Pulmonary Manifestations of Disseminated Cryptococcosis in Patients with AIDS* Vtjay Chechani, M.D.;t and Stephan L. Kamholz, M.D., F.C.C.R+

Forty-eight patients with disseminated cryptococcosis and AIDS were retrospectively studied to define the pulmonary manifestations. Cryptococcus neoformam (CN) was 6rst isolated from a pulmonary site in 12 patients. Disseminated disease was subsequently documented in all these patients. Symptoms and roentgenographic manifestations (normal, nodular/circumscribed in6ltrates, pleural effusions, lobar consolidation) were diverse. Interstitial in6ltrates predicted the presence of another opportunistic lung infection besides cryptococcosis in 6ve patients (three untreated and two treated patients). Infectious causes other than cryptococ-

cosis were established by culture and clinical course in 6ve of the ten patients who developed chest roentgenographic abnormalities during amphotericin B therap~ Endobronchial abnormalities were identified in four patients at bronchoscopy. Bronchoalveolar lavage (9/9) and pleural fluid (3/3) cultures were sensitive tests for detection of pulmonary involvement with CN. (Chest 1990; 98:1060-66)

he spectrum of pulmonary manifestations of crypT tococcosis in patients with AIDS remains to be s

NY. Complete medical records and chest roentgenograms, which were available for 48 of these 84 patients, were retrospectively reviewed. These 48 patients included the 12 patients from whom CN was first isolated from a pulmonary site. The diagnosis of AIDS was made according to the criteria of Centers for Disease Control. 7 All chest roentgenograms were reviewed by both of us. Roentgenowaphic abnormalities noted were considered to be unequivocally due to CN only when CN was cultured from sputum! bronchoalveolar lavage (BAL)/transbronchial lung biopsy specimen! pleural fluid/pleural biopsy specimen; other opportunistic lung infections were excluded by the examination and culture of bronchoscopic/pleural specimen. New roentgenographic abnormalities

fully defined. 1- Descriptions of the chest roentgenographic abnormalities noted in association with cryptococcosis in patients with AIDS have been limited, and in these few reports, the presence of coexistent opportunistic pulmonary pathogens has complicated the interpretation ofthese findings. l In a recent review of 106 patients with cryptococcosis complicating AIDS, four patients had isolated pulmonary cryptococcosis, but cough or dyspnea was present in 31 percent of the patients, suggesting more frequent pulmonary involvement with Cryptococcus neofor6 TrUlns (CN) in the presence of dissemination. During an 18-month period, we identified 12 AIDS patients from whom CN was first cultured from a pulmonary site. Systemic dissemination was then documented in all 12 patients subsequent to the identification of eN in the pulmonary tissue/fluid. This study focuses on the perplexities of diagnosis of cryptococcal pulmonary disease in patients with AIDS and pulmonary complications encountered during therapy. MATERIAL AND METIIODS

Cryptococcus neoformans was isolated from one or more sites in 84 patients during an 18-month period Ouly 1987 through December 1988) at two university-affiliated municipal hospitals in Brooklyn, *From the Divisions of Pulmonary Medicine, Department of Medicine, State University of New York Health Science Center at Brooklyn, Brooklyn, NY (Dr. Kamholz), and University of MissouriColumbia School of MedicineIHarrv S. Tnlman Memorial Veterans Hospital, Columbia, MO (Dr. Chechani). t Assistant Professor of Medicine. tProfessor of Medicine. Manuscript received September 20, 1989; revision accepted April 30,1990. Reprint requests: Dr. Chechani, Chief: Pulmonary Section (111 B), Truman Memorial VA Hospital, Columbia, MO 65201

1060

=

eN Cryptococcu. neoforman.; AB pcp = Pneumocystia caring pneumonia

=amphotericin

B;

Table 1-Characteristics of48 Patients with Cryptococcosis and AIDS Feature

No.(%)

Mean age, 35 yr Sex M

40 (83)

F

8 (17)

AIDS risk Intravenous drug abuse Homosexuality Heterosexual (born outside United States) Heterosexual (born in United States) Prior/concomitant opportunistic infections Pneumocystis carinii pneumonia Esophageal candidiasis Progressive disseminated histoplasmosis Total Symptoms and signs Fever Cough Sputum production Dyspnea Chest pain Hemoptysis Headache Oral thnlsh Diffuse lymphadenopathy Nuchal rigidity

