml
Sernm-[TP]
Serum-[Alb]
392±174 320±187 630±355t* 71±84
204±99 151±93 236±127 39±51
0.5±0.2 0.5±0.3 1.0±0.5t* NA
0.6±0.2 0.5±0.3 0.9±0.5* NA
*Alb,' albumin concentration; n
BAL[CIt-Globulin], ~glml (n) ND
(0) 46 (1) 71±56 (9) ND (0)
total protein concentration; NA, not available; ND, not detectable; BAL-[TP]lserum-[TP] ratio, 100 x ~ALF protein concentration/serum protein concentration; BAL-[Alb]lsernm-[Alb] ratio, 100 x BALF albumin concentration/serum albumiD concentration. tCompared with group 1: p
85
2000
120 0 0
100
0
0
n=36 r=-O.50 P
0
.........
E
0
C;;
<,
5 0
80
--J
a..
a
........... u,
0
-c rn
N
0
1500
0" ::J
J:
E
n=38 r=O.60 P
1000
a
c:
60
a
0
Do O 0
c:
.Qj -+oJ
0
a.. ~
40
500
o
20
~_--'--_--L
o
250
_ _~ _ - - ' -
500
750
a
0
cO
o _ _" " - - - _ - J
1000
1250
1500
Protein in BALF (ug/ml)
O~-",,"--_..a..-_...I.-_---~---'---~
a
10
c 0
20
30
40
50
60
70
% of PMN in BALF
2. Correlation between protein concentration in BALF and
FICURE 3. Correlation between percent PMN count in BALF and total protein concentration in BALF for AIDS patients with pcp (groups 2 and 3).
The concentration ratio of BALF protein to serum protein in group 3 was significantly higher than in groups 1 and 2. The concentration ratio of BALF albumin to serum albumin in group 3 was significantly higher than in group 2. Protein electrophoresis of BALF showed the presence of as-globulin in nine of 19 specimens (47 percent) in group 3 (71 ± 56 JLglml) and only o~e of 19 (5 percent) in group 2 (46 ~glml). In group 3, the protein concentration in BALF showing detectable «t-globulln (655± 332 JLgI~l) was similar to that in BALF without detectable (l2-globulin (607 ± 390 p,glml). The same specimens that showed as-globulins also showed detectable levels of (1- and p-globulins. The ~-globulin was not detectable in group 1 or in a group of BALF samples from normal volunteers, Protein and albumin concentrations of patients who were receiving corticosteroids before bronchoscopy (protein: 6;)2 ± 593 JLWml, albumin: 268 ± 269 P,Wml) were not different from those in the rest ofthe patients in this group (protein: 615 ± 441 p,glml, albumin: 218 ±'127 JLglml). Two ofnine patients with detectable ~-globulins were receiving corticosteroids ·before bronchoscopy
percentage was used in the analyses (Pa02: r= -0.42, p
FICURE
initial PaOI (Flo. 0.21) for AIDS patients with pcp (groups 2 and
3).
Correlation of N~trophilia and 7btal Protein in BALF of pCP with Arterial Oxygenation Measurements For patients with PCP (groups 2 and 3), BAL neutrophil percentage was inversely related to Pa02 (r= -0.39, p
Follow-up Bronchoscopy Follow-up bronchoscopy (Iable 5) was performed in four patients in group 3. Two patients had bronchoscopy two weeks, one ten days, and the other three weeks after the first lavage. One of these patients had been receiving corticosteroid treatment, which was stopped three days prior to follow-up bronchoscopy As shown in Table 5, neutrophil and PMN percentages had fallen to a normal value in three patients. Protein concentration fell in three of the four patients. Comparison of electrophoresis was made in one patient (No.' SO). The first BALf showed the presence of Usglobulins, which could not be detected in the second BALF sample.
Outcomeand Mortality during the Acute Episodeof PCP Mortality during the acute episode was defined as the number of deaths during treatment for PCI! No patient in group 1
Huang, Eden)
Table 5-C~
~
Finltmtl Second BAL in Ibdenta tDitIa PCp·
DS
Neutrophil, %
n~wml
Patient No.
1st
2nd
1st
2nd
1st
2nd
40 41 42 50
2 3 0 3
0 0 0 0
18.8 17.7 5.8 39.4
0.5 13.9 0.6 0.6
219 383 NA 299
61 189 NA 107
~
total protein concentration; 1st, 6rst lavage; 2nd, second lavage; NA, not available.
