Genitourin Med 1991;67:250-255

Clinrico-pathological conference

Adult respiratory distress syndrome complicatingPneumocystis carinii pneumonia

A Scoular, J Moxham, S B Lucas, R F Miller

Case report (Dr A Scoular)This 34 year old man presented with a 3 week historyof fever, dry cough and exertional dyspnoea. He hadreturned from holiday in Madeira only 2 dayspreviously. He was a non-smoker and drank alcoholmoderately. In the past he had been treated forsyphilis in 1974. At that time he also had genitalherpes. He remained well until 1980 when he presen-ted with acute hepatitis A and was also found to behepatitis B immune, with positive anti-core and anti-surface antibodies. In September 1988 he presentedwith cutaneous lesions of Kaposi's sarcoma and wasfound to be HIV-1 antibody positive. He commen-ced zidovudine shortly afterwards. He was lookedafter at another hospital and remained well forapproximately 1 year when he developed oeso-phageal candida, increasingly widespread lesions ofKaposi's sarcoma and was commenced on a-inter-feron therapy. Despite this his Kaposi's sarcoma skinlesions continued to enlarge and become more wide-spread. At this point his CD4 count was 30 and hewas p24 antigen positive. Therapy was then changedand epirubicin was given on a weekly basis but hebecame anaemic very quickly on this and so it wastemporarily discontinued. Shortly afterwards he wasadmitted to this hospital. At the time ofadmission hewas taking zidovudine 250 mg tds, acyclovir 400 mgtds, and Fansidar (pyrimethamine 25 mg and sul-fadoxine 500 mg) 1 tablet per week (as primaryprophylaxis against Pneumocystis carinii pneumoniaas he was thought to be allergic to co-trimoxazole)and epirubicin 20 mg once a week. On examination atthe time ofadmission he was febrile at 37 8°C, he hadwidespread lesions of cutaneous and also oral

Department of Genitourinary Medicine, TheMiddlesex Hospital, LondonA ScoularDepartment of Thoracic Medicine, Kings CollegeSchool of Medicine and Dentistry, LondonJ MoxhamDepartment ofHistopathologyS B LucasDepartment of Medicine, UCMSM, The MiddlesexHospital, London WlN 8AA, UKR F Miller

Kaposi's sarcoma. His heart rate was 84 per minute,his blood pressure was 110/70 mm Hg and he had arespiratory rate of 18 per minute. Auscultation of thechest revealed no significant abnormalities and therest of the examination was normal. On admission achest radiograph was performed (fig 1). This showedbilateral interstitial shadowing in the upper zones,the mid and lower zones were relatively clear.Investigations showed he was anaemic with ahaemoglobin of 8-9 g/dl; the white cell count was1 8 x 109/1 with 50% neutrophils. Arterial bloodgases taken breathing air showed a PO, of 12-1 kPaand a PCO, of 3-9 kPa. Blood cultures, urea andelectrolytes, and liver function tests showed noabnormalities. Serologically he had evidence ofpreviously treated syphilis and immunity to hepatitisB. A provisional diagnosis of Pneumocystis cariniipneumonia was made and bronchoscopy was plannedfor the following day; treatment was begun withnebulised pentamidine and the zidovudine was dis-continued. At bronchoscopy the bronchial tree wasnormal and no endobronchial Kaposi's sarcoma wasseen. Laboratory examination of the broncho-alveolar lavage fluid showed only Pneumocystiscarinii; subsequent culture was sterile. After 5 days ofnebulised pentamidine the patient was still spiking afever although he felt better. He was active, mobileand self-caring around the ward. At this point repeatblood cultures were performed which were negative;he remained pyrexial. On day 6 of the admission hewas transfused with 4 units of blood. One week afteradmission the patient was slightly more breathlessbut otherwise remained clinically well, his arterialblood gases had shown a marked deterioration, hisP02 breathing air having fallen to 6-1 kPa, and PCO2remaining at 3 9 kPa. A repeat chest radiograph onday 9 showed more extensive alveolar shadowing (fig2). As the patient had continuing fever it wasconsidered that a change in therapy was appropriate.Intravenous pentamidine was begun and a 3-daycourse of mega-dose methylprednisolone (1 g perday intravenously) was given. The following day thepatient had improved and blood gases showed a PO2of 10-3 kPa on air. By day 11 the patient was verymuch improved, he was apyrexial for the first timeand symptomatically felt better. Four days later (on

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Adult respiratory distress syndrome complicating Pneumocystis carinii pneumonia

Figure I Chest radiograph on admission showing bilateralupper zone shadowing, the mid and lower zones are relativelyclear.

