Rev Inst. Med. trop. São Paulo37 (2): 93-98, março/abril, 1995.

MYCOBACTERlUM AVIUM COMPLEX (MAC): AN UNUSUAL POTENTIAL PATHOGEN INCEREBROSPINAL FLUIO OF AIOS PATIENTS

David Jamil HADAD (I), Tereza Cristina PETRY (2), Anaenza Freire MARESCA (3), Lucilaine FERRAZOLl (4),Maria Conceição MARTlNS (4), Maria Cecilia de Almeida PALHARES (5), Walkyria Pereira PINTO(6),

Adauto CASTELO FILHO (7) & Moises PALACI (4)

SUMMARY

Mycobacterium avium complex (MAC) is frequently isolated from patients with late complica-tions of Acquired Immunodeficiency Syndrome (AIOS), especially in North America and Europe.However, its isolation from the central nervous system (CNS) has been seldom reported in thesecountries. MAC infections in AIOS patients in African and Latin American countries are believed tobe uncommon. ·We report the isolation of MAC from cerebrospinal fluid (CSF) of 11 AIOS patientsout of 1723 (0.63%) seen at "Centro de Referência e Treinamento - AIOS", São Paulo and discuss thesignificance of its isolation.

KEYWORDS: Mycobacterium avium complex (MAC); Cerebrospinal fluid (CSF); Acquiredimmunodeficiency syndrome (AIOS).

INTRODUCTION

Since the initial description of Acquired Imrnu-nodeficiency Syndrome (AIOS) in 1981, mycobacterialdisease have represented an important group of oppor-tunistic infections 13. 15.23.

In Brazil tuberculosis has been the most commoninfection reported in AIDS patients after oralcandidiasis and Pneumocystis carinii pneumonia 26. Incontrast little is known about the frequency of MACinfections I. 4. BARRETO et a!. 2, at Instituto deInfectologia Emilio Ribas (São Paulo, Brazil), isolatedMAC from 23 (J 8.4%) out of 125 patients with persist-ent fever, anemia and leucopenia among 2628 admittedto the hospital between May 1990 and April 1992.

These mycobacterial diseases are usually causedby Mycobacterium tuberculosis (M. tuberculosis) orMycobacterium avium complex (MA C) 1. MAC iscomposed of two species called M. avium and M.intracellulare 16, indistinguishable by routine identifi-cation tests employed in clinical laboratories 29. 30 Since the description of the first AIOS cases 24

(I) Médico infectologista do Centro de Referência e Treinamento AIOS (CRTA), Mestre em Doenças Infecciosas e Parasitárias pela Escola Paulista deMedicina.

(2) Médico Infectologista do CRTA.(3) Ex-Infectologista do CRTA.(4) Pesquisadores Científicos do Setor de Micobactérias do Instituto Adolfo Lutz;(5) Chefe do Laboratório do CRTA.(6) Diretora Técnica do CRTA.(7) Professor Adjunto da Disciplina de Doenças Infecciosas e Parasitárias da Escola Paulista de Medicina.

Correspondence to: David Jamil Hadad, Rua Dr. Diogo de Faria, 666/35 - Vila Clementino, 04037-222 São Paulo, S.P., Brasil.

j 93

HADAD, D. J.; PETRY, T c., MARESCA, A. F.; FERRAZOLI, L, MARTINS, M. c. PAlHARES, M. C. de A.; PINTO, W. P.; CASTELO FilHO, A.& PAlACI, M. - Mycobacterium avium complex (MAC): an unusual potential pathogen in cerebrospinal fluid of AIDS patients. Rev. Inst. Med.trop. S. Paulo, 37(2): 93-98, 1995.

OBJECTIVESdisseminated disease has become the most frequentclinical form of MAC infection. The impact of oppor-tunistic infections due to MAC in AIOS varies fromregion to region. In North America and Europe, MAChas been described as the most frequent systemicbacterial infection in this group of patients 15 31. In theUnited States, the prevalence of disseminated MACdisease ranges between 17 to 24% 17 and about 50% atautopsy 9. However, it is extremely rare in Africa,South America and Asia 18

The records of the Bacteriology Department,Instituto Adolfo Lutz, for the period from January 1989to August 1990 were reviewed and the charts of pa-tients from whom MAC was isolated from CSF wereanalyzed in detail at "Centro de Referência e Treina-mento AIOS".

In this report we describe uncommon findings ofMAC in CSF of 1I patients with AIOS in São Paulo(Brazil) and discuss its probable clinical significance.