38 (79)

4 (8) 3 (6) 3 (6)

9 3 1 13

(19) (6) (2) (27)

39 (81) 13 (27) 8 (17) 9 (19) 6 (13) 1 (2)

37 (77) 26 (54)

23 (48) 14 (29)

Disseminated Cryptococcosis in AIDS Patients (Chechani, Kamholz)

Table 2-Characteristics of 12 Patients with Pulmonary Cryptococcallnvolvement Proven by Culture· Patient ~o.

5

6

7

8

PF, PB, S, B BAL, CSF, B BAL, CSF, B BAL, B, CSF 5, EBB

BAL, B, CSF

BAL, TBLB, B,C5F

BAL, CSF, B, TBLB, TBNA

BAL, B, CSF

PF, CSF, B

PB PB, PF B

BAL BAL CSF

BAL CSF

Not done Not done

result

Negative PB: chronic inflammation tCN

OtherOU

None

None

Sites sampled forCN Pulmonary sites +CN by Cytology Culture Other sites +CN culture SeromCN Ag Biopsy site

and

4

3

2

Variable

Sputum B,CSF

BAL CSF

BAL BAL CSF

BAL, TBLB BAL, TBLB B,CSF

BAL, TBLB BAL CSF

>1:1,024 Endobron· chial: granulation tCN

>1:1,024 Not done

>1:1,024 Not done

>1:1,024 TBLB: no granuloma, no inflammation, CN present

>1:1,024 TBLB: noinHamma· tion tCN

Not done Not done

None

None

None

None

None

None

9

10

11

12

BAL, EBB, CSF, B, PF

BAL, B, EBB, CSF

BAL, B, TBLB

PF CSF,B

BAL BAL, PF CSF

BAL, EBB BAL, EBB CSF

BAL

Not done Not done

Not done Not done

Not done EBB: focal ulceration with 6brinoos exudate+CN

None

BAL: MTB, MAl PF; MTB, MAl B: Staphylo-

BAL: Histoplasma

1:10 TBLB:a1veo~

6lled with foamy eosinophiliceludate (PCP); CN not seen BAL: PCP, MAl, CMV

coccw auf'eW,

K1eblitlls Chest roentgenogram

P(A =a)O.

Tberapyand course

Endobronchial abnor-

LLLconso~-

RULand dation RLLcircumscribed intil· trate with cav· itation 31 47 221 50 PF: exudate Treated with Resolution of Spontaneous WBC,400; penicillin t nodules with partial resolu· P47% gentamicin for ABT(2~, lion inOO lA71, M7%; 10 days with- new progres- days when total resolu- out improve- sivebilateral FOB was tion of nodule ment, FOB intentitialin- done, total and PE with done then, 6ltrates and resolution j)daysABT partial resolu- fever due to \\ith 18 day tionofinfilPCP by sub- ABT,O.5g (0.36~ trate at death sequent FOB (10 days ABT, treated with 0.2[7) T-S success· fully FOBn~done Circumferen- Red plaques None tial narrowing

LLL2cm nodule +left pleural effusion

Large bilateral nodules with cavita· tion, ITA

Rt hilaradenopathy

Normal

BiiateralPE, ITA

14 46 "Hot" gallium Developed PE withABT scan that resolved spontaneously

21 Increased uptake in Rt biJar area on gallium scan, TBNAnondiagnostic, TBLB not cui· tured

M

m

None

None

None

None

None

Normal

Normal

pneumonitlt Intentitialin- Bilateralmili- Bilateral in6ltrateRt ary infiltrates terstitialinfillung, Rt PE, trates ITA ITA 43

dative pleural e8'usionsfrom CHF; bone marrow hiopsy: nonnecrotizinggranuloma, no pathogens

transudate, tamicin, AB, cbronic renal in6ltrates failure, acute wonened, transverse early death myeUtis, early death (0.28 ~

