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The continuing utility of bronchoalveolar lavage to diagnose opportunistic infection in AIDS patients
The Continuing Utility of Bronchoalveolar Lavage to Diagnose Opportunistic Infection in AIDS Patients Robert P. Baughman, MD, Michael N. Dohn, MD, Peter T. Frame, MD, Cincinnati, Ohio PURPOSE: To determine whether bronchoalveolar lavage (BAL) remains a useful technique in assessing human immunodeficiency virus (HIV)infected patients with pulmonary symptoms. PATIENTS AND METHODS:All HIV-infected patients with pulmonary symptoms referred to a university hospital-based pulmonary service underwent bronchoscopy and BAL within 24 hours of referral. All samples were handled in a standardized fashion. The results of the lavage were compared with chest roentgenograms and clinical results. RESULTS:A total of 894 lavages were performed on HIV-infected patients over a 7-year period. The overall diagnostic yield was 60%, with 420 patients having Pneumocystis carinii. Infections other than P carinii were found in 185 cases, including 75 lavages with P carinii and another infection. The other infections included Mycobacterium tuberculosis (17 patients), Mycobacterium kansasii (15 patients), Histoplasma capsulatum (24 patients), Cryptococcus neoformans (17 patients), and bacterial infection (103 patients). For 364 lavages, no diagnosis was made. Chest roentgenograms were not useful in predicting what infection would be diagnosed. There was no difference in the yield of BAL over the 7-year period, despite the introduction of aerosol pentamidine prophylaxis and antiretroviral therapy. CONCLUSION:Bronchoscopy with BAL continues to have a role in the evaluation of HIV-infected patients with pulmonary symptoms.
M
ethods of diagnosing the cause of pneumonia in human immunodeficiency virus. (HIV)-infected patients have been widely studied in the past 10 years.1-4 These studies have demonstrated that Pneumocystis carinii is a common infection in the HIV-infected patient, that bronchoscopy with bronchoalveolar lavage (BAL) has good sensitivity for diagnosing P carinii pneumonia, and that bronchoFrom the Department
of Medicine,
University
of Cincinnati Medical
scopy is well tolerated by the patient. However, there remain several issues unresolved in the management of the HIV-infected patient with diffuse lung infiltrates. Induced sputum has been shown to be diagnostic of P carinii in many patients.5-7 The sensitivity of sputum can be enhanced by the use of immunofluorescent stains of the sputum specimen. BAL may be unnecessary in some patients because a simpler, less costly measure can be used to diagnose P car&ii pneumonia. With the widespread problems with P car&ii pneumonia, physicians have used various forms of prophylaxis therapy to prevent it. That has resulted in a lower incidence of the pneumonia in HIV-infected patients.*-lo For patients taking aerosol pentamidine prophylaxis, there is a reduced but still present risk of developing P carinii pneumonia. In studying patients on pentamidine prophylaxis who develop the pneumonia, it has been found that they have more atypical presentations, and at least one study suggested BAL alone may not be sufficient to diagnose P car&ii pneumonia.ll BAL sensitivity may be enhanced by performing lavage in two or more regions in the lung.12-15 As patients with HIV infection live longer, it is not uncommon for them to develop other treatable pulmonary infections besides P car&ii. It has been recognized that HIV-infected patients are at risk for developing other pulmonary infections, including Mycobacterium tuberculosis, deep-seated fungal infections, and bacterial pneumonias.” Bronchoscopy with BAL directed to the area of pulmonary infiltrate may still provide useful information in evaluating pulmonary infiltrates in HIV-infected patients. 12-15We have used bronchoscopy as the major method to diagnose pulmonary infections in HIV patients for over 7 years, with all patients undergoing lavage. Lavage was examined for P carinii, mycobacterial, fungal, bacterial, and viral infection in all cases. We have found that the use of BAL significantly enhances our understanding of the cause of pulmonary infiltrates in the HIV-infected patient. By using BAL, more than 20% of our patients were found to have pulmonary pathogens associated with active disease beyond P carinii.
METHODS MD, 231 Bethesda Avenue, Cincinnati, Ohio 45267.0564. Manuscript submitted November 23, 1993 and accepted
In revised
On January 1, 1985, we instituted a standardized policy of handling all HIV-infected patients referred to the pulmonary service for evaluation of cough, December 1994 The AmericanJournal of Medicine@Volume 97
515
PC ALONE 345
PC + ANOTHER
ORGANISM 75
ANOTHER
ORGANISM 110
NO DIAGNOSIS 364
fever, shortness of breath, or new or worsening pulmonary infiltrates. l6 All patients un d er-went clinical evaluation and bronchoscopy with BAL within 24 hours of referral to the pulmonary service. Patients were not referred for evaluation if their overall condition was considered terminal. Only 9 patients who did not have a definitive diagnosis of P car&ii were treated with empiric anti-P carinii therapy. The recording of information and standard handling of the BAL specimen followed a protocol approved by our Institutional Review Board. At the time of bronchoscopy, the chest roentgenogram was evaluated and the pattern was scored as diffuse, localized (less than two-lobe involvement or a single mass), or normal. A patient with a pleural effusion and otherwise clear lung fields was considered to have a normal lung pattern. Bronchoscopy and lavage was performed in a standardized manner, with either RPB or MND performing the bronchoscopy for more than 95% of patients. Flexible fiberoptic bronchoscopy was done and all airways were examined. BAL with 120 mL to 240 mL was performed in the area leading to the infiltrate, using our previously described technique.l” In patients with diffuse infiltrates, lavage was performed in either the right middle lobe or left lingula. Starting in November 1989, patients underwent dual lavages of both the apical segment and the right middle or left lingular area, as previously described.13 This was not done in the few patients whose respiratory status was considered marginal. In those cases, lavage was only done in the area with the most infiltrate. 516
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Figure 1. The number of bronchoalveolar IaGge procedures demonstrating diagnosis of Pneumocystis carinii (PC)alone, P carinii in combination with another organism, another organism alone, or no diagnosis by lavage.
BAL specimens were all handled in the same way. Aliquots were sent for mycobacterial smear and culture, fungal culture, cryptococcal antigen, cytologic examination using both Papanicolaou and methenamine silver stain, cytomegalovirus culture, herpes culture, legionella culture, and bacterial culture. Bacterial culture was done using a semiquantitative method similar to that used for urine and the results were reported in colony-forming units (cfu) per milliliter of BAL fluid. Using a quantitative loop, 0.01 mL of the unprocessed BAL fluid was directly applied onto each of four culture media: sheep’s blood agar, MacConkey’s agar, CNA agar (blood agar that contains colistin and nalidixic acid), and chocolate blood agar In addition, cytocentrifuge-prepared slides using 100 pL to 200 pL of unconcentrated BAL specimen were made. These were stained with a modified Wright-Giemsa stain (Diff-Quik, McGaw Park, Illinois). A differential count was performed of all nucleated cells.17 The following criteria were used to determine whether the bronchoscopy was diagnostic. Patients were felt to have P car&ii if the pathogen was identified using silver stain. Mycobacterial infections were all confirmed by culture and only patients with either M tuberculosis or Myobacterium kansasii were felt to have significant mycobacterial infection.l* Patients in whom Mycobacterium avium-intracellulare alone was isolated were not felt to have a diagnostic bronchoscopy. Fungal infections were all confirmed by culture.1s Patients were felt to have deep-seated fungal infection if Histoplasma capsulatum, Cryptococcus neoforrnans, or Coccidioides immitis were 97
BRONCHOALVEOLAR
/
n
PNEUM~CY~T~S
”
1985
ALONE FZIPNEUMOCYSTIS
1986
1987
1938
+ OTHER
1989
1990
q
o~-~ERAL~NE
1991
!SINO DIAGNOSIS
1992
I
identified. Patients in whom Candida or Aspergillus organisms were identified were not felt to have diagnostic bronchoscopy. Bacterial infections were diagnosed on the basis of the semiquantitative culture re,~ults.~~J~For a bacterial infection to be diagnostic, the bacteria had to be >lO,OOO cfu/mL of BAL fluid. Patients who grew either Nocardia or Rhodococcus organisms were felt to be infected, regardless of the quantity. Although viral cultures were performed, we did not use the results of viral culture as diagnostic for infection. Patients with cytopathic changes consistent with CMV infection and positive cultures were considered to have ClMV pneumonia.20 The results of all bronchoscopies were recorded into a database (DataEase, DataEase International, Trumbull, Connecticut), which also included the chest roentgenogram pattern and cytologic, microbiologic, viral, and fungal culture results.