MATERIALS AND METHODS

While the incidence of tuberculous rnenin-goencephalitis is higher in H[V positive than H[Vnegative patients 3, there is little infonnation regardingMAC isolation from CSF and its pathogenicity in rela-tion to the CNS 20. 22. 3D The diagnosis of AIOS was confinned according

Table 1

Clinical deseriplion of I I AIOS patients, with MAC isolated from eerebrospinal fluido

Patient Risk Group Classification prior tornycobacteriosis diagnosis/(Opportunistic Infections)

Clinical Picture underinvestigation

Indieation for Lumbar Puncture(date of spinal tap)

Intravenous drug addictlBisexual

IVCI,2(Cerebral toxoplasmosis and Oral

candidiasis)IVCI

(PCP and Cerebral toxoplasmosis)

Intraeranial hypertension syndrorne(1220.89)

Seizures

2 Bisexual Fever Frontal headaehe and fever for 8days, Neck Stiffness

(0418.90)Syrnpathetic hyperactivity and loss

of sphincter control(10.0689)

Frontal headache and fever for 5days

(02.20.90)Fever of unknown origin

(O 1.2490)Drowsiness, left hemiparesis

(02.23.89)

Intravenous drug addict 11(-)

FebrilIe pneumopathy

4 Promiseuous heterosexual/Intravenous drug addiet

IVCI'(Cerebral toxoplasmosis)

Diarrhoea

5 Homosexual IVC2(Oral candidiasis and PCP)

IVCI + D'(Cerebral toxoplasmosis

and PCP)IV AI, C2

(Constitutional diseaseOral candidiasis*)

IVCI(PCP)IVCI(PCP)

IVAI.C!'(Constitutional disease,

Pulmonary mycobacteriosis)IVCI,2'

(Cerebral toxoplasmosis andcryptococcosis, oral candidiasis

and PCP)

Fever

6 Bisexual Fever

Bisexual None Headaehe. fever for 6 days(08.11.89)

NoneBisexual Mental confusion. drowsiness(07.12.90)

Headache, nausea for 2 days(06.06.90)

Mental confusion(07.11.90)

9 Hornosexual None

10 Blood Transfusion None

None Spinal tap control for cerebraleryptococcosis

(05.10.89)

11 Bisexual

PCP = Pneumocystis carinii pneumonia § - Patient with shigeIlosis1- Patient with Whipple's disease

* - Patients with Iymph node mycobaeteriosist - Patient with pulmonary myeobaeteriosist - Patient with Kaposi' s Sarcorna

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~-----------------------------------------------------------------BADAD,D. J.; PETRY, T C. MARESCA, A. F., FERRAZOLl, L, MARTINS, M. C, PAlHARES, M. CdeA.; PINTO, W P.; CASTELO FILHO, A.& PAlACI, M. - Mycobacterium "vil/n/ complex (MAC): an unusual potential pathogen in cerebrospinal fluid of AIDS patients. Rev, Inst. Med.rrop- S. Paulo, 37(2): 93-98, 1995.~-~--------------------~----------------------------------------------

Table 2

8iochemical and cytological findings in the cerebrospinal fluid ofpatients with Mycobucterium avium cornplex.

Cerebrospinal Fuid Mycobacteria Culture from other sites:

GlucoseProtein (mg/dl) Cells Lirnphocytes PMN MnRT Sputum Blood Bone

Patient Date (rng/d l ) (mmol/l) (lmm3) (%) (%) (%) marrow

I 12.20.89 14 35 1,92 378 61 36 2 NA MAC MAC2 04.18.90 118 64 3,52 48 10 87 33 10.06.89 2020 12 0,66 3840 25 73 24 02.20.90 170 33 1,81 1210 2 94 4 NA5 01.24.90 58 33 1,81 I MAC MAC6 02.23.89 180 45 2,47 5 NA7 08.11.89 260 38 2,09 1194 13 83 48 07.12.90 100 43 2,36 26 14 84 2

08.02.90 2500 36 1.98 40 18 78 49 06.06.90 375 31 1,70 399 3 96 I10 07.11.90 50 33 1,81 9 (damaged cells) MAC11 03.06.89 70 27 1,48 I

05.10.89 91 27 1.48 206.19.89 96 19 1,04 4

PMN ~ Polymorphonuciear cells; MnRT ~ monoreticular cells: MAC ~ M (/vi1l111 cornplex: NA ~ Not available; - ~ negative

10 rhe 1987 Centers for Disease Control (CDC) classi-fication 5 Spinal taps were performed if the patientshad a presentation consistent with CNS involvement,except for one patient who was being investigated fora febrile syndrome.

For each chart reviewed, the following informa-non was recorded: CSF analysis, age, sex, risk group,c1assification prior to mycobacteriosis diagnosis, op-portunistic infections, clinical picture under investiga-rion, indication of lumbar puncture, and time betweenMAC isolation from CSF and death.