respiratory failure. Respiratory status deteriorated in three other patients, and two of these required intubation. All three patients eventually improved. There was no significant difference in mortality among the three groups. DISCUSSION
Pneumocystis carinii pneumonia remains a major cause of morbidity and mortality in AIDS patients. Approximately 20 to 30 percent of patients with a first episode of PCP develop respiratory failure. A mortality of 30 percent was reported in earlier studies. 1.2 An alveolar-arterial oxygen gradient greater than 30 mm Hg and the degree of abnormality on initial chest roentgenograms were suggested as determinants of a poor prognosis. 1 Previous studies which examined cell differential counts in BALF of patients with AIDS and pcp have provided evidence for the role of the neutrophil as a prognostic factor of morbidity and/or mortality Smith et ale reported a small series of 19 patients with AIDS and PC~ Twelve of these patients with elevated neutrophil counts in BAL (>5 percent) had a higher P(A-a)02 (mean, 54.4 mm Hg). Four of 12 patients died of respiratory failure, but sputum cultures of three of them were positive for a bacterial pathogen. Although the mortality rate did not reach statistical significance, elevated neutrophil counts in BAL were associated with more severe respiratory compromise. Mason et al,? in a retrospective study of 60 patients with AIDS and PC~ reported 11 deaths (18 percent) among the 15 patients who developed respiratory failure. Fourteen of these 15 patients had an elevated (>5 percent) neutrophil count in BALF. Again, patients with a concomitant pulmonary infection were not excluded. We took care to exclude patients with PCP and an associated pulmonary infection which may increase neutrophil counts and contribute to mortality All lavage specimens were routinely cultured for bacteria on multiple media and in enrichment broth and were centrifuged before being cultured for fungal and mycobacterial organisms. Bronchoalveolar lavage is an excellent technique for the diagnosis of pulmonary infection, with sensitivities ranging from 74 to 93 percent,l1·12 and although we did not perform quanti-
tative cultures, we excluded all patients showing evidence of bacterial growth on culture. Our findings provide strong circumstantial evidence for a specific role of the alveolar neutrophil in the pathogenesis of respiratory failure in severe PC~ First, an elevated neutrophil count in BALF (~5 percent) correlated with greater dyspnea, more severe gas exchange abnormalities, and a greater morbidity. Second, a greater number of cells was present in the lavage fluid of AIDS patients without PCP and respiratory compromise than in patients with PC~ Furthermore, total cell counts were unrelated to the severity of PC~ This argues against any suggestion that the neutrophil is part of a general inHux of cells into the lung during PC}! Third, the first aliquot of BAL, which contains more airway neutrophils, was not used for cell analysis. Furthermore endobronchial evidence of bronchitis was not significantly different between those patients with high neutrophil counts in BALF and those without, which suggests that airway inflammation is not contributing to the observed increase in neutrophils. Fourth, in four patients, resolution of severe PCP was associated with a fall in the neutrophil count in alveolar lavage fluid. The influx of neutrophils into the lung in severe PCP was associated with increased total alveolar protein and this increase strongly correlates to gas exchange abnormalities. It could be argued that the increase in protein is a nonspecific indicator of pulmonary inflammation and originates as a product of pulmonary cells responding to infection. Indeed, protein concentration in BALF in patients with AIDS has previously been reported to be increased, although patients were not characterized according to the type of pulmonary disease." More recently, Phelps and Rosel3 reported increased concentrations of total protein albumin and high-molecular-weight proteins in BALF of AIDS patients with PC~ We confirm that total BALF protein and the BALF to serum protein concentration ratio are increased in all patient groups with AIDS and pulmonary disease. However, with respiratory compromise in severe PC~ BALF protein increases to approximately twice the value in patients with mild PCP and 1.5 times the value in patients with noninfectious lung disease. The ratio ofBALF to serum protein concentration is also greater in the CHEST I 102 I 1 I JUL'( 1992
87
group with severe PC~ These changes occur without a concomitant increase in total cell concentration and suggest an extrinsic source of the additional protein. The presence ofhlgh-molecular-weight <
barrier is compromised before the development of severe PCE With additional neutrophil influx, further loss of epithelial integrity occurs. Last, patients who develop ARDS do not respond to corticosteroids. Inhibition of mediator release from suppressor lymphocytes and alveolar macrophages by corticosteroids may reduce pulmonary inflammation and explain the salutary effects of these agents in patients with severe PCP and respiratory failure. Z4 It is noteworthy that nine of the 21 patients in group 3 received adjunctive corticosteroid therapy which probably reduced the observed mortality compared to earlier studies. I •1 Those patients started on corticosteroid therapy did not have more neutrophils or protein in BALF, and other factors are probably important in determining severity of respiratory compromise in PCE In conclusion, our study shows that a high neutrophil proportion in BALF correlates with increased morbidity and greater gas exchange abnormalities, and is associated with an increase of total protein and the presence of high-molecular-weight proteins in the alveolar space. These abnormalities improve as the PCP resolves. We believe the findings are consistent with the development of high-permeability pulmonary edema in some patients with PCP in which the neutrophil plays an important but not exclusive role. ACKNOWLEDGMENTS: The authors wish to thank Dr. J. Bhattacharya for his helpful comments and the technical staff in the clinical chemistry laboratory at the Roosevelt Site.