RESULTS A total of 894 patients underwent bronchoscopy with BAL during the ‘i-year period. Figure 1 and Table I summarize the BAL results for all patients. As can be seen, P curirzii was the most common diagnosis encountered. In patients with P carinii pneumonia, 18% (75 of 420) also had an additional diagnosis determined by the BAL. They included patients with fungal infections, mycobacterial infection, bacterial infections, and cytomegalovirus. An additional 12% of the patients were diagnosed as having pneumonia with no evidence of P catinii. The most common alternative diagnosis was bacterial pneumonia, although a significant number of patients had fungal or mycobacterial infection.
ET AL
/
TOTAL
YEAR
LAVAGE IN AIDS/BAUGHMAN
Figure 2. The relative yield per year for Pneumocystis carinii alone, P carinii plus other organism, another organism alone, or no diagnosis. There was no difference in the relative yields over the 7 years of the study.
TABLE I Results of Bronchoalveolar Yield in AIDS Patients Diagnosis Number Percent All Pneumocystis 420 47 PC alone 345 39 PC + fungal 12 PC + Mylobacterium tuberculosis k.2 PC + Mylobacterium kansasii 6’ 0.6 PC + bacterial 36 4 PC + bacterial + fungal 2 0.2 PC + bacterial + CMV* 1 0.1 PC + CMV 16 2 Another diagnosis 110 12 Bacterial 54 6 Bacterial + MTB 2 0.2 Bacterial + MTB + CMV 1 0.1 Bacterial + CMV 0.2 Fungal 2: 3 Fungal + bacterial 2 0.2 MTB 12 1 M kansasii 9 1 No diagnosis 364 41 ‘CMV positive only if cytology positive. PC = P carinii; CMV = cytomegalovirus;MTB = M tuberculosis.
During
the 7-year period, 420 episodes of P pneumonia were diagnosed by bronchoscopy. An additional 4 patients were diagnosed by follow-up evaluation, including 2 open-lung biopsies and 2 transbronchial biopsies. As noted above, empiric therapy for P carinii pneumonia was rarely given, so that our overall sensitivity for P carinii pneumonia was more than 95%. Of the 894 bronchoscopies, 497 (56%) had dual lavages, that is, lavages in both the upper and middle lobe or lingula. Of the 420 episodes of P carinii, car&ii
December 1994 The American Journal of Medicine@ Volume 97
517
CAUSE OF PNEUMONIA
n q
P~Eurdoc~sT~s
m TUBERCULOSIS
BACTERIAL
q
0 FUNGAL
NO DIAGNOSIS
801
I
DIFFUSE
LOCALIZED
ROENTGENOGRAPHIC
NORMAL PATTERN
218 (52%) were diagnosed by the dual lavage technique. We have previously reported our experience of dual lavages over a g-month period, which is included in this study.13 Our evaluation of the dual lavage uses a modified Wright-Giemsa stain to examine the individual lobe lavage results.13 This stain is less sensitiive than the methenamine silver stain used to examine the combined BAL fluid analyzed in this study,21 and in no case was P carinii found in the modified Wright-Giemsa stain and not confirmed by the methenamine silver stain. Of the 218 patients found to have P carinii by the dual lavage method, 11 did not have any P car&A seen in the middle lobe and 1 did not have any P car&ii seen in the upper lobe. Of these 12 (6%) patients, 10 were on aerosol pentamidine prophylaxis. Shown in Figure 2 is the yearly yield for P carinii alone, P carinii plus another pathogen, another pathogen alone, or no diagnosis over the 7-year period. There was no consistent pattern of diagnostic yield, despite changes of therapy during this time, including the widespread introduction of anti-HIV therapy and P car&ii prophylaxis (chi-square analysis, P >0.05). The chest roentgenographic pattern of diffuse, localized, or normal was seen in more than 90% of patients. Figure 3 compares the roentgenographic pattern for the various types of pneumonia diagnosed by BAL (P carinii, mycobacterial, fungal, and bacterial) versus the pattern seen when no diagnosis was made. Only those patients with a single 518
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Figure 3. The chest roentgenographic appearance associated with a diagnosis of Pneumocystis carinii, tuberculous, fungal, and bacterial pneumonia compared with no diagnosis by bronchoalveolar lavage.
pathogen identified were included in this analysis. Those patients with a diffuse pattern were more likely to have a diagnostic bronchoscopy (chi-square = 20.1, P
BRONCHOALVEOLAR
Granulomatous
Infections Identified Number of Cases Mycobacterium’ 32 M tuberculosis 17 M kansasii 15 Fungal 46 Histoplasmosis 24 Cryptococcosis 17 Coccidioidomycosis 5 *Not including Mycobacterium
I”“”
by Bronchoscopy Number With Pneumocystis 8 2 6 13 5 8 0
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ET AL
Bacterial Infections Diagnosed in HIV-Infected Patients Undergoing Broncloalveolar Lavage
avium-intraceffulare.
quently identified our first AIDS patient with Legionella pneumonia. We have used bronchoscopy with lavage to diagnose Legionella in several nonHIV-infected patients during the same time. Also shown in Table III is the frequency of the various pathogens identified by BAL. The most common organism encountered was Haemophilus inji’uenzae. The second most common isolate was alpha streptococcus, which may be associated with other mouth flora, including anaerobic organisms. Anaerobic cultures were not performed on the BAL fluid. A significant number of patients had other pulmonary pathogens, including S. pneumoniae and gram-negative rods. The gram-negative enteric pathogens were usually encountered in either neutropenic patients or patients on mechanical ventilation. We have included the number of patients with >lOO,OOOcfu/mL BAL isolates as well as those with >lO,OOO cfu/mL of BAL isolates. There have been several articles demonstrating that > 100,000 cfu/mL of BAL is a more specific criteria for identifying bacterial pneumonia.16J2-z3 However, a recent consensus conference recommended using the >lO,OOO cfu/mL of BAL cut-off point.lg Since all patients in this study had pulmonary signs and symptoms suggestive of lower respiratory tract infection, we used the criteria of >lO,OOOcfu/mL of BAL. In order to determine the effect of prior antibiotics on the bacterial cultures of BAL, we compared the lavage cultures to antibacterial antitiobitcs. Table IV summarizes the various groups. We did’ not include
> 100,000
Organism cfu/mL Haemophilus influenza 12 Alpha Streptococcus 4 Streptococcus pneumoniae 4 Staphylococcus aureus 4 Moraxella [Branhamellal 1 catarrhalis Gram-negative rods 5 Pseudomonas aeruginosa 4 Klebsiella pneumoniae :, Escherichia coli Proteus morabilus 0 Rhodococcus equini 3 Nocardia’ 2 Total 35
10b,000
cfu/mL 21 20
>10,000 cfu/mL 33 24 13
7 8 4 : 1
67
13 8 2 2 1 3 2 102
‘These organisms not quantitated. cfu = colony-forming units.