A smear for acid-fast bacilli was obtained from alICSF specimens submitted to mycobacterial culture as amatter of laboratory routine. The samples were stainedby the Ziehl-Neelsen and Gram methods and inoculateddirectly onto Lowenstein-Jensen, Sabouraud culturemedia and MuelIer Hinton agar base containing 5%sheep blood (Difco Laboratories, Detroit, Michigan,USA). The cultures were incubated at 37°C and exarn-ined for the visible growth of bacteria and fungi accord-ing to specific standardized procedures 16. 17.25. Whenisolated, mycobacteria were identified by routine cul-ture and biochemical test 8. 17

In addition to spinal fluid samples, sputum, bron-chial washing, bone marrow and blood samples fromthe same patients were cultured for mycobacteria 8. 17

RESULTS

Of 1723 patients who underwent spinal taps, 20(1.16%) and II (0.63%) had M. tuberculosis and MACisolated from CSF, respectively.

(i) Table I shows epidemiological and clinical data forI I HIV cases associated with recovery of MACfrom CSF. Of the II patients, 10 were males. Thepatient age ranged from 24 to 57 years (average =

35.5 years old).

Cases 2, 4, 7 and 9 had headache as the neurologi-cal manifestation which lead the physician to performthe lumbar puncture; 6 and 8, drowsiness; I, intra-cranial hypertension; 8 and 10, mental confusion; and3, sympathetic hyperactivity. In case 5 a spinal tap wasperformed for the investigation of a febrile syndrome(no neurological manifestations were reported), and incase 11 the procedure was performed for the control ofcerebral cryptococcosis.

Table I also list stages of HIV infection based onthe CDC classification. Cases 2,4,8,9 were classified asIV C1; 10, IVA, C1; I and lI, IV C1.2; 6, IV CJ' D; 5,IV C2; 7, IVA, C2; and 3, I!. Amo'!-g these cases, fivealso had cerebral toxoplasmosis (I, 2, 4, 6 and 11) andone (11) cerebral crytococcosis.

HADAD, D. J.; PETR Y, T c, MARESCA, A. F.; FERRAZOLl, L; MARTINS, M. c., PALHARES, M. C. de A.; PINTO, W. P; CASTELO FILHO, A.& PALACI, M. - Mycobacterium avium cornplex (MAC): an unusual potential pathogen in cerebrospinal fluid of AIDS patients. Rev. Inst. Med.trop. S. Paulo, 37(2): 93-98, 1995.

Typical disseminated MAC infection was ob-served in cases I, 5, and 10. These patients had MACisolated from CSF, blood and bone marrow aspirate. lnaddition, MAC was isolated two and .three times, re-spectively, from the CSF of patients 8 and II (Table 2).

(ii) The time between MAC isolation from CSF anddeath ranged from less than 10 hours to 12 monthswith a mean of 2.5 months.

(iii) Bacteriological analysis. All isolates were slowlygrowing nonphotochromogenic acid-fast bacilli,and colonies on egg-based media appeared smoothand domed. Biochemical analyses demonstratedthat they do not produce niacin, nitrate reductase orurease, that they have </= 45mm of catalase activ-ity and do not hydrolyze Tween. The organismsshow resistance to most of the antimicrobial agentsto which M. tuberculosis is usually susceptible. Noaerobic bacteria or fungi were isolated from theCSF. Also, anti-toxoplasrna IgG was not detectedby indirect immunofluorescence in the CSF speci-mens from which MAC was isolated.

DISCUSSION

During the Iast 10 years, along with the increasedincidence of AIDS, disseminated infections caused byMAC have been increasingly reported 11. 12. 15.20. How-ever, there have been few reports of MAC disease fromdeveloping countries, presumably reflecting inadequatecare and consequent high mortality due to infection byother more virulent organisms at earlier stages of HIVdisease 6.

It is now well recognized that disseminated MACinfections develop relatively late during the course ofHIV infection after the circulating CD4 + counts havefallen to less than 100 cells/mm ] 15.

When dissemination occurs, many organs may beinvolved with massive numbers of intracellular bacilliand little or no tissue reaction 15.25 The most commonlydescribed are blood, bone marrow, Iiver, spleen, Iymphnodes and gastrointestinal tract 15 In contrast, CNSinvolvernent seems to be an uncommon feature forMAC infection in AIDS patients 22

The detection of e1even patients with MAC iso-lates from CSF in our series of 1723 AIDS patients isparticular1y striking, especially when compared to the

96

absence of these microorganisms observed in CSF sam.pIes from non-AIDS patients detected during the pre-ceding 10 years at our institution 27 However, thesefindings cannot be used as a marker of menin_goencephalitis since other disorders such as CNS infec-tion by human immunodeficiency virus, Herpessimplex virus, Toxoplasma gondii and Cryplococcusneoformans could be present in these patients. Indeed,five of them (cases I, 2, 4, 6 and 11) had cerebraltoxoplasmosis and one (case 11) had cerebralcryptococcosis, as shown in Table 1. Furthermore, theubiquitous nature of MAC means that caution should betaken when a diagnosis is being made on the basis ofculture, which may merely signify contamination of lhespecimen.