REFERENCES 1 Murray JF, Felton C~ Garay SM, Gottlieb MS, Hopewell PC, Stover DE, et al. Pulmonary complications of the acquired immunodeficiency syndrome. N Engl J Med 1984; 310:1682-88 2 Brenner M, Ognibene F~ Lack EE, Simmons JT, Std£redini AF, Lane HC, et al. Prognostic factors and life expectancy of patients with acquired immunodeficiency syndrome and PneumocystiBcarinii pneumonia. Am Rev Respir Dis 1987; 136:11991206 3 White DA, Gellene RA, Gupta S, Cunningham-Rundles C, Stover DE. Pulmonary cell populations in the immunooompromised patient. Chest 1985;88:352-59 4 Venet A, Dennewald G, Sandron D, Stern M, Jaobert F, Leibowitch J. Bronchoalveolar lavage in acquired immunodeficiency syndrome [letter to the editor]. Lancet 1983; 2:53 5 Young KR Jr, Ran1dn RA, Noegel G~ Paul ES, Reyolds HY. Bronchoalveolar lavage cells and protein in patients with the acquired immunodeficiency syndrome. Ann Intern Med 1985;
103:522-33
6 Smith RL, EI-Sadr WM, Lewis ML. Correlation ofbronchoalveolar lavage cell populations with clinical severity of PneumocyBtis carinii pneumonia. Chest 1988; 92:60-64 7 Mason GI: Hashimoto CH, Dickman PS, Foutty LF, Cobb CJ. Prognostic implications of bronchoalveolar lavage neutrophilia in patients with Pneumocy8ti8 carini' pneumonia and AIDS. Am Rev Respir Dis 1989; 139:1336-42 8 Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Bioi Chern 1951;
193:265-75 9 Glantz SA. Primer of biostatistics. New York: McGraw-Hill Book Company, 1981
Con8Idon of BALfindings to Se\wiIy of pcp (Sadaghdc Huang, Eden)
10 Snedecor G~ Cochran WG. Statistical methods, 7th ed. Ames, Iowa: Iowa State University Press, 1980 11 Johanson WG Jr, Seidenfeld JJ, Gomez ~ Santos BDL, Coalson JJ. Bacteriologic diagnosis of nosocomial pneumonia following prolonged mechanical ventilation. Am Rev Respir Dis· 1988; 137:259-64 12 Pugin J, Auckenthaler R, Mili N, Janssens J~ Lew PD, Suter PM. Diagnosis of ventilato~associated pneumonia by bacteriologic analysis of bronchoscopic and nonbronchoscopic "blind" broncboalveolar lavage Suid. Am RevBespir Dis 1991; 143:112129
13 Phelps DS, Bose RM. Increased recovery of surfactant protein A in AIDS related pneumonia. Am Rev Bespir Dis 1991; 143: 1072-75 14 Tate RM, Repine JE. Neutrophils and the adult respiratory distress syndrome. Am Rev Respir Dis 1983; 128:552-59 15 Weiland JE, Davis WB, Holter JF, Mohammed JR, Dorinsky PM, Gadek JE. Lung neutrophils in the adult respiratory distress syndrome. Am Rev Respir Dis 1986; 133:218-25 16 Rinaldo JE, Rogers RM. Adult respiratory distress syndrome: cbaogingconcepts of lunginjury and repair. N Engi J Med 1982;
300:900-09
17 McGuire ~ Spragg RD, Cohen AM, Cochrane CG. Studies on the pathogenesis of the adult respiratory distress syndrome. J Clio Invest 1982; 69:543-53 18 Fox RB, Hoidal JR, Brown DM, Repine JE. Pulmonary inftam-
19
20
21
22 23
24
mation due to oxygen toxicity: involvement of chemotactic factors and polymorphonuclear leukocytes. Am Rev Respir Dis 1981; 123:521-23 Sbasby DM, Fox RB, Hanada RN, Repine JE. Reduction of the edema of acute hyperoxic lung injury by granulocyte depletion. J Appl Physioll982; 52:1237-44 Holter JF, Weiland JE, Pacht ER, Gadek JE, Davis B. Protein permeability in the adult respiratory distress syndrome: loss of size selectivity of the alveolar epithelium. J Clin Invest 1986; 78:1513-22 Gelb AF, Klein E. Hemodynamic and alveolar protein studies in noncardiac pulmonary edema. Am Rev Respir Dis 1976; 114:831-35 Fein A, Grossman RF, Jones JG, Overland E, Pitts L, Murray JF, et ale The value of edema Buid protein measurement in patients with pulmonary edema. Am J Med 1979; 67:32-8 Meignan M, Gullion J, Denis M, Joly ~ Rosso J, Carette MF, et ale Increased lung epithelial permeability in "IV-infected patients with isolated cytotoxic T-Iymphocytic alveolitis. Am Rev Respir Dis 1990; 141:1241-48 Bozzette SA, Sattler FR, Chiu J, Wu AW, Gluckstein 0, Kemper C, et ale A controlled trial of early adjunctive treatment with corticosteroid for Pneumocystis carinii pneumonia in the acquired immunode6ciency syndrome. N Engl J Med 1990; 323:1451-57
15th Annual OCcupational safety and Health Summer
Institute
North Carolina Occupational Safety and Health Educational Resource Center at the University of North Carolina will sponsor this program in Williamsburg, Virginia, August 1014. For information, contact NCOSHEducational Research Center, University of North Carolina, 109 Conner Drive, Suite 1101, Chapel Hill 27514 (919:962-2101).
CHEST I 102 I 1 I JUL~
1992
89
for the Development of HighPulmonary Edema ~
Hamid Sadaghdar, M.D., F.C.C.R;t Zheng-Bo Huang, M.D.; and Edward Eden, M.D.