Figure 2 Chest radiograph, day 9, showing more extensiveshadowing in the upper zones. There is also mid and lowerzone shadowing, with sparing of the costophrenic angles.There is volume loss in the right upper lobe and the lesserfissure is pulled up (arrows).

Figure 3 Chest radiograph, day 16, showing there has beenno improvement.

the eighth day of intravenous pentamidine) thepatient remained apyrexial, and was again mobile andself-caring. Arterial blood gases showed a PO2 of9-3 kPa on air. The serum albumin had fallen to 23 g/l as had his sodium level. The chest radiograph on the16th day of the admission showed no significantimprovement (fig 3), but the patient had improvedclinically. The only event of note at this stage wasthrombocytopenia (platelet count = 22 x 106/1).There was no spontaneous bleeding nor easy bruis-ing.

It was felt that the patient had improved sufficien-tly to consider changing back to nebulised pen-tamidine therapy; however, within 48 hours he againbecame dyspnoeic, intravenous pentamidine wasrecommenced and nebulised therapy was stopped.The slight clinical deterioration was paralleled by hisarterial blood gases, the PO2 had fallen to 8-4 kPa onair. On the 21st day of his admission the patient wasstill pyrexial. A bacterial co-infection was thoughtpossible and so intravenous cefuroxime 750 mg tdswas added empirically. Blood and urine culturesprior to starting cefuroxime were negative; thepatient was unable to spontaneously expectoratesputum. Over the next 2 days there was furtherdeterioration in blood gases so a repeat bronchoscopywas carried out on day 24. The endobronchialappearances were again normal. Pneumocystis cariniiwas again seen in the lavage together with a heavygrowth of Enterobacter cloacae which was fully sen-sitive to cefuroxime. A chest radiograph (fig 4) taken

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Scoular, Moxham, Lucas, Miller

on day 26 showed a marked deterioration. The PO2breathing 60% oxygen was 7-5 kPa.To summarise events up to day 27, the patient had

received 4 weeks therapy, comprising 8 days ofnebulised pentamidine, then 9 days of intravenouspentamidine, back on nebulised pentamidine for 3days then a further 8 days of intravenous pen-tamidine. Overall there was no significantimprovement clinically, radiologically or in hisarterial blood gases. The patient was thought to beallergic to co-trimoxazole, but it was decided tochallenge him with a test dose of co-trimoxazole. Hetolerated this without adverse effects and subsequen-tly intravenous co-trimoxazole was begun, initially ata low-dose, over the next 2 days increasing to a high-dose regime. In order to improve oxygenation and inan attempt to reduce dyspnoea continuous positiveairways pressure (CPAP) ventilation was begunusing a face mask. The patient tolerated the intraven-ous co-trimoxazole very well but he remained dysp-noeic and anxious, and was unable to tolerate CPAPfor any length of time. For symptomatic relief of hisdyspnoea he was given small doses of subcutaneousdiamorphine. There was progressive clinical andradiographical deterioration and on day 31 thepatient was given a further 3-day course of intraven-ous methylprednisolone, which did not produce anyimprovement. The patient became progressivelymore distressed and tired, and was given increasingdoses of diamorphine to relieve his dyspnoea. Sub-sequently he expressed a wish to discontinue allactive treatment and died peacefully.