antiviral or anti-P carinii therapy as prior antibiotics. Patients who were receiving trimethoprimkulfamethoxazole for prophylaxis were not considered to be on antibiotics for this episode, since they had been on chronic suppressive therapy at the time they developed new pulmonary symptoms. Included in Table IV are patients on intravenous antibiotics. Although there was a trend for those patients with higher number of bacteria not to be on any antibiotics, the difference was not significant (&i-square, P >0.05). About 90% of the patients were not on any antibiotics at the time of the bronchoscopy. We have analyzed patients who had cytopathic changes consistent with CMV. However, since the presence of CMY in the lung does not clearly Cause pulmonary disease,24J5 we have chosen not to consider those instances where CMY occurred alone as a diagnostic bronchoscopy. We have excluded from our overall diagnostic yield the 21 patients in whom the only diagnosis was cytopathic changes due to C&IV, although these patients were sometimes treated for their CMV pneumonia by their attending physician. We also identified 21 patients who had
TABLE IV Effect of Antibiotic Bacteria Recovered (cfu/mL) >100,000 10,000-100,000 l,OOO-10,000
Therapy on Semiquantitative Total Number of Patients’ 30 67 116 676
Bacterial Cultures from Broncloalveolar Lavage’ Number of Patients Number of Patients on on Antibiotics Intravenous Antibiotics? 2 (7%) 0 (0%) 8 (12%) 2 (3%) 9 (8%) 2 (2%) 90 (13%) 35 (5%)
*Patients with Nocardia and Rhodococcus excluded from analysis. *Anti-viral or anti-Pneumocystis carinii prophylaxis not considered. cfu = colony-forming units.
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herpes simplex virus recovered from the BAL specimen. Fourteen of these eases also had P carinii infection. It is not clear whether these patients had disease due to herpes in the lung. We therefore considered the isolation of herpes of no diagnostic significance.
shown that lavage directed to the area of most infiltrate, especially to the apical segments of the lung, has a higher yield for P car&ii. It appears that dual lavages, especially to the upper lobes, result in a better diagnostic yield. 12-14,2g In the current study, dual lavages were done in more than half of our patients. We have previously demonstrated more P car&ii in COMMENTS the upper lobes than middle lobes, whether or not The identification of the causative agent of pul- the patient was on aerosol pentamidine.13 Of the 12 monary symptoms in the HIV-infected patient still patients who had P car&ii seen in only only one remains important. The proper approach to these pa- lobe, 10 were on aerosol pentamidine. During this tients remains unclear. In the current study, we ex- study period, there were 4 cases of P catinii pneuamined the use of BAL in diagnosing pneumonia. We monia documented in patients who had a negative found the overall yield by BAL was 60%, with 47% BAL, for an overall sensitivity of BAL greater than overall having P carinii and 20% of patients having 95%, similar to previous studies.la2 an organism in addition to or instead of P car&ii. The diagnosis of mycobacterial infections has been increasing over the past several years in both This study demonstrates that P carinii represents the most common pulmonary pathogen identified in the HIV-infected and non-HIV-infected populapatients with HIV infection and respiratory symp- tions.30 In this study, we found a significant number toms. This has been noted by others.le4 The wideof both M tuberculosis and M kansasii infections. spread use of prophylactic agents has made P qlthough 1M kansasii infection is seen in non-HIVcatinii infections less frequent and apparently infected patients in our area, &f tuberculosis is 10 milder than in the past.8-12 times more frequent than M kansasii in the impatient (Robert Loudon, MB, ChB, Although P car&ii was seen frequently, most pa- munocompetent tients had either negative bronchoscopy results or a personal communication, May 1994). Interestingly, pathogen other than or in addition to P car&ii iden- 25% of our patients with mycobacterial infection tified. Only 9 patients were treated after the bronalso had P carinii infection. choscopy with empiric anti-P carinii therapy and Fungal infections, including histoplasmosis and only an additional 4 patients were subsequently cryptococcal infection, were seen in 5% of patients. found to have P carinii pneumonia. Our study would Although some of these patients may have been disuggest that empiric use of anti-P car&ii antibiotics agnosed by alternative means, BAL represented a would be incomplete or ineffective therapy in more specific and first diagnosis in the majority of pathan half of HIV patients with pulmonary symptoms. tients. We have previously reported on the use of The use of sputum induction to diagnose P carinii measurement of cryptococcal antigen in the BAL for infection has been stressed in the recent literature.5rapid diagnosis of cryptococci,31 but we did not use 7 Although it is a less costly technique, it is not clear the cryptococcal antigen test in this study. that it is an effective method of diagnosis at all cenBacterial pathogens were the second most comters.26 Some institutions have had difficulty in get- monly identified cause of respiratory symptoms in ting reasonable samples for staining and the overall our patients. The use of semiquantitative cultures to yield for sputum induction has varied greatly, from diagnose pneumonia has been used by us and by othas low as 20% to as high as 90% of patients who are ers for some time.16,22s23The major controversies resubsequently proven to have P carinii pneumonia.5garding its use revolve around the effect of prior an7a27The yield for sputum induction can be enhanced tibiotics and what is an appropriate level of bacterial by the use of liquification of the specimen,28 by mongrowth that distinguishes between infection and coloclonal antibodies against P car&ii to enhance de- onization. The majority of patients in this study were tection5 and by a laboratory dedicated overall to the seen as outpatients and not heavily treated with andiagnosis of P carinii in sputum. tibiotics prior to bronchoscopy. We have chosen to Another issue has been the fact that aerosol pen- use the >lO,OOOcfu/mL of BAL as the criteria for ditamidine may affect the number of organisms and agnosis, since this cutoff was suggested by a conthe presentation of P carinii pneumonia. In a study sensus conference.lg We provide the number of paby Jules-Elysee et al, l1 diagnosis of P car&ii pneu- tients with >lOO,OOOcfu/mL of BAL, which provides monia by BAL was reduced to 60% in patients re- information not significantly different from the ceiving aerosol pentamidine prophylaxis. That group >lO,OOOcfu/mL criteria. subsequently reported a higher yield for BAL if The most common bacteria isolated were H inlavage was performed in two areas of the lung.15 fluenzae, streptococcal species, and staphylococci. More recently, several groups, including ours, have These results are similar to other reports.3234 Patients 520
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did not routinely undergo blood cultures at the time of bronehoscopy, so the incidence of bacteremia is not available. Others have noted an increased incidence of septicemia in HIV-infected patients with pneumococcal pneumonia.35 Gram-negative bacteria were found in some patients, usually in the setting of hospital-acquired pneumonia or with leukopenic patients. The role of viral infections in causing pulmonary disease in HIV-infected patients is unclear.24~25 Cytomegalovirus may be present in the lower respiratory tract without any associated disease. The finding of cytopathic changes due to CMV does represent more clear-cut disease, but again it is not clear that this needs to be treated. Herpes simplex virus has been recovered from the lower respiratory tract in patients with adult respiratory distress syndrome and no specific therapy seems warranted.36 It is unclear if it has any role in HIV infection. In an analysis of our own patients, we could not detect any disease specifically due to herpes simplex and there was no apparent effect of antiviral therapy. It should be noted that there was a 21% incidence of significant infection in addition to the P car&ii found in the BAL fluid. These other organisms included bacterial, mycobacterial, and fungal infections. Sputum induction alone used to evaluate HIVinfected patients with pulmonary symptoms would have missed many of these additional infections. Although mycobacterial infections may be detectable in sputum (if, in fact, a specimen would be sent for smear and culture), fungal infections are rarely diagnosed by sputum examination and culture. This study did not examine the utility of identifying CMV or M aviuna-intracellulare infections. However, both could be useful information in certain settings. Positive CMV cytology alone in the absence of other explanations for symptoms and findings was treated with antiviral therapy and clinical improvement was seen in some patients. The finding of 1M avium-intracellulare in the BAL fluid was sometimes its first isolation from a patient, and had an impact on therapy. In that situation, further investigation for systemic M avium-intracellulare infection was begun and the patient may have been given therapy. We conclude that BAL still has a role in the evaluation of HIV-infected patients with new pulmonary symptoms. The changing therapeutic practices and diagnostic procedures over the past 7 years have had many effects on the HIV-infected population. Many pathogens other than P carinii were present in the lower respiratory tract.