None

Not done

None

oflingular

mality

segmental bronchus Pulmonary

symptoms

None

None

Cough, dysp·

Productive

nea

cough

30

30

Developed hi- PF:CN Agti- Treated with Clearing of in- Clearing of in· lateral transu- ter >1:1,024 nafctllin, geo- 6ltrates with filtrates with ABT(O.5~

sudden death

21 days ofT-S therapy, discharged from hospital, recurrent fever treated with AB with clinical resolution

White thrush- Mucosal granlike plaques; ularity biopsy culture KreWonly CN

Productive

Productive

Productive

Dyspnea,

Productive

Productive

cough, pleuriticchest pain

cough, dyspnea, pleuritis chest pain

cough, dysp-

chest pain

cough, dysp-

cough, dysp-

nea

nea

nea

*PF = pleural fluid; PB = pleural biopsy; BAL = bronchoalveolar lavage; B = blood; CSF = cerebrospinal fluid; TBLB = transbronchial lung biopsy; EBB = endobronchial biopsy; TBNA = transbronchial needle aspiration; eN = Cryptococcus neoformans; OLI = opportunistic lung infection; LLL=left lower lobe; RUL=right upper lobe; RLL=right lower lobe; ITA = intrathoracic adenopathy; P(A=a)O,=alveolararterial O2 difference; ABT = amphotericin B therapy; FOB = 6beroptic bronchoscopy; eHF = congestive heart failure; MAl = Mycobacterium avium-intracellulare; MTB = Mycobacterium tuberculosis; CMV = cytomegalovirus; PCP = Pneumocystis carinii pneumonia; TS = trimethoprim-sulfamethoxazole.

CHEST I 98 I 5 I NOVEMBER, 1990

1081

developin~

during amphotericin B (AB) therapy were L'Onsidered to have another etiologic diagnosis only if supported by microbiolo~ic diagnosis and response to anti-infective a~ents. Bronchoscopies in eight of ten patients were performed by one of us. Descriptive reports of bronchoscopies were available for the other two patients. Transbronchial (n = 3) and endobronchial (n = 2) biopsies were done at the discretion of the hronchos2 cm) nodule or circumscribed infiltrate (n = 3) with cavitation (n = 2), lobar acinar consolidation (n = 1), unilateral or bilateral interstitial lung infiltrates (n =3), pleural effusion (n = 3), and intrathoracic adenopathy (n = 5).

FIGURE 3. Pleural hiopsy specimen showing hudding Cryptococcus neofonruJns amidst orl!:anizinl!: pleural inflammatory exudate (eMS stain, x 1,000).

Figure 4 illustrates some of these abnormalities (patients 1, 2, and 4; Table 2). All three patients with initial interstitial infiltrates (patients 10, II, and 12; Table 2) had another opportunistic lung infection that could have been responsible for the noted abnormality. One patient (patient 12) had complete clearing of interstitial infiltrates with 21 days of trimethoprimsulfamethoxazole therapy of the coexistent P carinii pneumonia (PCP) prior to beginning AB therapy. Two patients (patients 3 and 5; Tables 2 and 3) had development of bilateral interstitial infiltrates during AB therapy, PCP was diagnosed at bronchoscopy, and remission of cryptococcosis was documented by negative fungal cultures of BAL and CSF. Thus, an additional opportunistic lung infection (besides CN) was documented in all five patients with diffuse interstitial infiltrates: PCP (n = 3), Mycobacterium tuberculosis, Mycobacterium avium-intracellulare, and disseminated histoplasmosis (all one each). Of the 36 patients with extrapulmonary disseminated cryptococcosis, 23 patients had a normal chest roentgenogram; seven patients had preexisting roentgenographic abnormalities that were unchanged and unrelated to the diagnosis of cryptococcosis. Six patients had new roentgenographic abnormalities related temporally to the diagnosis ofcryptococcosis. Bacterial and mycobacterial causes for the roentgenowaphic abnormalities were excluded by multiple sputum and blood cultures in all six patients, but bronchoscopic confirmation of CN and exclusion of other pathogens, eg, P carinii, was lacking. The following abnormalities were noted: large (>2 cm) cavitating nodule/circumscribed infiltrate (n = 5), small (1 cm) nodule (n = 1), and bilateral interstitial infiltrates (n = 1), Two of these patients showed spontaneous resolution (without any therapy) of the roentgenographic abnormalities while in the other four patients, no change was noted despite AB therapy. New chest roentgenographic abnormalities developed in ten patients during AB therapy (Table 3). In five patients (patients 1, 2, 3, 5, and 8), cryptococcosis was shown to be inactive (negative culture of the initially involved site) at the time that the new roentgenographic abnormality was noted. A specific bacterial or protozoan cause was established for the noted roentgenographic abnormality in all five patients and resolution was noted with specific therapy. New roentgenographic abnormalities appearing in patients responding to anticryptococcal therapy thus should not be ascribed to cryptococcosis. A search for another infectious cause should be initiated. Four patients (patients 4, 7, 9, and 10) had received insufficient doses of AB and the activity of cryptococcosis was not established by a repeated culture. Acute lower lobe infiltrates in patients 4 and 7 coincided with worsening mental status, and aspiration pneumonia was the likely CHEST 198 151 NOVEMBER, 1990