Discussion (Professor J Moxham)This patient was at high risk of Pneumocystis cariniipneumonia. At the time of his current admission theCD4 count was less than 30 and he was antigenpositive. Such an extremely immunosuppressedpatient is almost certain to develop Pneumocystiscarinii pneumonia sooner or later.' This being thecase, most centres now use prophylaxis againstpneumocystis and commonly this is with nebulisedpentamidine in doses of300 mg or more each month.2This prophylaxis is extremely effective. Probably theonly patients who subsequently develop pneumo-cystis pneumonia with the occasional exception arepatients who do not take their prophylaxis correctly.An altemative regime for prophylaxis would be oralco-trimoxazole. My own preference is for nebulisedpentamidine because I am always concemed thatpatients may develop sulphonamide sensitivity. Afurther altemative would be dapsone 100 mg daily.We do not use Fansidar as prophylaxis, and I am notaware of any large studies that have evaluated it asprophylaxis for Pneumocystis carinii pneumonia. Weuse Fansidar as prophylaxis against toxoplasmosisbut at a dose ofone tablet twice a week, and not once a

Figure 4 Chest radiograph, day 26. The appearances havedeteriorated markedly. In addition to extensive patchyalveolar shadowing, pleural changes are now evident(arrows).

week as taken by this patient. Furthermore whenputting patients on Fansidar for toxoplasmosisprophylaxis, we continue to give them nebulisedpentamidine as prophylaxis against Pneumocystis.Overall I am not surprised that this patient developedPneumocystis carinii pneumonia.Turning to the patient's presentation with

pneumocystis pneumonia, the chest radiograph israther unusual (fig 1). It is characteristic ofPneumocystis carinii pneumonia that the mid andlower zones are affected more often than the upperzones. We are used to seeing sparing of the costo-phrenic angles, but we are not used to the lower andmid zones being as clear as in this patient. Lack ofclarity of the branches of the right basal pulmonaryartery is often the earliest radiological change ofclassical pneumocystis pneumonia. Despite theseobservations, I accept, however, that the chestradiograph is consistent with Pneumocystis cariniipneumonia and it is important to note that there is noadenopathy and no pleural disease. In our clinicalpractice, when we see predominantly apical diseaselike this, it usually means that patients have not beentaking their nebulised pentamidine effectively and weknow that nebulised drugs reach the apex of the lungless well than the bases. So, I am left with slightconcern about the chest radiograph, and it would beinteresting to know whether the upper lobes werelavaged at bronchoscopy with the possibility oftuberculosis in mind. When patients have relativelygood arterial blood gases, we not infrequently per-form transbronchial biopsy. I think that given theslightly atypical chest radiograph, we would almostcertainly have biopsied this patient. Sometimes suchtransbronchial biopsies provide additional, usefulinformation.Let us, for the moment, assume that the diagnosis

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Adult respiratory distress syndrome complicating Pneumocystis carinii pneumonia

of Pneumocystis carinii pneumonia is secure. Assess-ing the severity of the illness is crucially important.We are given the information that the patient hadsymptoms for 3 weeks, which is about average forPneumocystis carinii pneumonia. I had been informedthat the patient was breathless on dressing, andbreathlessness in patients who are performing suchminor tasks is a good indication that the respiratorysystem is under considerable stress. On that basis Iwould have graded the pneumonia as moderatelysevere. The chest radiograph changes are obviousand affect both lungs, and once again I would gradethem "as being of moderate severity. The arterialhypoxaemia is relatively mild but there is widening ofthe alveolar-arterial oxygen gradient. Taking intoaccount the history, examination and chestradiograph, my conclusion would be that this patienthad a moderate disease. In view of the treatment thatthis patient subsequently received, this initial assess-ment is crucial.In most circumstances the treatment of choice for

Pneumocystis carinii pneumonia is high-doseintravenous co-trimoxazole. I know of no literatureto suggest that any other treatment is superior, andthere are some data to suggest that some treatmentsare not as good. In this particular case there was apossible problem' of the patient being allergic to co-trimoxazole. Usually this allergy is due to the sul-phonamide component of the drug and it is surpris-ing that the patient was taking regular Fansidar.Fansidar has been noted to cause rather more allergyproblems than co-trimoxazole. The sulphonamide inFansidar has a longer half life and the drug hasproduced a Stevens-Johnson syndrome in a numberof patients. On the available evidence, I would nothave accepted that this patient was allergic to sul-phonamides and would have treated him withintravenous high-dose co-trimoxazole, keeping acareful eye on his response. If the patient were trulyallergic, then our first strategy would be to treat himwith trimethoprim and dapsone, a regime that isfound very effective in these circumstances.4The decision was made by the clinicians caring for