REFERENCES 1. Broaddus C, Dake MD, Stulbarg MS, et al. Bronchoalveolar lavage and transbronchial biopsy for the diagnosis of pulmonary Infections in the acquired immunodeficiency syndrome. Ann Intern Med. 1985;102:747-752. December
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2. Murray JF, Garay SM, Hopewell PC, et al. Pulmonary complications of the acquired immunodeficiency syndrome: an update: report of the second National Heart, Lung and Blood Institute Workshop. Am Rev Respir Dis. 1987;135:504-509, 3. Golden JA, Hollander H, Stulbarg MS, Gamsu G. Bronchoalveolar lavage as the exclusive diagnostic modality for Pneumocystis carinii pneumonia: a prospective study among patients with acqurred immunodeflciency syndrome. Chest. 1986;90:18-22. 4. Gal AA, Klatt EC, Koss MN, et al. The effectiveness of bronchoscopy in the diagnosis of Pneumocystis carini and cytomegalovirus pulmonary infections in acquired immunodeficiency syndrome. Arch Pathol lab Med. 1987;lll: 238-241. 5. Kovacs JA, Ng VL, Masur H, et al. Diagnosis of Pneumocystis carinii pneumonia: improved detection in sputum with use of monoclonal antibodies. NEJM. 1988;318:589-593. 6. Pitchenik AE, Ganlel P, Torres A, et al. Sputum examination for the diagnosis of Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. Am Rev Respir Dis. 1986;133:226-229. 7. Bigby TD, Margolskee D, Curtis JL, et al. The usefulness of induced sputum in the diagnosis of immunodeficiency syndrome. Am Rev Respir Dis. 1986;133:515-518. 8. Montaner JSG, Lawson LM, Gervais A, et al. Aerosol pentamidine for secondary prophylaxis of AIDS-related Pneumocystis carinii pneumonia: a randomized, placebo-controlled study. Ann lnlern Med. 1991;114:948-953. 9. Leoung GS, Feigal DW, Montgomery AB, et al. Aerosolized pentamidine for prophylaxis against Pneumocystis carinii pneumonia: the San Francisco community prophylaxis trial. NEJM. 1990;323:769-775. 10. Schneider MME, Hoepelman AIM, Schattenkerk JKME, et al. A controlled trial of aerosolized pentamidine or trimethoprim-sulfamethoxazole as primary prophylaxis against Pneumocystis carinii pneumonia in patients with human immunodeficiency virus infection. NEJM. 1992;327:1836-1841. 11. Jules-Elysee KM, Stover DE, Zaman MB, et al. Aerosollzed pentamidlne: effect on diagnosis and presentation of Pneumocystis carinii pneumonia. Ann Intern Med. 1990;112:750-757, 12. Levine SJ, Masur H, Gill VJ, et al. Effect of aerosolized pentamidine prophylaxis on the diagnosis of Pneumocystis carinii pneumonia by induced sputum examination in patients infected with the human lmmunodeficiency virus. Am Rev Respir Dis. 1991;144:760-764. 13. Baughman RP, Dohn MN, Shipley R, et al. Increased Pneumocystis carinii recovery from the upper lobes in pneumocystis pneumonia: the effect of aerosol pentamidine prophylaxis. Chest. 1993;103:426-432, 14. Yung RC, Weinacker AB, Steiger DJ, et al. Upper and middle lobe bronchoalveolar lavage to diagnose Pneumocystis carinii pneumonia. Am Rev Aespir Dis. 1993;148:1563-1566. 15. Meduri GU, Stover DE, Green0 RA, et al. Bilateral bronchoalveolar lavage in the diagnosis of opportunistic pulmonary infections. Chest. 1991;lOO: 1272-1276. 16. Thorpe JE, Baughman RP, Frame PT, et al. Bronchoalveolar lavage in diagnosing acute bacterial pneumonia. J infect Dis. 1987;155:855-862. 17. Baughman RP, Strohofer S, Kim CK. Variation of differential cell counts of bronchoalveolar lavage fluid. Arch Pathol Lab Med. 1986;110:341-343. 18. Baughman RP, Dohn MN, Loudon RG, Frame PT. Bronchoscopy with bronchoalveolar lavage in tuberculosis and fungai infections. Chest. 1991;99:92-97. 19. Meduri GU, Johanson WG. International Consensus Conference: clinical investigation of ventilator-associated pneumonia. Chest. 1992;102: 5515-588s. 20. Craighead JE. Pulmonary cytomegalovirus in the adult. Am J Pathol. 1971;63:487-499. 21. Baughman RP, Strohofer SS, Clinton BA, et al. The use of an indirect fluorescent antibody test fordetecting Pneumocystis carinii. Arch Pathol Lab Med. 1989;113:1062-1065. 22. Meduri GU, Beals DH, Maijub AG, Baselski V. Protected bronchoalveolar lavage: a new bronchoscopic technique to retrieve uncontaminated distal airway secretions. Am Rev Respir Dis. 1991;143:855-864. 23. Kahn FW, Jones JM. Diagnosing bacterial respiratory infectlon by bronchoalveolar lavage. J Infect Dis. 1987;155:862-869. 1994
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24. Miles PR, Baughman RP, Linnemann CC. Cytomegalovirus in the bronchoalveolar lavage fluid of patients with AIDS. Chest. 1990;97: 1072-1076. 25. Millar AB, Patoo G, Miller RF, et al. Cytomegalovirus in the lungs of patients with AIDS. Respiratory pathogen or passenger? Am Rev Respir Dis. 1990;141:1474-1477, 26. Miller RF, Semple SJG, Kocjan G. Difficulties with sputum induction for diagnosis of Pneumocystis carinii pneumonia. Lancet. 1990;1:112. Letter. 27. Del Rio C, Guarner J, Honig EG, Slade BA. Sputum examination in the diagnosis of Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. Arch Pathol Lab Med. 1988;112:1229-1232. 28. Zaman MK, Wooten OJ, Suprahmanya B, et al. Rapid noninvasive diagnosis of Pneumocystis carinii from induced liquefied sputum. Ann Intern Med. 1988;109:7-10. 29. Read CA, Cerrone R, Busseniers AE, et al. Differential lobe lavage for diagnosis of acute Pneumocystis carinii pneumonia in patients receiving prophylactic aerosolized pentamidine therapy. Chest. 1993;103:1520-1523. 30. Centers for Disease Control. Update: tuberculosis elimination-United States. l@MWR. 1990;39:153-156.