We correlated bronchoalveolar lavage 6ndings with the clinical course and outcome of Pneumocystis pneumonia. Forty-eight patients with AIDS and a coo6rmed diagnosis of P oo"';"ii pneumonia were studied. Patients with additional pulmonary infections were excluded. On the basis of lIAL findings, they were ~vided into those with a low neutrophil count (<5 percent) and those with a high neutrophil count (~5 percent). Sixteen patients with AIDS but' without PCP served as a control group. All BAL ftuid samples from the control group showed a low neutrophil count. The group with PCP and a high neutrophil count
carinii pneumonia (PCP) continues to P. beneumocystis a major source of morbidity and mortality in
patients with AIDS. Bronchoalveolar lavage with or without biopsy has been the cornerstone of diagnoSiS. I ,2
Previous studies of cell differential counts in BAL fluid (BALF) showed an increase in total cells, lymphocytes, and occasionally neutrophils and eosinophils compared to normal.P" Elevated neutrophil counts have been reported to correlate with the severity and mortality ofPCE6,7 However, prior studies have failed to exclude patients with PCP and a concomitant bacterial or viral pulmonary infection, which could independently increase the percentage of neutrophils in BALF. In addition, it was unclear how an elevated neutrophil count contributed to the increased mortali~ Biopsy analysis failed to show differences in pathologic severity between those with and those without BAL neutrophilia. 7 Because of these discrepancies, we studied the relationship between BAL neutrophilia, protein concentration, morbidity, and mortality in PCE We were careful to exclude those patients with concomitant pulmonary infections. We find that an increase in the number of BA~ neutrophils is associated with an *From the Department of Medicine, St. LukeslRoosevelt Hospital Center, College of Physicians and Surgeons, Columbia University, New York. tCurrently in the Division of Critical Care Medicine, University of California, Irvine. Manuscript received July 8; revision accepted October 10. Reprint requests: Dr. Eden, 126 wm 60th Street, New York City
10023
had more severe respiratory compromise and greater morbidity than the group with PCP and a low neutrophil count. Mortality rate was not different. The group showing a high BALF neutrophil count also showed a higher HALF protein concentration, a higher ratio of BALF protein concentration to plasma protein concentration, and the presence of as-globulins compared with other groups. The'se findings suggest that increased alveoJar..capillary permeability occurs during severe PCP. (Chat 1992; 102:63-69)
I
DS = dyspnea score
I
increased total alveolar protein and the presence of high-molecular-weight proteins. These changes correlate with the severity of disease and suggest the development of high alveolar epithelial permeability in some patients with severe PCE PATIENTS AND METHODS
Subjects
Between June 1989 and March 1990, 72 patients with risk factors for or known HIV infection whose pulmonary diagnosis was not apparent by clinical or other means underwent fiberoptic bronchoscop~
The diagnosis of PCP was made in 48 patients. Of these, five were excluded for improper mixing of lavage aliquots and two were excluded because of cytologic evidence for pulmonary cytomegalovirus (CMV) infection. The remaining 41 patients were divided into two groups based on the number of neutrophils (see below). At the time of bronchoscopy, 40 of 41 patients were receiving therapy or prophylaxis for PC}! No patients had clinical evidence of sepsis. Twenty-four patients did not have PC}! Of these, seven were excluded for the following reasons: presence of gross blood in BALF, lavage in segments other than right middle lobe or lingula, improper mixing of lavage returns, or positive bacterial cultures. One died of acute respiratory failure, and autopsy showed Toxoplasma and Staphylococcus aureus pneumonia without PC~ Of the 16 patients remaining after exclusion (group 1), four were diagnosed with pulmonary Kaposi's sarcoma and one with pulmonary lymphoma. No specific diagnosis was made in the 11 others. Bronchoscopy with BAL was also performed in a group of eight healthy, nonsmoking HIV-negative volunteers as part of an approved study. The severity of dyspnea on initial evaluation was determined and a dyspnea score (DS) was assigned: 0, no dyspnea; 1, dyspnea on exercise (climbing stairs, fast walk); 2, dyspnea with minimal exertion (dressing, shaving); 3, dyspnea at rest. Initial gasexchange was evaluated by admission arterial blood gas analysis performed CHEST I 102 I 1 I JUL'Y. 1992
83
Table I-DGta on BAL Cell AntJlpia Patients*
Total Cells, x 100/ml
Macrophages, x 10't/ml (%)
Lymphocytes, x 10't/ml(If,)
Neutropbils, x ~()'t/ml (if,)
Eosinopbils, x 10't/ml(,.)
Group I Group 2 Group 3
0.6±0.3t 0.3±0.2 0.4±O.3
375±277t (64±22) 182±IOB (61±19) 170± 116 (45± 19)
187± 117 (34±21) 124±II0 (37±18) 126± 140 (30± 14)
4±6 (O.8± 1.4) 4±5 (1.2±1.0) 84±79§ (21.6± 15.7)
3±9 (O.5± 1.2) 3±3 (1.1±1.4) 14±45 (2.1±4.2)
*Group I, AIDS without PCP; group 2, AIDS with PCP and BAL neutrophil <5,.; group 3, AIDS ~th tCompared with group 2: p
pcp and BAL neutrophil ~5".
with the patient breathing room air. Patients with a Pa0l s55 mm Hg generally received adjuvant corticosteroid therapy, but the final decision was made by the primary physician and based on the clinical evaluation. Other measured values included serum lactate dehydrogenase, serum albumin, and total protein.
to plasma protein (BALF/plasma) was calculated for each patient and expressed as a ratio x 100.5 The concentration of particular protein classes in BALF was obtained indirectly by multiplying the BALF protein eoncentradon by the percentage of each protein class as resolved by electrophoresis,
BAL and CeU Analysis
Statistics
Fiberoptic bronchoscopy was performed after ob~ng informed consent. Transbronchial biopsy, if obtained, was performed after BAL. Bronchial inJlammation was estimated by visual inspection of the segmental and subsegmental airways for erythema, secretions, and edema by two of the authors. The appearance was assigned a score as follows: 0, normal; I, mild bronchitis; 2, moderate bronchitis; 3, severe bronchitis. The bronchoscope was then wedged in either the right middle lobe or lingular subsegmental bronchus. Next, 150 ml of normal saline solution was instilled, in 5O-ml aliquots, and immediately aspirated with a syringe. The first aliquot of lavage was discarded. Lavage 8uid from the second and third aliquots was mixed and divided into aliquots for cytologic, bacteriologic, mycobacteriologic, and mycologic examination. Samples of lavage 8uid sent for bacterial analysis were cultured in enrichment broth as well as being plated directly on chocolate agar, MacConkey, CNA, blood, and anaerobic plates. The presence and identity of any bacterial colonies were reported. Specimens submitted for mycobacterial and fungal culture were centrifuged and the cell pellet plated. Cultures for 'CM·V or other viruses were not performed routinely. An aliquot of lavage 8uid was filtered through a layer of surgical gauze. The cell concentration was measured, and the sample was centrifuged at 400 g for 10 min. The cell pellet was resuspended in Hanks balanced salt solution. The cytospin slides were stained, and differential cell counts were performed.