the patient, to give this patient nebulised pen-tamidine. Much of what we know about nebulisedpentamidine as therapy for pneumocystis pneumoniacomes from this hospital. As I understand the data,nebulised pentamidine is best reserved for patientswith mild to moderate disease, and in such patientsan 80% response rate is to be expected.5 Further-more, the clinical response will be slower than whenco-trimoxazole is used. Looked at from a differentviewpoint, we can say that in 20% of patients withmild to moderate disease nebulised pentamidine willfail and it might be a week or so before it is clear thatthe therapy is failing. Most physicians would nottreat patients with Pneumocystis carinii pneumoniawith nebulised pentamidine, except when confidentthat the disease is mild.

On admission the patient was anaemic and he wastaking zidovudine 250 mg tds; this drug was stopped.It is our usual practice to stop zidovudine when weare treating patients with pneumocystis pneumoniabecause both the disease itself and therapy depressmarrow function, which can cause substantial dif-ficulties in the delivery of adequate treatment for thepneumonia.Reviewing the results of the first week of therapy

with nebulised pentamidine, we are told that thearterial tension started at 12 1 kPa and ended at6-1 kPa. Clearly the patient had deteriorated and wasin the 20% or so of patients who do not respond wellto nebulised therapy. The questions that then arosewere firstly whether the patient's treatment should bealtered and if so which drug should be used, andsecondly whether there was a place for steroidtherapy. We use steriods frequently in our patients,and we use them early. I suspect that a fall in PaO2from 12 to 10 kPa would have been sufficient indica-tion for us to have used steroids and to have changedthe patient's therapy. As I have indicated we preferco-trimoxazole for the treatment of pneumocystispneumonia and would have changed the patient tothis drug, or if we had been persuaded about allergyto sulphonamide, we would have used trimethoprimand dapsone.

After 1 week oftherapy the patient's treatment waschanged to intravenous pentamidine, and he was alsogiven methylprednisolone. It is possible to predictwith a fair degree of accuracy what would thenhappen. As soon as patients are given steroids theyimprove rapidly.67 Pneumocystis carinii pneumoniacauses very leaky lung vasculature and steroidsimprove this situation, and blood gases rapidly getbetter. The hope is that this improvement buys timefor the drug therapy to get on top of the infection. Inthis patient the PO0 dramatically improved within 24hours of starting steroids. I would stress that this hadnothing to do with the treatment of the underlyingpneumocystis pneumonia. Weknow that intravenouspentamidine is slow to have much effect because theaccumulation of the drug in the lung takes severaldays, and only has maximum effect approximately 1week after starting therapy.38 This patient was givenmega-dose steroids for 3 days, other centres may uselower doses for longer periods.7 Most ofour patientswho get steroids are treated for 7-10 days, after whichwe gradually tail off the dose. I would not normallythink of reducing the dose of steroids unless I wasabsolutely certain that the specific anti-pneumocystistherapy was being effective.By the end of the second week of treatmnent, at

which time the patient was continuing to receive IVpentamidine, there appeared to be some gradualimprovement. Partly because of the low plateletcount and also because it was thought that the patientwas sufficiently improved, he was switched fromintravenous to nebulised pentamidine. We have

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Scoular, Moxham, Lucas, Miller

already observed that the patient did not respondwell to nebulised pentamidine when his disease wasjudged to be no less severe, and it seems unlikely,certainly in retrospect, that nebulised pentamidinewould be any more effective at this later stage.The patient deteriorated and the question was