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31. Baughman RP, Rhodes JC, Dohn MN, et al. Detection of cryptococcal antigen in bronchoalveolar lavage fluid: a prospective study of diagnostic utility. Am Rev Respir Dis. 1992;145:1226-1229. 32. Polsky B, Gold JWM, Whimbey E, et al. Bacterial pneumonia in patients with the acquired immunodeficiency syndrome. Ann Intern Med. 1986;104: 38-41. 33. Witt DJ, Cravens DE, McCabe WR. Bacterial infections in adult patients with human immunodeficiency virus infection (HIV) and AIDS. JAMA. 1987;82: 900-906. 34. Magnenat J-L, Nicod LP, Auckenthaler R, Junod AF. Mode of presentation and diagnosis of bacterial pneumonia in human immunodeficiency virusinfected patients. Am Rev Respir Dis. 1991;144:917-922. 35. GarciaCeoni ME, Morena S, Rodeho P, et al. Pneumococcal pneumonia in adult hospitalized patients infected with the human immunodeficiency virus. Arch Intern Med. 1952;142:1808-1812. 36. Tuxen D, Wilson JW, Cade JF. Prevention of lower respiratory herpes simplex virus infection with acyclovir in patients with the adult respiratory distress syndrome. Am Rev Respir Dis. 1987;136:402-405.
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ethods of diagnosing the cause of pneumonia in human immunodeficiency virus. (HIV)-infected patients have been widely studied in the past 10 years.1-4 These studies have demonstrated that Pneumocystis carinii is a common infection in the HIV-infected patient, that bronchoscopy with bronchoalveolar lavage (BAL) has good sensitivity for diagnosing P carinii pneumonia, and that bronchoFrom the Department
of Medicine,
University
of Cincinnati Medical
scopy is well tolerated by the patient. However, there remain several issues unresolved in the management of the HIV-infected patient with diffuse lung infiltrates. Induced sputum has been shown to be diagnostic of P carinii in many patients.5-7 The sensitivity of sputum can be enhanced by the use of immunofluorescent stains of the sputum specimen. BAL may be unnecessary in some patients because a simpler, less costly measure can be used to diagnose P car&ii pneumonia. With the widespread problems with P car&ii pneumonia, physicians have used various forms of prophylaxis therapy to prevent it. That has resulted in a lower incidence of the pneumonia in HIV-infected patients.*-lo For patients taking aerosol pentamidine prophylaxis, there is a reduced but still present risk of developing P carinii pneumonia. In studying patients on pentamidine prophylaxis who develop the pneumonia, it has been found that they have more atypical presentations, and at least one study suggested BAL alone may not be sufficient to diagnose P car&ii pneumonia.ll BAL sensitivity may be enhanced by performing lavage in two or more regions in the lung.12-15 As patients with HIV infection live longer, it is not uncommon for them to develop other treatable pulmonary infections besides P car&ii. It has been recognized that HIV-infected patients are at risk for developing other pulmonary infections, including Mycobacterium tuberculosis, deep-seated fungal infections, and bacterial pneumonias.” Bronchoscopy with BAL directed to the area of pulmonary infiltrate may still provide useful information in evaluating pulmonary infiltrates in HIV-infected patients. 12-15We have used bronchoscopy as the major method to diagnose pulmonary infections in HIV patients for over 7 years, with all patients undergoing lavage. Lavage was examined for P carinii, mycobacterial, fungal, bacterial, and viral infection in all cases. We have found that the use of BAL significantly enhances our understanding of the cause of pulmonary infiltrates in the HIV-infected patient. By using BAL, more than 20% of our patients were found to have pulmonary pathogens associated with active disease beyond P carinii.
METHODS MD, 231 Bethesda Avenue, Cincinnati, Ohio 45267.0564. Manuscript submitted November 23, 1993 and accepted
In revised
On January 1, 1985, we instituted a standardized policy of handling all HIV-infected patients referred to the pulmonary service for evaluation of cough, December 1994 The AmericanJournal of Medicine@Volume 97
515
PC ALONE 345
PC + ANOTHER
ORGANISM 75
ANOTHER
ORGANISM 110
NO DIAGNOSIS 364
fever, shortness of breath, or new or worsening pulmonary infiltrates. l6 All patients un d er-went clinical evaluation and bronchoscopy with BAL within 24 hours of referral to the pulmonary service. Patients were not referred for evaluation if their overall condition was considered terminal. Only 9 patients who did not have a definitive diagnosis of P car&ii were treated with empiric anti-P carinii therapy. The recording of information and standard handling of the BAL specimen followed a protocol approved by our Institutional Review Board. At the time of bronchoscopy, the chest roentgenogram was evaluated and the pattern was scored as diffuse, localized (less than two-lobe involvement or a single mass), or normal. A patient with a pleural effusion and otherwise clear lung fields was considered to have a normal lung pattern. Bronchoscopy and lavage was performed in a standardized manner, with either RPB or MND performing the bronchoscopy for more than 95% of patients. Flexible fiberoptic bronchoscopy was done and all airways were examined. BAL with 120 mL to 240 mL was performed in the area leading to the infiltrate, using our previously described technique.l” In patients with diffuse infiltrates, lavage was performed in either the right middle lobe or left lingula. Starting in November 1989, patients underwent dual lavages of both the apical segment and the right middle or left lingular area, as previously described.13 This was not done in the few patients whose respiratory status was considered marginal. In those cases, lavage was only done in the area with the most infiltrate. 516
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Figure 1. The number of bronchoalveolar IaGge procedures demonstrating diagnosis of Pneumocystis carinii (PC)alone, P carinii in combination with another organism, another organism alone, or no diagnosis by lavage.
BAL specimens were all handled in the same way. Aliquots were sent for mycobacterial smear and culture, fungal culture, cryptococcal antigen, cytologic examination using both Papanicolaou and methenamine silver stain, cytomegalovirus culture, herpes culture, legionella culture, and bacterial culture. Bacterial culture was done using a semiquantitative method similar to that used for urine and the results were reported in colony-forming units (cfu) per milliliter of BAL fluid. Using a quantitative loop, 0.01 mL of the unprocessed BAL fluid was directly applied onto each of four culture media: sheep’s blood agar, MacConkey’s agar, CNA agar (blood agar that contains colistin and nalidixic acid), and chocolate blood agar In addition, cytocentrifuge-prepared slides using 100 pL to 200 pL of unconcentrated BAL specimen were made. These were stained with a modified Wright-Giemsa stain (Diff-Quik, McGaw Park, Illinois). A differential count was performed of all nucleated cells.17 The following criteria were used to determine whether the bronchoscopy was diagnostic. Patients were felt to have P car&ii if the pathogen was identified using silver stain. Mycobacterial infections were all confirmed by culture and only patients with either M tuberculosis or Myobacterium kansasii were felt to have significant mycobacterial infection.l* Patients in whom Mycobacterium avium-intracellulare alone was isolated were not felt to have a diagnostic bronchoscopy. Fungal infections were all confirmed by culture.1s Patients were felt to have deep-seated fungal infection if Histoplasma capsulatum, Cryptococcus neoforrnans, or Coccidioides immitis were 97
BRONCHOALVEOLAR
/
n
PNEUM~CY~T~S
”
1985
ALONE FZIPNEUMOCYSTIS
1986
1987
1938
+ OTHER
1989
1990
q
o~-~ERAL~NE
1991
!SINO DIAGNOSIS
1992
I
identified. Patients in whom Candida or Aspergillus organisms were identified were not felt to have diagnostic bronchoscopy. Bacterial infections were diagnosed on the basis of the semiquantitative culture re,~ults.~~J~For a bacterial infection to be diagnostic, the bacteria had to be >lO,OOO cfu/mL of BAL fluid. Patients who grew either Nocardia or Rhodococcus organisms were felt to be infected, regardless of the quantity. Although viral cultures were performed, we did not use the results of viral culture as diagnostic for infection. Patients with cytopathic changes consistent with CMV infection and positive cultures were considered to have ClMV pneumonia.20 The results of all bronchoscopies were recorded into a database (DataEase, DataEase International, Trumbull, Connecticut), which also included the chest roentgenogram pattern and cytologic, microbiologic, viral, and fungal culture results.