All data are expressed as mean ± SD. Analysis of variance and Kruskal-Wallis 'test were used to compare multiple groups of normally distributed data and nonparametrie data, respectivel~
BALF Protein Analysis The concentration of protein was determined by the Lowry method." Protein electrophoresis on 80 to 100 times concentrated BALF was performed by the gel electrophoresis method. The BALF total protein concentration and as-globulins representing intermediate- to high-molecular-weight proteins (100,000820,000 daltons) were used as an index ~f alveolar-capillary membrane protein permeability. A concentration ratio of BALF protein
Further comparisons between each two groups were subject to Bonferroni correction.· Correlation between two variables was evaluated by Pearson correlation coefficient. Categorical data were compared' with a chi-square test. Dyspnea index and bronchitis index were analyzed by a method for assigned scores. lO Differences were considered sign~cant when p
lbtient Groups On the basis of differential cell counts, patients with PCP were divided into those showing <5 percent neutrophils (group 2) and those showing ~5 percent neutrophils (group 3). Of the 41 patients with PC~ 20 showed a neutrophil count of <5 percent, and 21 showed a neutrophil count ~5 percent. Group 'I comprised those patients with AIDS and lung disease but without peE Results of BAL cell analysis are shown in Table I, All 16 patients without PCf (group 1) had a B~L neutrophil count of <5 percent. The total cell concentration in BALF was higher in group 1 compared to group 2. The only difference in cell counts between groups 2 and 3 was a higher neutrophil count in the latter. The eosinophil count and proportion were increased' in group 3 but not significantly so. There were no significant- differences for age, sex, race, risk factors for AIDS, smoking history, or previ-
Table 2-Epitlerniologic ClaartJClBridica ofthe Study Population.
Group I (n = 16) Group 2 (n = 20) Group 3 (n = 21)
Age, yr
Sex, M:F (n)
Race, B:H:W (n)
37.8±8.2 35.3±6.6 38.3± 10.9
15:1 20:0 20:1
2:3:11 5:3:12 3:4:14
H:IVD:T (n)
Smolcing Status, C:E:N (n)
Prior pcp (n)
14:1:0 14:5:1 19:2:0
4:3:9 8:7:5 7:4:10
3 4 3
RF,
*B, black; H, Hispanic; ~ white; RF, risk factors; H, homosexual; IVD, intravenous drug user; T, transfusion; C, current smoker; E, exsmoker; and N, nonsmoker.
84
Con8IaIIon of ~ findings to 8eYertty of pcp
(Sadag~
Huang, Eden)
Table 3-RapirGtorfl MetJlUrementa No. of Patients with Dyspnea Scores Group 1 Group 2 Group 3
120
of 0:1:2:3
P(A-a)O., mmHg
PaO., mmHg
2:12:2:0 4:4:10:2 1:3:3:14*
35.3± 11.6 34.2± 19.2 54.6± 14.2*
83.0±14.6 77.7 ± 20.9 56.7±12.6*
*Compared with group 1 and 2: p
n=38
C;; J:
E
5 0
ous history of PCP among the three groups (Iable ~). More patients in group 1 were taking prophylaxis (nine cases), but no difference was found between groups 2 and 3 (five and four cases, respectively). In group 3, seven patients were receiving systemic corticosteroids in addition to standard therapy three to five days before bronchoscopy No patients in group 1 and only one in group 2 were treated With steroids. The BALli' neutrophilia or eosinophilia was not significantly different between the patients who received adjuvant corticosteroid therapy (17.9± 14.2 percent and 2.6 ± 6.3 percent, respectively) and those who did not (23.5 ± 16.6 percent and 2.0 ± 2.9 percent, respectively).
Clinical,- Laboratory, an4 Respiratory Data There were more cases with a higher DS in group 3 (lable 3). The PaO! was significantly lower, and the alveolar-arterial Po! gradient measured at air Flo! 0.21 was significantly higher in group 3 (Table 3). No difference was noted between groups 1 and 2. Serum total protein level was 6.6± 1.3, 7.1 ±O.9, and 6.4± 1.0 mwdl for the three groups, respectively Similarly, serum albumin value was 3.0 ± 0.7, 3.1±0.5, and 2.7±0.6 mg/ml, and serum lactate dehydrogenase level was 322 ± 122, 424 ± 250, and 514 ± 219 lUlL. There was' no significant difference between the three groups,
Bronchoscopic Data and Lavage CeU Population Because ofthe severity ofhypoxemia, bronchoscopy was performed later after admission in group 3 compared to group 1 (4.8±2.9 vs 2.6±2.6 days, p
r=-O.42 P
100
0
80
•
N
a...