raised as to whether there was a second pathogen.This is, ofcourse, a common clinical dilemma in suchpatients, and particularly in cases such as this when,after three weeks of therapy, the patient is ratherworse than on admission. The chest radiographswere showing deterioration and, particular in view ofthe upper lobe disease, I would certainly have alsobeen concemed about the possibility of tuberculosis.At rebronchoscopy Pneumocystis carinii was againfound, together with Enterobacter cloacae. I notedthat the bronchial tree looked normal. One of theextraordinary things about pneumocystis pneumoniais that even in a patient dying of hypoxaemia thebronchial tree looks entirely normal. In somepatients who have a complicating bronchial infec-tion, as sometimes occurs in those with a lowneutrophil count, the bronchial mucosa may bemarkedly inflamed. At this stage, the patient returnedto intravenous pentamidine but there was thechallenge ofhaving to make up for the few days whenintravenous therapy had been discontinued. By the4th week of treatment the patient was desperately ill.The PO0 was 9 3 kPa, but this was on 60% oxygenand lungs were clearly in advanced failure. By nowthe patient had very severe Pneumocystis cariniipneumonia, and I would also have predicted that hehad advanced adult respiratory distress syndrome(ARDS). In an attempt to improve oxygenationCPAP was tried.9 Although this produced improvedblood gases, the patient was unable to tolerate thetreatment so you had to discontinue it.

If lung biopsies are undertaken in patients withadvanced pneumocystis pneumonia who aredeteriorating after 2 or 3 weeks treatment, what isseen by the pathologist is ARDS and a great deal ofhya1line membrane formation. The lung is virtuallysolid and there are many fibroblasts and some organ-ised fibrous tissue and only scant evidence ofP cariniiorganisms present.'0 It would appear that the treat-ment often cures the infection but the patient diedbecause of the ARDS initiated in the lung. In thispatient I think the situation might be slightly dif-ferent, because repeated lavage late in the illnessshowed persistent P carinii and I do not think that thetreatment ever really coped with the infection. Iwould predict that the pathology will show organis-ing pneumocystis pneumonia as well as advancedARDS.

Dr R MillerYou say you perform transbronchial biopsies in somepatients and that these sometimes provide additional

information. This has not been our experience." Areyou concerned by the increased rate of complicationsreported in HIV-1 positive patients undergoingtransbronchial biopsies? In whom should transbron-chial biopsies be performed? Is there a cost-benefitratio?

Professor J MoxhamI accept that there is an increased risk to performingtransbronchial biopsies in HIV positive patients,although I am not sure how clinically important thisis. Certainly we have never caused a patient greatharm. We certainly do not perform transbronchialbiopsies in most of patients presenting with res-piratory symptoms and signs. I would estimate thatsuch biopsies are undertaken in 10 to 15%. Yourpatient may well have fallen into this group, giventhat the chest radiographs are somewhat atypical andthat at the time of presentation the patient had goodarterial blood gases and would have coped well evenhad he developed a pneumothorax following theinvestigation.

Clinical diagnoses:1. Pneumocystis carinii pneumonia2. Adult respiratory distress syndrome

Pathology (Dr S Lucas)The patient was thin but not wasted. There werenumerous lesions of Kaposi's sarcoma on the skin,some ofwhich had a white halo indicating regression.Internally, the major findings were in the lungs.Before coming to them, letme summarise the findingsin the other viscera. The heart was normal. In thegastrointestinal tract there were lesions of Kaposi'ssarcoma on the palate, tongue, oesophagus and smallbowel (in this latter site lesions up to 5 mm diameterwere seen). The colo-rectum was normal. Micros-copy of the intestine did not reveal CMV infection.The liver showed only fatty change. Lymph nodesand spleen were atrophic. The bone marrow was ofnormal colour and microscopically was cellular,displaying increased haemosiderin (a common find-ing in patients with AIDS); megakaryocytes werenormal in appearance and quantity. In the adrenalsthere was histological evidence of CMV adrenalitiswith some foci ofnecrosis. The brain weighed 1400 gand was entirely normal, both grossly and histo-logically.The larynx, trachea and bronchi were congested

and contained no Kaposi's sarcoma, in fact there wasno evidence of Kaposi's sarcoma anywhere in thelungs. Both lungs were very heavy, the left lungweighed 1450 g (normal = 560 g), and the right1700 g (normal = 620 g). A fibrinous exudate wasvisible on the pleura. On section of the lungs therewas complete meaty-red consolidation. Under themicroscope. this was seen to be the result of two

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Adult respiratory distress syndrome complicating Pneumocystis carinii pneumonia

..v.... 3 X

Figure S Lung (x 10 magnification). The normalarchitecture is destroyed. Clusters of Pneumocystis carinii(pale amorphous material) lie within the remaining alveoli.Extensive interstitialfibrosisis evident (H and E).