RESULTS A total of 894 patients underwent bronchoscopy with BAL during the ‘i-year period. Figure 1 and Table I summarize the BAL results for all patients. As can be seen, P curirzii was the most common diagnosis encountered. In patients with P carinii pneumonia, 18% (75 of 420) also had an additional diagnosis determined by the BAL. They included patients with fungal infections, mycobacterial infection, bacterial infections, and cytomegalovirus. An additional 12% of the patients were diagnosed as having pneumonia with no evidence of P catinii. The most common alternative diagnosis was bacterial pneumonia, although a significant number of patients had fungal or mycobacterial infection.
ET AL
/
TOTAL
YEAR
LAVAGE IN AIDS/BAUGHMAN
Figure 2. The relative yield per year for Pneumocystis carinii alone, P carinii plus other organism, another organism alone, or no diagnosis. There was no difference in the relative yields over the 7 years of the study.
TABLE I Results of Bronchoalveolar Yield in AIDS Patients Diagnosis Number Percent All Pneumocystis 420 47 PC alone 345 39 PC + fungal 12 PC + Mylobacterium tuberculosis k.2 PC + Mylobacterium kansasii 6’ 0.6 PC + bacterial 36 4 PC + bacterial + fungal 2 0.2 PC + bacterial + CMV* 1 0.1 PC + CMV 16 2 Another diagnosis 110 12 Bacterial 54 6 Bacterial + MTB 2 0.2 Bacterial + MTB + CMV 1 0.1 Bacterial + CMV 0.2 Fungal 2: 3 Fungal + bacterial 2 0.2 MTB 12 1 M kansasii 9 1 No diagnosis 364 41 ‘CMV positive only if cytology positive. PC = P carinii; CMV = cytomegalovirus;MTB = M tuberculosis.
During
the 7-year period, 420 episodes of P pneumonia were diagnosed by bronchoscopy. An additional 4 patients were diagnosed by follow-up evaluation, including 2 open-lung biopsies and 2 transbronchial biopsies. As noted above, empiric therapy for P carinii pneumonia was rarely given, so that our overall sensitivity for P carinii pneumonia was more than 95%. Of the 894 bronchoscopies, 497 (56%) had dual lavages, that is, lavages in both the upper and middle lobe or lingula. Of the 420 episodes of P carinii, car&ii
December 1994 The American Journal of Medicine@ Volume 97
517
CAUSE OF PNEUMONIA
n q
P~Eurdoc~sT~s
m TUBERCULOSIS
BACTERIAL
q
0 FUNGAL
NO DIAGNOSIS
801
I
DIFFUSE
LOCALIZED
ROENTGENOGRAPHIC
NORMAL PATTERN
218 (52%) were diagnosed by the dual lavage technique. We have previously reported our experience of dual lavages over a g-month period, which is included in this study.13 Our evaluation of the dual lavage uses a modified Wright-Giemsa stain to examine the individual lobe lavage results.13 This stain is less sensitiive than the methenamine silver stain used to examine the combined BAL fluid analyzed in this study,21 and in no case was P carinii found in the modified Wright-Giemsa stain and not confirmed by the methenamine silver stain. Of the 218 patients found to have P carinii by the dual lavage method, 11 did not have any P car&A seen in the middle lobe and 1 did not have any P car&ii seen in the upper lobe. Of these 12 (6%) patients, 10 were on aerosol pentamidine prophylaxis. Shown in Figure 2 is the yearly yield for P carinii alone, P carinii plus another pathogen, another pathogen alone, or no diagnosis over the 7-year period. There was no consistent pattern of diagnostic yield, despite changes of therapy during this time, including the widespread introduction of anti-HIV therapy and P car&ii prophylaxis (chi-square analysis, P >0.05). The chest roentgenographic pattern of diffuse, localized, or normal was seen in more than 90% of patients. Figure 3 compares the roentgenographic pattern for the various types of pneumonia diagnosed by BAL (P carinii, mycobacterial, fungal, and bacterial) versus the pattern seen when no diagnosis was made. Only those patients with a single 518
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Figure 3. The chest roentgenographic appearance associated with a diagnosis of Pneumocystis carinii, tuberculous, fungal, and bacterial pneumonia compared with no diagnosis by bronchoalveolar lavage.
pathogen identified were included in this analysis. Those patients with a diffuse pattern were more likely to have a diagnostic bronchoscopy (chi-square = 20.1, P
BRONCHOALVEOLAR
Granulomatous
Infections Identified Number of Cases Mycobacterium’ 32 M tuberculosis 17 M kansasii 15 Fungal 46 Histoplasmosis 24 Cryptococcosis 17 Coccidioidomycosis 5 *Not including Mycobacterium
I”“”
by Bronchoscopy Number With Pneumocystis 8 2 6 13 5 8 0
LAVAGE IN AIDS/BAUGHMAN
ET AL
Bacterial Infections Diagnosed in HIV-Infected Patients Undergoing Broncloalveolar Lavage
avium-intraceffulare.
quently identified our first AIDS patient with Legionella pneumonia. We have used bronchoscopy with lavage to diagnose Legionella in several nonHIV-infected patients during the same time. Also shown in Table III is the frequency of the various pathogens identified by BAL. The most common organism encountered was Haemophilus inji’uenzae. The second most common isolate was alpha streptococcus, which may be associated with other mouth flora, including anaerobic organisms. Anaerobic cultures were not performed on the BAL fluid. A significant number of patients had other pulmonary pathogens, including S. pneumoniae and gram-negative rods. The gram-negative enteric pathogens were usually encountered in either neutropenic patients or patients on mechanical ventilation. We have included the number of patients with >lOO,OOOcfu/mL BAL isolates as well as those with >lO,OOO cfu/mL of BAL isolates. There have been several articles demonstrating that > 100,000 cfu/mL of BAL is a more specific criteria for identifying bacterial pneumonia.16J2-z3 However, a recent consensus conference recommended using the >lO,OOO cfu/mL of BAL cut-off point.lg Since all patients in this study had pulmonary signs and symptoms suggestive of lower respiratory tract infection, we used the criteria of >lO,OOOcfu/mL of BAL. In order to determine the effect of prior antibiotics on the bacterial cultures of BAL, we compared the lavage cultures to antibacterial antitiobitcs. Table IV summarizes the various groups. We did’ not include
> 100,000
Organism cfu/mL Haemophilus influenza 12 Alpha Streptococcus 4 Streptococcus pneumoniae 4 Staphylococcus aureus 4 Moraxella [Branhamellal 1 catarrhalis Gram-negative rods 5 Pseudomonas aeruginosa 4 Klebsiella pneumoniae :, Escherichia coli Proteus morabilus 0 Rhodococcus equini 3 Nocardia’ 2 Total 35
10b,000
cfu/mL 21 20
>10,000 cfu/mL 33 24 13
7 8 4 : 1
67
13 8 2 2 1 3 2 102
‘These organisms not quantitated. cfu = colony-forming units.
antiviral or anti-P carinii therapy as prior antibiotics. Patients who were receiving trimethoprimkulfamethoxazole for prophylaxis were not considered to be on antibiotics for this episode, since they had been on chronic suppressive therapy at the time they developed new pulmonary symptoms. Included in Table IV are patients on intravenous antibiotics. Although there was a trend for those patients with higher number of bacteria not to be on any antibiotics, the difference was not significant (&i-square, P >0.05). About 90% of the patients were not on any antibiotics at the time of the bronchoscopy. We have analyzed patients who had cytopathic changes consistent with CMV. However, since the presence of CMY in the lung does not clearly Cause pulmonary disease,24J5 we have chosen not to consider those instances where CMY occurred alone as a diagnostic bronchoscopy. We have excluded from our overall diagnostic yield the 21 patients in whom the only diagnosis was cytopathic changes due to C&IV, although these patients were sometimes treated for their CMV pneumonia by their attending physician. We also identified 21 patients who had
TABLE IV Effect of Antibiotic Bacteria Recovered (cfu/mL) >100,000 10,000-100,000 l,OOO-10,000
Therapy on Semiquantitative Total Number of Patients’ 30 67 116 676
Bacterial Cultures from Broncloalveolar Lavage’ Number of Patients Number of Patients on on Antibiotics Intravenous Antibiotics? 2 (7%) 0 (0%) 8 (12%) 2 (3%) 9 (8%) 2 (2%) 90 (13%) 35 (5%)
*Patients with Nocardia and Rhodococcus excluded from analysis. *Anti-viral or anti-Pneumocystis carinii prophylaxis not considered. cfu = colony-forming units.