60
• •• • •
40
• 20
• •
~-~_....L-_..-.I...._"""""'_---L_----I_----'
o
10
•
20
30
40
50
60
70
% of PMN in BALF FICURE 1. Correlation between PMN percentage in BALF and PaO. for AIDS patients with pcp (groups 2 and 3). PMN indicates polymorphonuclear cells (neutrophils + eosinopbils); BALF, bronehoalveolar lavage 8uid.
group 3 and group 2 (3.3 ± 2.5 days). The lavage recoveries among three groups (63 ± 6 percent, 56 ± 13 percent, and 52 ± 13 percent, p>O.05) were not significantly different. The number of cases assigned to a specific bronchitis index from 0 to 3 were 9:5:2:0 for group 1, 7:9:3:1 for group 2, and 4:13:3:0 for group 3. There was no significant difference among the three groups.
Protein Analysis in BALF The concentrations ofprotein and albumin in BALF and their ratios to concentrations in serum are shown in Table 4. Protein concentration in BALF of group 3 was significantly higher than in group 1 and group 2. There was no difference in albumin concentration among the three groups, so the proportion of albumin to total protein ill BALF fell in group 3. However, both protein and albumin concentrations in all three patient groups were higher than that of a normal population surveyed in o~ laboratory (Iable 4).
Table 4- Protein AntJlr/Bis of BALF*
Group 1 Group 2 Group 3 Normal (n =8)
BAL-[TP]
BAL-[Alb]
BAL-[TP], ..,glml
BAL-[Alb], ..,glml
Sernm-[TP]
Serum-[Alb]
392±174 320±187 630±355t* 71±84
204±99 151±93 236±127 39±51
0.5±0.2 0.5±0.3 1.0±0.5t* NA
0.6±0.2 0.5±0.3 0.9±0.5* NA
*Alb,' albumin concentration; n
BAL[CIt-Globulin], ~glml (n) ND
(0) 46 (1) 71±56 (9) ND (0)
total protein concentration; NA, not available; ND, not detectable; BAL-[TP]lserum-[TP] ratio, 100 x ~ALF protein concentration/serum protein concentration; BAL-[Alb]lsernm-[Alb] ratio, 100 x BALF albumin concentration/serum albumiD concentration. tCompared with group 1: p
85
2000
120 0 0
100
0
0
n=36 r=-O.50 P
0
.........
E
0
C;;
<,
5 0
80
--J
a..
a
........... u,
0
-c rn
N
0
1500
0" ::J
J:
E
n=38 r=O.60 P
1000
a
c:
60
a
0
Do O 0
c:
.Qj -+oJ
0
a.. ~
40
500
o
20
~_--'--_--L
o
250
_ _~ _ - - ' -
500
750
a
0
cO
o _ _" " - - - _ - J
1000
1250
1500
Protein in BALF (ug/ml)
O~-",,"--_..a..-_...I.-_---~---'---~
a
10
c 0
20
30
40
50
60
70
% of PMN in BALF
2. Correlation between protein concentration in BALF and
FICURE 3. Correlation between percent PMN count in BALF and total protein concentration in BALF for AIDS patients with pcp (groups 2 and 3).
The concentration ratio of BALF protein to serum protein in group 3 was significantly higher than in groups 1 and 2. The concentration ratio of BALF albumin to serum albumin in group 3 was significantly higher than in group 2. Protein electrophoresis of BALF showed the presence of as-globulin in nine of 19 specimens (47 percent) in group 3 (71 ± 56 JLglml) and only o~e of 19 (5 percent) in group 2 (46 ~glml). In group 3, the protein concentration in BALF showing detectable «t-globulln (655± 332 JLgI~l) was similar to that in BALF without detectable (l2-globulin (607 ± 390 p,glml). The same specimens that showed as-globulins also showed detectable levels of (1- and p-globulins. The ~-globulin was not detectable in group 1 or in a group of BALF samples from normal volunteers, Protein and albumin concentrations of patients who were receiving corticosteroids before bronchoscopy (protein: 6;)2 ± 593 JLWml, albumin: 268 ± 269 P,Wml) were not different from those in the rest ofthe patients in this group (protein: 615 ± 441 p,glml, albumin: 218 ±'127 JLglml). Two ofnine patients with detectable ~-globulins were receiving corticosteroids ·before bronchoscopy
percentage was used in the analyses (Pa02: r= -0.42, p
FICURE
initial PaOI (Flo. 0.21) for AIDS patients with pcp (groups 2 and
3).
Correlation of N~trophilia and 7btal Protein in BALF of pCP with Arterial Oxygenation Measurements For patients with PCP (groups 2 and 3), BAL neutrophil percentage was inversely related to Pa02 (r= -0.39, p
Follow-up Bronchoscopy Follow-up bronchoscopy (Iable 5) was performed in four patients in group 3. Two patients had bronchoscopy two weeks, one ten days, and the other three weeks after the first lavage. One of these patients had been receiving corticosteroid treatment, which was stopped three days prior to follow-up bronchoscopy As shown in Table 5, neutrophil and PMN percentages had fallen to a normal value in three patients. Protein concentration fell in three of the four patients. Comparison of electrophoresis was made in one patient (No.' SO). The first BALf showed the presence of Usglobulins, which could not be detected in the second BALF sample.
Outcomeand Mortality during the Acute Episodeof PCP Mortality during the acute episode was defined as the number of deaths during treatment for PCI! No patient in group 1
Huang, Eden)
Table 5-C~
~
Finltmtl Second BAL in Ibdenta tDitIa PCp·
DS
Neutrophil, %
n~wml
Patient No.