1063

FICI'IIE 4. Chest roentgenograms of three patients showing three diH"erent abnormalities of pulmonary cryphK.'>ct"sis. A (Ii'!t). Left lung nodule with ipsilateral pleural effusion (arrow) (patient I. ulhle 2). B (cl'ntl'r). Left lung consolidation (patient 2. Tahle 2). C (right). I\jodular lesions wilh cavitations in the right upper lohe and the right lower lohe (patient 4, Tahle 2).

cause. Patient 9 had multiorgan failure and adult respiratory distress syndrome develop; it is not known whether this was due to disseminated cryptococcosis. Lower lobe collapse in patient 10 caused immediate death and was not fitrther evaluated. Patient 6 had left pleural eA'usion develop that resolved spontaneously. Endolmmchial AIJTlofflwlities

Endobronchial abnormalities were uoted in four of the ten patients who underwent bronchoscopy. In

patient 11 (Table 2), white mucosal plaques were found in the trachea and major bronchi. Biopsy specimens of these lesions revealed fi>eally ulcerated bronchial mucosa with fibrinous exudation and CN-like yeast in the tissue. Although Histoplasma cflpsulatum and CN were cultured from the BAL, only eN was cultured from the endobronchial biopsy specimen. Cherry red plaques were seell in the trachea and major bronchi in patient 3 (l1tbles 2 alld 3). Endobronchial biopsy specimens revealed granulation tissue

Table 3-New Roentgenographic Abnormalities Appearing During Amphotericin B (AB) Therapy· Patient No.

l(,tal AB Dose. WDays of AB Therapy

New Hoentgenographic AllIIormality Cardiomegaly (pericanlial dli.sion). hilah'ral pleural effusions

2

2.4166

Bilateral patchy nodular infiltrates

3

2.0/fiO

Progressive Ilt'rihilar inh'rstitial infiltratt·

4

O.()4/01

.'j

2.0/fiO

fi

i

1.2I2S O.2i/1O

S

0.4/12

9

O.3i/15 (l.lS/OO

Bilateral lower 101... al""olar infiltratt's

10

Bilateral interstitial infiltrates

Left pleural etl'us;on Bilateral lower loht, alveolar infiltrates Cardiomegaly (pericardial eHilsion. hilateral pleural eHilsions Diffuse alveolar infiltrates Left lower lohl' t"lIapse

Etiolo).,'y Plenral eH'usion was a transudate and sterile; Baderial pericarditis (Enterot'>ceus. Proteus); pericardia! window; AB therapy to 2.2 g. discharged from hospital Septic pulmonary emholi from Staphylococcus aUlT!us endocarditis; resolution with oxacillin. AB to 2.i g; disdJargt'd from hospital Hesolution of initial nodules with AB therapy; Subse'1uently Prll'ul/lOcystis carinii aud CN identified on BAL cytolo).,'y hut CN not cultured; AB to 2.02 g; ""solution of neW infiltrates with TI\I P-SMX; discharged from hospital Aspiratioll pneumonia (worsening melltal status); death BAL: P carinii alld CN Seen 011 cytolo).,'y hut CN not cultured; AB therapy stopped; resolutiou with TMp· SMX Not ,'valuated; AB to 2.0 g; discharged from hospital Aspiration pneumonia (worsenillg mental status); d"ath CllF (pump failure); Clostridium p/,r!ri'Ig.·,1S haderemia; pleural effusion was transudative and sterile AHDS. mllltiorgan failure; death Not evaluated; death