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herpes simplex virus recovered from the BAL specimen. Fourteen of these eases also had P carinii infection. It is not clear whether these patients had disease due to herpes in the lung. We therefore considered the isolation of herpes of no diagnostic significance.
shown that lavage directed to the area of most infiltrate, especially to the apical segments of the lung, has a higher yield for P car&ii. It appears that dual lavages, especially to the upper lobes, result in a better diagnostic yield. 12-14,2g In the current study, dual lavages were done in more than half of our patients. We have previously demonstrated more P car&ii in COMMENTS the upper lobes than middle lobes, whether or not The identification of the causative agent of pul- the patient was on aerosol pentamidine.13 Of the 12 monary symptoms in the HIV-infected patient still patients who had P car&ii seen in only only one remains important. The proper approach to these pa- lobe, 10 were on aerosol pentamidine. During this tients remains unclear. In the current study, we ex- study period, there were 4 cases of P catinii pneuamined the use of BAL in diagnosing pneumonia. We monia documented in patients who had a negative found the overall yield by BAL was 60%, with 47% BAL, for an overall sensitivity of BAL greater than overall having P carinii and 20% of patients having 95%, similar to previous studies.la2 an organism in addition to or instead of P car&ii. The diagnosis of mycobacterial infections has been increasing over the past several years in both This study demonstrates that P carinii represents the most common pulmonary pathogen identified in the HIV-infected and non-HIV-infected populapatients with HIV infection and respiratory symp- tions.30 In this study, we found a significant number toms. This has been noted by others.le4 The wideof both M tuberculosis and M kansasii infections. spread use of prophylactic agents has made P qlthough 1M kansasii infection is seen in non-HIVcatinii infections less frequent and apparently infected patients in our area, &f tuberculosis is 10 milder than in the past.8-12 times more frequent than M kansasii in the impatient (Robert Loudon, MB, ChB, Although P car&ii was seen frequently, most pa- munocompetent tients had either negative bronchoscopy results or a personal communication, May 1994). Interestingly, pathogen other than or in addition to P car&ii iden- 25% of our patients with mycobacterial infection tified. Only 9 patients were treated after the bronalso had P carinii infection. choscopy with empiric anti-P carinii therapy and Fungal infections, including histoplasmosis and only an additional 4 patients were subsequently cryptococcal infection, were seen in 5% of patients. found to have P carinii pneumonia. Our study would Although some of these patients may have been disuggest that empiric use of anti-P car&ii antibiotics agnosed by alternative means, BAL represented a would be incomplete or ineffective therapy in more specific and first diagnosis in the majority of pathan half of HIV patients with pulmonary symptoms. tients. We have previously reported on the use of The use of sputum induction to diagnose P carinii measurement of cryptococcal antigen in the BAL for infection has been stressed in the recent literature.5rapid diagnosis of cryptococci,31 but we did not use 7 Although it is a less costly technique, it is not clear the cryptococcal antigen test in this study. that it is an effective method of diagnosis at all cenBacterial pathogens were the second most comters.26 Some institutions have had difficulty in get- monly identified cause of respiratory symptoms in ting reasonable samples for staining and the overall our patients. The use of semiquantitative cultures to yield for sputum induction has varied greatly, from diagnose pneumonia has been used by us and by othas low as 20% to as high as 90% of patients who are ers for some time.16,22s23The major controversies resubsequently proven to have P carinii pneumonia.5garding its use revolve around the effect of prior an7a27The yield for sputum induction can be enhanced tibiotics and what is an appropriate level of bacterial by the use of liquification of the specimen,28 by mongrowth that distinguishes between infection and coloclonal antibodies against P car&ii to enhance de- onization. The majority of patients in this study were tection5 and by a laboratory dedicated overall to the seen as outpatients and not heavily treated with andiagnosis of P carinii in sputum. tibiotics prior to bronchoscopy. We have chosen to Another issue has been the fact that aerosol pen- use the >lO,OOOcfu/mL of BAL as the criteria for ditamidine may affect the number of organisms and agnosis, since this cutoff was suggested by a conthe presentation of P carinii pneumonia. In a study sensus conference.lg We provide the number of paby Jules-Elysee et al, l1 diagnosis of P car&ii pneu- tients with >lOO,OOOcfu/mL of BAL, which provides monia by BAL was reduced to 60% in patients re- information not significantly different from the ceiving aerosol pentamidine prophylaxis. That group >lO,OOOcfu/mL criteria. subsequently reported a higher yield for BAL if The most common bacteria isolated were H inlavage was performed in two areas of the lung.15 fluenzae, streptococcal species, and staphylococci. More recently, several groups, including ours, have These results are similar to other reports.3234 Patients 520
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did not routinely undergo blood cultures at the time of bronehoscopy, so the incidence of bacteremia is not available. Others have noted an increased incidence of septicemia in HIV-infected patients with pneumococcal pneumonia.35 Gram-negative bacteria were found in some patients, usually in the setting of hospital-acquired pneumonia or with leukopenic patients. The role of viral infections in causing pulmonary disease in HIV-infected patients is unclear.24~25 Cytomegalovirus may be present in the lower respiratory tract without any associated disease. The finding of cytopathic changes due to CMV does represent more clear-cut disease, but again it is not clear that this needs to be treated. Herpes simplex virus has been recovered from the lower respiratory tract in patients with adult respiratory distress syndrome and no specific therapy seems warranted.36 It is unclear if it has any role in HIV infection. In an analysis of our own patients, we could not detect any disease specifically due to herpes simplex and there was no apparent effect of antiviral therapy. It should be noted that there was a 21% incidence of significant infection in addition to the P car&ii found in the BAL fluid. These other organisms included bacterial, mycobacterial, and fungal infections. Sputum induction alone used to evaluate HIVinfected patients with pulmonary symptoms would have missed many of these additional infections. Although mycobacterial infections may be detectable in sputum (if, in fact, a specimen would be sent for smear and culture), fungal infections are rarely diagnosed by sputum examination and culture. This study did not examine the utility of identifying CMV or M aviuna-intracellulare infections. However, both could be useful information in certain settings. Positive CMV cytology alone in the absence of other explanations for symptoms and findings was treated with antiviral therapy and clinical improvement was seen in some patients. The finding of 1M avium-intracellulare in the BAL fluid was sometimes its first isolation from a patient, and had an impact on therapy. In that situation, further investigation for systemic M avium-intracellulare infection was begun and the patient may have been given therapy. We conclude that BAL still has a role in the evaluation of HIV-infected patients with new pulmonary symptoms. The changing therapeutic practices and diagnostic procedures over the past 7 years have had many effects on the HIV-infected population. Many pathogens other than P carinii were present in the lower respiratory tract.