1st
2nd
1st
2nd
1st
2nd
40 41 42 50
2 3 0 3
0 0 0 0
18.8 17.7 5.8 39.4
0.5 13.9 0.6 0.6
219 383 NA 299
61 189 NA 107
~
total protein concentration; 1st, 6rst lavage; 2nd, second lavage; NA, not available.
respiratory failure. Respiratory status deteriorated in three other patients, and two of these required intubation. All three patients eventually improved. There was no significant difference in mortality among the three groups. DISCUSSION
Pneumocystis carinii pneumonia remains a major cause of morbidity and mortality in AIDS patients. Approximately 20 to 30 percent of patients with a first episode of PCP develop respiratory failure. A mortality of 30 percent was reported in earlier studies. 1.2 An alveolar-arterial oxygen gradient greater than 30 mm Hg and the degree of abnormality on initial chest roentgenograms were suggested as determinants of a poor prognosis. 1 Previous studies which examined cell differential counts in BALF of patients with AIDS and pcp have provided evidence for the role of the neutrophil as a prognostic factor of morbidity and/or mortality Smith et ale reported a small series of 19 patients with AIDS and PC~ Twelve of these patients with elevated neutrophil counts in BAL (>5 percent) had a higher P(A-a)02 (mean, 54.4 mm Hg). Four of 12 patients died of respiratory failure, but sputum cultures of three of them were positive for a bacterial pathogen. Although the mortality rate did not reach statistical significance, elevated neutrophil counts in BAL were associated with more severe respiratory compromise. Mason et al,? in a retrospective study of 60 patients with AIDS and PC~ reported 11 deaths (18 percent) among the 15 patients who developed respiratory failure. Fourteen of these 15 patients had an elevated (>5 percent) neutrophil count in BALF. Again, patients with a concomitant pulmonary infection were not excluded. We took care to exclude patients with PCP and an associated pulmonary infection which may increase neutrophil counts and contribute to mortality All lavage specimens were routinely cultured for bacteria on multiple media and in enrichment broth and were centrifuged before being cultured for fungal and mycobacterial organisms. Bronchoalveolar lavage is an excellent technique for the diagnosis of pulmonary infection, with sensitivities ranging from 74 to 93 percent,l1·12 and although we did not perform quanti-
tative cultures, we excluded all patients showing evidence of bacterial growth on culture. Our findings provide strong circumstantial evidence for a specific role of the alveolar neutrophil in the pathogenesis of respiratory failure in severe PC~ First, an elevated neutrophil count in BALF (~5 percent) correlated with greater dyspnea, more severe gas exchange abnormalities, and a greater morbidity. Second, a greater number of cells was present in the lavage fluid of AIDS patients without PCP and respiratory compromise than in patients with PC~ Furthermore, total cell counts were unrelated to the severity of PC~ This argues against any suggestion that the neutrophil is part of a general inHux of cells into the lung during PC}! Third, the first aliquot of BAL, which contains more airway neutrophils, was not used for cell analysis. Furthermore endobronchial evidence of bronchitis was not significantly different between those patients with high neutrophil counts in BALF and those without, which suggests that airway inflammation is not contributing to the observed increase in neutrophils. Fourth, in four patients, resolution of severe PCP was associated with a fall in the neutrophil count in alveolar lavage fluid. The influx of neutrophils into the lung in severe PCP was associated with increased total alveolar protein and this increase strongly correlates to gas exchange abnormalities. It could be argued that the increase in protein is a nonspecific indicator of pulmonary inflammation and originates as a product of pulmonary cells responding to infection. Indeed, protein concentration in BALF in patients with AIDS has previously been reported to be increased, although patients were not characterized according to the type of pulmonary disease." More recently, Phelps and Rosel3 reported increased concentrations of total protein albumin and high-molecular-weight proteins in BALF of AIDS patients with PC~ We confirm that total BALF protein and the BALF to serum protein concentration ratio are increased in all patient groups with AIDS and pulmonary disease. However, with respiratory compromise in severe PC~ BALF protein increases to approximately twice the value in patients with mild PCP and 1.5 times the value in patients with noninfectious lung disease. The ratio ofBALF to serum protein concentration is also greater in the CHEST I 102 I 1 I JUL'( 1992
87
group with severe PC~ These changes occur without a concomitant increase in total cell concentration and suggest an extrinsic source of the additional protein. The presence ofhlgh-molecular-weight <
barrier is compromised before the development of severe PCE With additional neutrophil influx, further loss of epithelial integrity occurs. Last, patients who develop ARDS do not respond to corticosteroids. Inhibition of mediator release from suppressor lymphocytes and alveolar macrophages by corticosteroids may reduce pulmonary inflammation and explain the salutary effects of these agents in patients with severe PCP and respiratory failure. Z4 It is noteworthy that nine of the 21 patients in group 3 received adjunctive corticosteroid therapy which probably reduced the observed mortality compared to earlier studies. I •1 Those patients started on corticosteroid therapy did not have more neutrophils or protein in BALF, and other factors are probably important in determining severity of respiratory compromise in PCE In conclusion, our study shows that a high neutrophil proportion in BALF correlates with increased morbidity and greater gas exchange abnormalities, and is associated with an increase of total protein and the presence of high-molecular-weight proteins in the alveolar space. These abnormalities improve as the PCP resolves. We believe the findings are consistent with the development of high-permeability pulmonary edema in some patients with PCP in which the neutrophil plays an important but not exclusive role. ACKNOWLEDGMENTS: The authors wish to thank Dr. J. Bhattacharya for his helpful comments and the technical staff in the clinical chemistry laboratory at the Roosevelt Site.