*Inilial chest roentgenogram was normal in all patients ('scept patient 3. BAL = hrondlOalveolar lavage; CN = Cryptococcus ,,.,o!onlums; CllF. t,mgestive heart failure; TM P-SMX = trimethoprim-sulfamethoxazole; alld ARDS = adult respiratory distress syndrome.

1064

Disseminated Cryptococcosis in AIDS Patients IChechani, Kamholz)

with abundant CN-Iike yeast in the tissue (Fig 2). Endobronchial biopsy specimens and BAL cultures for CN were negative. This patient had already received 2 g of AB prior to bronchoscopy; thus, failure to isolate CN confirmed inactivity of cryptococcal disease. In this patient, P carinii was identified in BAL. The patient defervesced and had clearing of interstitial infiltrates with anti-Pneumocystis therapy. In two patients, biopsy specimens of the endobronchial abnormalities of narrowing of the lingular segmental bronchus (patient 2, Table 2) and mucosal granularity (patient 12, Table 2) were not taken, and thus, exact causes could not be established. DISCUSSION

Cryptococcus neofonnans frequently infects patients with AIDS.9-11 Cryptococcus neofonnans gains access to the host via inhalation; however, the central nervous system is the initial site of infection identified in the majority of patients. Prior descriptions of the pulmonary manifestations of cryptococcosis in AIDS are limited, and the ability to attribute specific abnormalities to CN is complicated by the frequent coexistence of other opportunistic lung infections. 1 We have attempted to identify the clinical features definitely attributable to pulmonary cryptococcal involvement; thus, growth in culture of CN from a pulmonary site was a requirement. In 12 patients, CN was first isolated from a pulmonary site. Further studies documented dissemination in all 12 patients. The three patients with coexistent opportunistic lung infection could not be distinguished from the nine patients with solitary pulmonary cryptococcal infection on the basis of symptoms. Spontaneous resolution of chest roentgenographic abnormalities due to CN has been well documented in normal hosts. 12 These lesions can also resolve in the face of dissemination. 13 Since cryptococcal infection is acquired through inhalation, the presence of normal chest roentgenograms in four of our patients with pulmonary cryptococcal involvement raises several questions. Has there been spontaneous resolution of the roentgenographic abnormality of newly acquired cryptococcal infection or has dissemination occurred from an old (roentgenographically occult) cryptococcal focus due to impaired immunity? Bronchoscopy was performed in these four patients with normal roentgenograms because of respiratory symptoms (two patients), widened A-a02 gradient (two patients), increased gallium uptake in the lungs (one patient), and unilateral hilar adenopathy (one patient). Transbronchial lung biopsy specimens documented CN in pulmonary tissue without a significant host response in two patients. One patient (patient 1, Table 2) definitely had a primary pulmonary cryptococcal infection manifested