REFERENCES 1. Broaddus C, Dake MD, Stulbarg MS, et al. Bronchoalveolar lavage and transbronchial biopsy for the diagnosis of pulmonary Infections in the acquired immunodeficiency syndrome. Ann Intern Med. 1985;102:747-752. December
LAVAGE IN AIDS,‘BAUGHMAN ET AL
2. Murray JF, Garay SM, Hopewell PC, et al. Pulmonary complications of the acquired immunodeficiency syndrome: an update: report of the second National Heart, Lung and Blood Institute Workshop. Am Rev Respir Dis. 1987;135:504-509, 3. Golden JA, Hollander H, Stulbarg MS, Gamsu G. Bronchoalveolar lavage as the exclusive diagnostic modality for Pneumocystis carinii pneumonia: a prospective study among patients with acqurred immunodeflciency syndrome. Chest. 1986;90:18-22. 4. Gal AA, Klatt EC, Koss MN, et al. The effectiveness of bronchoscopy in the diagnosis of Pneumocystis carini and cytomegalovirus pulmonary infections in acquired immunodeficiency syndrome. Arch Pathol lab Med. 1987;lll: 238-241. 5. Kovacs JA, Ng VL, Masur H, et al. Diagnosis of Pneumocystis carinii pneumonia: improved detection in sputum with use of monoclonal antibodies. NEJM. 1988;318:589-593. 6. Pitchenik AE, Ganlel P, Torres A, et al. Sputum examination for the diagnosis of Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. Am Rev Respir Dis. 1986;133:226-229. 7. Bigby TD, Margolskee D, Curtis JL, et al. The usefulness of induced sputum in the diagnosis of immunodeficiency syndrome. Am Rev Respir Dis. 1986;133:515-518. 8. Montaner JSG, Lawson LM, Gervais A, et al. Aerosol pentamidine for secondary prophylaxis of AIDS-related Pneumocystis carinii pneumonia: a randomized, placebo-controlled study. Ann lnlern Med. 1991;114:948-953. 9. Leoung GS, Feigal DW, Montgomery AB, et al. Aerosolized pentamidine for prophylaxis against Pneumocystis carinii pneumonia: the San Francisco community prophylaxis trial. NEJM. 1990;323:769-775. 10. Schneider MME, Hoepelman AIM, Schattenkerk JKME, et al. A controlled trial of aerosolized pentamidine or trimethoprim-sulfamethoxazole as primary prophylaxis against Pneumocystis carinii pneumonia in patients with human immunodeficiency virus infection. NEJM. 1992;327:1836-1841. 11. Jules-Elysee KM, Stover DE, Zaman MB, et al. Aerosollzed pentamidlne: effect on diagnosis and presentation of Pneumocystis carinii pneumonia. Ann Intern Med. 1990;112:750-757, 12. Levine SJ, Masur H, Gill VJ, et al. Effect of aerosolized pentamidine prophylaxis on the diagnosis of Pneumocystis carinii pneumonia by induced sputum examination in patients infected with the human lmmunodeficiency virus. Am Rev Respir Dis. 1991;144:760-764. 13. Baughman RP, Dohn MN, Shipley R, et al. Increased Pneumocystis carinii recovery from the upper lobes in pneumocystis pneumonia: the effect of aerosol pentamidine prophylaxis. Chest. 1993;103:426-432, 14. Yung RC, Weinacker AB, Steiger DJ, et al. Upper and middle lobe bronchoalveolar lavage to diagnose Pneumocystis carinii pneumonia. Am Rev Aespir Dis. 1993;148:1563-1566. 15. Meduri GU, Stover DE, Green0 RA, et al. Bilateral bronchoalveolar lavage in the diagnosis of opportunistic pulmonary infections. Chest. 1991;lOO: 1272-1276. 16. Thorpe JE, Baughman RP, Frame PT, et al. Bronchoalveolar lavage in diagnosing acute bacterial pneumonia. J infect Dis. 1987;155:855-862. 17. Baughman RP, Strohofer S, Kim CK. Variation of differential cell counts of bronchoalveolar lavage fluid. Arch Pathol Lab Med. 1986;110:341-343. 18. Baughman RP, Dohn MN, Loudon RG, Frame PT. Bronchoscopy with bronchoalveolar lavage in tuberculosis and fungai infections. Chest. 1991;99:92-97. 19. Meduri GU, Johanson WG. International Consensus Conference: clinical investigation of ventilator-associated pneumonia. Chest. 1992;102: 5515-588s. 20. Craighead JE. Pulmonary cytomegalovirus in the adult. Am J Pathol. 1971;63:487-499. 21. Baughman RP, Strohofer SS, Clinton BA, et al. The use of an indirect fluorescent antibody test fordetecting Pneumocystis carinii. Arch Pathol Lab Med. 1989;113:1062-1065. 22. Meduri GU, Beals DH, Maijub AG, Baselski V. Protected bronchoalveolar lavage: a new bronchoscopic technique to retrieve uncontaminated distal airway secretions. Am Rev Respir Dis. 1991;143:855-864. 23. Kahn FW, Jones JM. Diagnosing bacterial respiratory infectlon by bronchoalveolar lavage. J Infect Dis. 1987;155:862-869. 1994
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24. Miles PR, Baughman RP, Linnemann CC. Cytomegalovirus in the bronchoalveolar lavage fluid of patients with AIDS. Chest. 1990;97: 1072-1076. 25. Millar AB, Patoo G, Miller RF, et al. Cytomegalovirus in the lungs of patients with AIDS. Respiratory pathogen or passenger? Am Rev Respir Dis. 1990;141:1474-1477, 26. Miller RF, Semple SJG, Kocjan G. Difficulties with sputum induction for diagnosis of Pneumocystis carinii pneumonia. Lancet. 1990;1:112. Letter. 27. Del Rio C, Guarner J, Honig EG, Slade BA. Sputum examination in the diagnosis of Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. Arch Pathol Lab Med. 1988;112:1229-1232. 28. Zaman MK, Wooten OJ, Suprahmanya B, et al. Rapid noninvasive diagnosis of Pneumocystis carinii from induced liquefied sputum. Ann Intern Med. 1988;109:7-10. 29. Read CA, Cerrone R, Busseniers AE, et al. Differential lobe lavage for diagnosis of acute Pneumocystis carinii pneumonia in patients receiving prophylactic aerosolized pentamidine therapy. Chest. 1993;103:1520-1523. 30. Centers for Disease Control. Update: tuberculosis elimination-United States. l@MWR. 1990;39:153-156.
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31. Baughman RP, Rhodes JC, Dohn MN, et al. Detection of cryptococcal antigen in bronchoalveolar lavage fluid: a prospective study of diagnostic utility. Am Rev Respir Dis. 1992;145:1226-1229. 32. Polsky B, Gold JWM, Whimbey E, et al. Bacterial pneumonia in patients with the acquired immunodeficiency syndrome. Ann Intern Med. 1986;104: 38-41. 33. Witt DJ, Cravens DE, McCabe WR. Bacterial infections in adult patients with human immunodeficiency virus infection (HIV) and AIDS. JAMA. 1987;82: 900-906. 34. Magnenat J-L, Nicod LP, Auckenthaler R, Junod AF. Mode of presentation and diagnosis of bacterial pneumonia in human immunodeficiency virusinfected patients. Am Rev Respir Dis. 1991;144:917-922. 35. GarciaCeoni ME, Morena S, Rodeho P, et al. Pneumococcal pneumonia in adult hospitalized patients infected with the human immunodeficiency virus. Arch Intern Med. 1952;142:1808-1812. 36. Tuxen D, Wilson JW, Cade JF. Prevention of lower respiratory herpes simplex virus infection with acyclovir in patients with the adult respiratory distress syndrome. Am Rev Respir Dis. 1987;136:402-405.
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