REFERENCES 1 Murray JF, Felton C~ Garay SM, Gottlieb MS, Hopewell PC, Stover DE, et al. Pulmonary complications of the acquired immunodeficiency syndrome. N Engl J Med 1984; 310:1682-88 2 Brenner M, Ognibene F~ Lack EE, Simmons JT, Std£redini AF, Lane HC, et al. Prognostic factors and life expectancy of patients with acquired immunodeficiency syndrome and PneumocystiBcarinii pneumonia. Am Rev Respir Dis 1987; 136:11991206 3 White DA, Gellene RA, Gupta S, Cunningham-Rundles C, Stover DE. Pulmonary cell populations in the immunooompromised patient. Chest 1985;88:352-59 4 Venet A, Dennewald G, Sandron D, Stern M, Jaobert F, Leibowitch J. Bronchoalveolar lavage in acquired immunodeficiency syndrome [letter to the editor]. Lancet 1983; 2:53 5 Young KR Jr, Ran1dn RA, Noegel G~ Paul ES, Reyolds HY. Bronchoalveolar lavage cells and protein in patients with the acquired immunodeficiency syndrome. Ann Intern Med 1985;
103:522-33
6 Smith RL, EI-Sadr WM, Lewis ML. Correlation ofbronchoalveolar lavage cell populations with clinical severity of PneumocyBtis carinii pneumonia. Chest 1988; 92:60-64 7 Mason GI: Hashimoto CH, Dickman PS, Foutty LF, Cobb CJ. Prognostic implications of bronchoalveolar lavage neutrophilia in patients with Pneumocy8ti8 carini' pneumonia and AIDS. Am Rev Respir Dis 1989; 139:1336-42 8 Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Bioi Chern 1951;
193:265-75 9 Glantz SA. Primer of biostatistics. New York: McGraw-Hill Book Company, 1981
Con8Idon of BALfindings to Se\wiIy of pcp (Sadaghdc Huang, Eden)
10 Snedecor G~ Cochran WG. Statistical methods, 7th ed. Ames, Iowa: Iowa State University Press, 1980 11 Johanson WG Jr, Seidenfeld JJ, Gomez ~ Santos BDL, Coalson JJ. Bacteriologic diagnosis of nosocomial pneumonia following prolonged mechanical ventilation. Am Rev Respir Dis· 1988; 137:259-64 12 Pugin J, Auckenthaler R, Mili N, Janssens J~ Lew PD, Suter PM. Diagnosis of ventilato~associated pneumonia by bacteriologic analysis of bronchoscopic and nonbronchoscopic "blind" broncboalveolar lavage Suid. Am RevBespir Dis 1991; 143:112129
13 Phelps DS, Bose RM. Increased recovery of surfactant protein A in AIDS related pneumonia. Am Rev Bespir Dis 1991; 143: 1072-75 14 Tate RM, Repine JE. Neutrophils and the adult respiratory distress syndrome. Am Rev Respir Dis 1983; 128:552-59 15 Weiland JE, Davis WB, Holter JF, Mohammed JR, Dorinsky PM, Gadek JE. Lung neutrophils in the adult respiratory distress syndrome. Am Rev Respir Dis 1986; 133:218-25 16 Rinaldo JE, Rogers RM. Adult respiratory distress syndrome: cbaogingconcepts of lunginjury and repair. N Engi J Med 1982;
300:900-09
17 McGuire ~ Spragg RD, Cohen AM, Cochrane CG. Studies on the pathogenesis of the adult respiratory distress syndrome. J Clio Invest 1982; 69:543-53 18 Fox RB, Hoidal JR, Brown DM, Repine JE. Pulmonary inftam-
19
20
21
22 23
24
mation due to oxygen toxicity: involvement of chemotactic factors and polymorphonuclear leukocytes. Am Rev Respir Dis 1981; 123:521-23 Sbasby DM, Fox RB, Hanada RN, Repine JE. Reduction of the edema of acute hyperoxic lung injury by granulocyte depletion. J Appl Physioll982; 52:1237-44 Holter JF, Weiland JE, Pacht ER, Gadek JE, Davis B. Protein permeability in the adult respiratory distress syndrome: loss of size selectivity of the alveolar epithelium. J Clin Invest 1986; 78:1513-22 Gelb AF, Klein E. Hemodynamic and alveolar protein studies in noncardiac pulmonary edema. Am Rev Respir Dis 1976; 114:831-35 Fein A, Grossman RF, Jones JG, Overland E, Pitts L, Murray JF, et ale The value of edema Buid protein measurement in patients with pulmonary edema. Am J Med 1979; 67:32-8 Meignan M, Gullion J, Denis M, Joly ~ Rosso J, Carette MF, et ale Increased lung epithelial permeability in "IV-infected patients with isolated cytotoxic T-Iymphocytic alveolitis. Am Rev Respir Dis 1990; 141:1241-48 Bozzette SA, Sattler FR, Chiu J, Wu AW, Gluckstein 0, Kemper C, et ale A controlled trial of early adjunctive treatment with corticosteroid for Pneumocystis carinii pneumonia in the acquired immunode6ciency syndrome. N Engl J Med 1990; 323:1451-57
15th Annual OCcupational safety and Health Summer
Institute
North Carolina Occupational Safety and Health Educational Resource Center at the University of North Carolina will sponsor this program in Williamsburg, Virginia, August 1014. For information, contact NCOSHEducational Research Center, University of North Carolina, 109 Conner Drive, Suite 1101, Chapel Hill 27514 (919:962-2101).
CHEST I 102 I 1 I JUL~
1992
89