Figure 6 Lung (x 200 magnification). Two residual alveoli

both contain Pneumocysti's carinii (arrows). Proliferatingfibroblasts are seen in the interstitium. (H and E).

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Figure 76 Lung (x 200 magnification). Twoereisidaa lelfibonsidtsabreinceaenolsictsuin the interstitium.AHadE

smallartery is visible in the bottom left corner of thefigure.~~~~~~~~

(Elastic Vang(Gi1e mgifcaio)nTer i

distinct processes. Firstly Pneumocystis cariniipneumonia and secondly pulmonary fibrosis (fig 5); inall zones there were persistent Pneumocystis cariniilying within the alveoli. The alveoli were lined withnecrotic material and foci of hyaline membrane(adult respiratory distress syndrome) were clearlyevident, but the most impressive abnormality was theamount of interstitial fibrosis (fig 6). The alveolararchitecture was greatly distorted and active fibro-plasia was evident (fig 7). No CMV inclusions noracid-fast bacilli were seen in the lungs.The pathogenesis of the adult respiratory distress

syndrome must include Pneumocystis cariniipneumonia and this contributed to the severe fibrosis.However, even without coexistent adult respiratorydistress syndrome Pneumocystis carinii pneumoniacan result in diffuse pulmonary fibrosis if there ispersistent infection of the lung.

Pathological diagnoses1. Pneumocystis cariniipneumonia2. Adult respiratory distress syndrome3. Diffuse pulmonary fibrosis4. Kaposi's sarcoma of skin and gut

Address correspondence to: Dr R F Miller.

1 Masur H, Ognibene FP, Yarchoan R, et al. CD4 counts aspredictors of opportunistic pneumonias in human immuno-deficiency virus infection. Ann Intern Med 1989;111:223-31.

2 Miller RF, Steel SJ. Nebulised pentamidine as prophylaxis forPneumocystis carinii pneumonia. J Antimicrob Chemother1991;27:153-7.

3 Sattler FR, Cowan R, Nielsen DM, Ruskin J. Trimethoprim-sulfamethoxazole compared with pentamidine for treatmentofPneumocystis carinii pneumonia in the acquired immuno-deficiency syndrome. Ann Intern Med 1988;109:280-7.

4 Medina I, Mills J, Leoung G, et al. Oral therapy for Pneumocystiscarinsi pneumonia in the acquired immunodeficiency syn-drome. A controlled trial of trimethoprim-sulfamethoxazoleversus trimethoprim-dapsone. N Engl J Med 1990;323:776-82.

5 Miller RF, Godfrey-Faussett P, Semple SJG. Nebulised pen-tamidine as treatment for Pneumocystis carinii pneumonia inthe acquired immunodeficiency syndrome. Thorax 1989;44:565-9.

6 Gagnon S, Boota AM, Fischl MA, et al. Corticosteroids asadjunctive therapy for severe Pneumocystis carinii pneumoniain the acquired inmunodeficiency syndrome. N Engl J Med1990;323:144-50.

7 Bozzetta SA, Sattler FR, Chin J, et al. A controlled trial of earlyadjunctive treatment with cortocosteroids for Pneumocystiscarinii pneumonia in the acquired immunodeficiency syn-drome. N EnglJMed 1990;323:1451-7.

8 Donelly H, Bernard EM, Rothkotter H, et al. Distribution ofpentamidine in patients with AIDS. J Infect Dis 1988;157:985-9.

9 Miller RP, Semple SJG. Continuous positive airway pressureventilation for respiratory failure associated with Pneumocystiscarinii pneumonia. Resp Med 1991;85:133-8.

10 Fitzgerald W, Bevelaqua FA, Garay SM, et al. The role of openlung biopsy in patients with the acquired immunodeficiencysyndrome. Chest 1987;91:659-61.

11 Griffiths MH, Kocian G, Miller RF, Godfrey-Faussett P.Diagnosis of pulmonary disease in human immunodeficiencyvirus infection: role of transbronchial biopsy and broncho-alveolar lavage. Thorax 1989;44:554-8.

Accepted for publication 22 February 1991

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