Thus lhe isolation of MAC from autopsy materialwith histologic changes compatible with a specific in-flammatory reaction was of help in establishing a de-finitive diagnosis of CNS disease in these e1even pa-tients. CHAPMAN7 reported a case of MAC CNS in-fection whose autopsy showed granulomatous meningi-tis. lACaS et a!. 19, in New York (USA), reported 16cases of MOTT CNS infection (15 MAC and 1 M

fortuitum) in AIDS patie~ts. The autopsy performed onthree of these cases showed extensive involvement ofliver, gastrointestinal tract, bone marrow, Iymph nodesand CNS with light inflammatory activity, loosegranulomas without Langhans's giant cells and alco-hol-acid fast bacilli observed at most sites. This is thefirst substantial evidence that MAC may play a patho-genic role in the CNS. However, unfortunately, autopsycould not be performed in our cases. On the other hand,if perfonned, it could not have provided any additionalinformation to clarify MAC pathogenicity in relation tothe CNS. A poor or no tissue response is frequentlyobserved in AIDS patients, which probably reflects theirinablility to mount an effective immune response 15.25.28.

In contrast to the above data, the presence of MACin five patients provided strong evidence in favour of itspathogenic role. Patient I, 5 and 10 had typical disserni-nated infection, whereas cases 8 and 1I had repeatedisolation of multiple colonies of MAC from CSF. Thislatter implication is well reported by KLEIN et a!. 22

In our series ali patients had moderate to markedprotein elevation, ranging from 50 to 2020 mg/dl, whichis a common finding in AIDS patients with neurologicaldisease 14. However, several CNS diseases such as HIVencephalitis, toxoplasmosis, cryptococcosis and brain

HADAD, D. J, PETRY, T c, MARESCA, A. F.; FERRAZOLl, L.; MARTINS, M. c, PALHARES, M. C. de A.; PINTO, W. P; CASTELO FILHO, A.& PALACI, M. - Mycobucterium avium eomplex (MAC): an unusual potential pathogen in cerebrospinal fluid of AIDS patients. Rev. Inst. Med.trop. S. Paulo, 37(2): 93-98, 1995.

primary lymphoma, which usually attack AIOS patients,rnake the interpretation of CSF findings quitetreacherous. Therefore, it is impossible to confirm adiagnostic hypothesis of CNS mycobacterial infectionbased only on chemocytological findings.

HOLLANDER 15 suggested that patients withrnarked pleocytosis should raise the suspicion of infec-tion caused by pathogens other than HIV. In our series,pleocytosis was documented in eight patients studied atthe time of MAC isolation. In none of them did wediagnose CNS infections caused by other bacteria orfungi. It should be pointed out that patients withpleocytosis above 1000 and neutrophilic pleocytosislead the physician to treat them for undetermined bac-terial meningitis (data not shown).

Taking into account either Davidson's criteria 10

for a definitive diagnosis of non-M. tuberculosis com-plex disease, or a case of meningeal lesion described byKLATT et a!. 21 at autopsy in 12 AIOS patients, itseems reasonable to admit the possibility that theseorganisms played an opportunistic role in cases I, 5, 8,10 and 11. Therefore, we may conclude that further andmore extensive investigations should be performed inorder to determine MAC pathogenicity for the CNS 111

AIOS patients.

RESUMO

Complexo Mycobacterium avium: um patógenopotencial pouco comum no líquido céfalo-

raquidiano de pacientes com AIDS

o complexo Mycobacterium avium (CMA) éfrequentemente isolado de pacientes com complicaçõestardias de Síndrome de Imunodeficiência Adquirida(AIOS), especialmente na América do Norte e Europa.Entretanto, existem poucos relatos do isolamento destecomplexo a partir do sistema nervoso central (SNC)nestes países. Acredita-se que infecções pelo CMAsejam raras entre pacientes portadores de AIDS empaíses da África e América Latina. Neste trabalhorelatamos o isolamento do CMA do Iíquor de 1Ipacientes portadores de AIOS dentre 1723 (0.63%)atendidos no Centro de Referência e Treinamento -AIOS, de São Paulo, e discutimos a significância desteachado.

ACKNOWLEDGEMENTS

We are grateful to Prof. Dr. Gildo Dei Negro, from

Faculdade de Medicina - Universidade de São Paulo,for his critical review of this manuscript.

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Recebido para publicação em 05/09/1994Aceito para publicação em 20/09/1994.