by the development of a new lung nodule and pleural effusion that had been absent two months previously. Blood cultures were also positive for CN; however, CSF (antigen, cytology, and culture) and serum cryptococcal antigen were negative (three samples). Interestingly, serum cryptococcal antigen became positive (titer 1:16) after two weeks of AB therapy. Three other patients (patients 2, 3, and 4; Table 2) with pulmonary cryptococcal involvement proven by culture had lung nodules/acinar infiltrates. Total clearing of infiltrates with AB therapy was seen in all three patients. Cryptococcus neofonnans is endemic in New York City and the Caribbean (birthplace of all 12 patients). Extrapulmonary dissemination is the natural history of untreated pulmonary cryptococcosis in immunocompromised hosts, 13 which is confirmed by this study. In patients suspected of having AIDS, culture of eN from sputum or bronchoscopic specimen should prompt both investigation to document dissemination and the initiation of therapy. Serum cryptococcal antigen was determined in 28 patients prior to the start of therapy. It was positive in 25 patients (89 percent) and negative in three patients. Extrapulmonary dissemination was documented by culture in all but one of these 28 patients (this patient refused lumbar puncture). Serum cryptococcaI antigen was determined in six patients with pulmonary involvement and was positive in all of them. Pleural fluid cryptococcal antigen was determined in one patient (patient 9, Table 2) and it was positive. Although pleural fluid chemistry studies suggested a transudative effusion (possibly due to chronic renal failure), pleural cryptococcosis was confirmed by positive pleural fluid culture for CN. These data suggest that serum cryptococcal antigen is a sensitive test for detection of disseminated cryptococcosis in patients with AIDS. In untreated patients, BAL (9/9 patients) and pleural fluid (3/3 patients) cultures for fungi were the most useful tests for establishing pulmonary cryptococcal involvement. In treated patients, culture results may be negative despite the demonstration of CN-like yeast on cytologic examination. This may have therapeutic implications, since five patients in the current series developed fever and abnormal chest roentgenogram during AB therapy (patients 1 to 3, 5, and 8; Table 3). However, cryptococcal disease was shown to be in remission by CSF (n = 5) and BAL (n = 2) cultures and other infectious causes were established. Amphotericin B therapy was discontinued at that point in four of them without clinical deterioration. Interstitial infiltrates in all three patients with untreated cryptococcosis and in two patients with treated disease were associated with another opportunistic lung infection. CHEST I 98 I 5 I NOVEMBER, 1990

1085

In patients with AIDS, previous reports have described endobronchial abnormalities of Kaposi's sarcoma,14 tuberculosis,15 and P carinii. 16 Endobronchial abnormalities in two of our patients (white plaques and cherry red plaques) were definitely due to eN, as proved by biopsy specimens. We believe this to be the first report of endobronchial abnormalities associated with pulmonary cryptococcosis. In summary, in patients with AIDS, symptoms and roentgenographic presentations of pulmonary cryptococcosis are diverse. Nodular/circumscribed infiltrates, pleural effusions, or even normal chest roentgenograms are compatible with cryptococcal pulmonary involvement. The presence of interstitial infiltrates should raise suspicion of other coexistent opportunistic lung infections. New infiltrates appearing during the course of anticryptococcal therapy are likely to have another infectious cause. Endobronchial abnormalities may occur due to eN. Bronchoalveolar lavage and pleural fluid cultures are sensitive tests for detection of pulmonary involvement with cryptococcosis. REFERENCES 1 Wasser L, Talavera W Pulmonary cryptococcis in AIDS. Chest 1987; 92:692-95 2 Suster B, Akennan M, Orenstein M, Wax MR. Pulmonary manifestations of AIDS: review of 106 episodes. Radiology 1986; 161:87-93 3 Perla EN, Maayan S, Miller SN, Ramaswamy G, Eisenberg H. Disseminated cryptococcosis presentin~ as the adult respiratory distress syndrome. NY State J Med 1985; 704-06 4 Newman TG, Soni A, Acaron S, Huan~ cr. Pleural cryptococcosis in the acquired immune deficiency syndrome. Chest 1987;

1066

91:459-60 5 Katz AS, Niesenhaum L, Mass B. Pleural effusion as the initial manifestation of disseminated cryptococcosis in acquired immune deficiency syndrome: diagnosis hy pleural hiopsy. Chest 1989; 96:440-41 6 Chuck SL, Sande MA. Infections with Cryptococcus neofonnans in the acquired immunodeficiency syndrome. N Engl J Med 1989; 321:794-99 7 Centers for Disease Control. Revision of the CDC surveillance case definition for acquired immunodeficiency syndrome. MMWR 1987; 36:1s-15s 8 Crystal RG, Reynolds HY, Kalica AR. Bronchoalveolar lavage: the report of an international conference. Chest 1986; 90:12231 9 Kovacs JA. Kovacs AA. Polis M, \Vri~ht \VC, Gill VJ, Tuazon CU, et al. Cryptoc'()Ccosis in the acquired immunodeficiency syndrome. Ann Inter Med 1985; 103:533-38 10 Zuger A, Louie E, Holzman RS, Simberkoff MS, Rahal JJ. Crypt