Human immunodeficiency virus-associated atypical mycobacterial skeletal infections

Human Immunodeficiency Virus-Associated Atypical Mycobacterial Skeletal Infections Rosemarie Hirsch, Susan M. Miller, Salahuddin Kazi, Thomas R. Cate, and John D. Reveille The clinical and laboratory features of six human immunodeficiency virus (HIV)-positive patients with atypical mycobacterial skeletal infections, seen at a county outpatient HIV facility or university outpatient clinic, are reviewed and compared with other reported cases. Atypical mycobacterial skeletal infections are a manifestation of advanced HIV disease, with most cases having CD4 counts < 1 0 0 / m m 3 at the time these infections become clinically apparent. Multiple sites are frequently involved, and concomitant skin infection with the same organism is common, especially with Mycobacterium haemophilum. The incidence of atypical mycobacterial skeletal infection in HIV-infected individuals was significantly higher than in the general county hospital district patient population, whereas the frequency of Myobacterium tuberculosis skeletal infection did not differ significantly between the two populations. The clinician therefore should maintain a high index of suspicion for atypical mycobacteria in a patient presenting with skeletal infection in the setting of a markedly depressed CD4 count. Semin Arthritis Rheum 25:347-356. Copyright © 1996 by W.B. Saunders Company INDEX WORDS: Atypical mycobacteria; osteomyelitis; septic arthritis; HIV-1 infection. AND JOINT infections in patients B ONE with the acquired immune deficiency syndrome (AIDS) are uncommon, 1 although case reports include examples of bacterial, mycobacterial, and fungal septic arthritis and osteomyelitis. v3° Depletion of CD4 + ceils in these patients results in cell-mediated immune suppression, predisposing them to mycobacterial infection. 1 Only 25 documented cases of atypical mycobacterial skeletal infections have been reported in patients infected with the human immunodeficiency virus (HIV). The causative agents were Mycobacterium avium intracellulare (MAI) in 2, 3,16Myobacterium haemophilum in 15,s,8,1°J3-15, 18-20,26,27 m. kansasii in 6, 2,4,7,9,23,28 and Myobacterium kansasii plus MAI in 2. 29,30 Three other probable cases have been reported, 12,21,22 the presumptive causative organisms being M haemophilum, M kansasii, and Myobacterium fortuiturn, although cultures were not obtained from skeletal sites. We report six HIV-positive patients who developed arthritis with or without osteomyelitis because of infection by atypical mycobacte-

ria, including MAI, Mkansasii, and Mhaemophilum. In one, the mycobacterial species isolated could not be identified, although M terrae was From the Division of Rheumatology and Clinicallmmunogenetics, Depamnent of Medicine, the Universityof Texas Health Science Center at Houston, and the Department of Medicine, Baylor Collegeof Medicine, Houston, TX. Rosemarie Hirsch, MD, MPH: Fellow,Division of Rheumatology and Clinical Immunogenetics, Department of Medicine, the Universityof Texas Health Science Center at Houston, TX; Susan M. Miller, MD, MPH: Assistant Professorof Medicine, Department of Medicine, Baylor Collegeof Medicine, Houston, TX; Salahuddin Kazi, MD: Fellow, Division of Rheuraatology and Clinical [mmunogenetics, Department of Medicine, the University of Texas Health Science Center at Houston, TX; Thomas R. Cate, MD: Professorof Medicine, Department of Medicine, Baylor College of Medicine, Houston, TX; John D. Reveille, MD: Associate Professor of Medicine, Division of Rheumatologyand ClinicalImmunogenetics, Departmentof Medicine, the Universityof TexasHealth ScienceCenterat Houston, TX.. Supported in part by NIH grants R29-AR39345, ROIAR42503, and MOI-RR-02558 (J.D.R.). Address reprintrequests to John D. Reveille, MD, Division of Rheumatology, University of Texas Health Science CenterHouston, MSB 5.270, P.O. Box 20708, Houston, TX 77225. Copyright © 1996 by W.B. Saunders Company 0049-0172/ 96/2505-000655.O0/0

Seminars in Arthritis and Rheumatism, Vo125, No 5 (April), 1996: pp 347-356

347

348

HIRSCH ET AL

isolated from another site. Five had definite septic arthritis, two with associated radiological evidence of osteomyelitis, whereas the sixth (case 2) had osteomyelitis and presumptive septic arthritis. We report the clinical features and incidence of joint and bone infections with atypical mycobacteria in a large cohort of individuals infected with HIV. METHODS

Patients in this case series were drawn from two locations. Patients 1 through 3, 5, and 6 were seen by the four coauthors between January 1991 and July 1994 at Thomas Street Clinic in Houston, Texas, a clinic of the Harris County Hospital District (HCHD) for care of HIVinfected adults; patient 4 was seen by two of the coauthors (J.D.R., S.M.M.) in their University outpatient clinics in the same county. Because of the rarity of atypical mycobacterial infections, their incidence in the HIVpositive and in the general patient populations treated within the HCHD were compared using a Poisson distribution of disease. The Poisson distribution reflects the probability of a certain number of events when the population is large, but the chance of an event in any one individual is small. For this reason, incidence estimates follow a Poisson distribution. Pneumocystis carinii pneumonia (PCP) prophylaxis is defined as one of the following: trimethoprim sulfamethoxasole DS, one tablet by mouth 3 times per week; dapsone, 100 mg by mouth 2 times per week; or monthly inhaled pentamidine. RESULTS

Tables 1 and 2 give case clinical and laboratory summaries.

and ethambutol was discontinued in January 1991 because of possible toxicity. Tender subcutaneous nodules were noted on his scalp, neck, and right arm in March 1991, and the patient reported intermittent symmetric large joint polyarthralgias. T-cell subsets were CD4 33/mm 3 and CD8 390/mm 3. Ciprofloxacin, 500 mg orally twice daily, was started, and amikacin, 465 mg intravenously every 12 hours, was given for 14 days for suspected cutaneous atypical mycobacterial infection, but the nodules continued to enlarge slowly. In May 1991, a punch biopsy showed granulomatous inflammation with an associated venulitis and possible fungi, and ketoconazole was begun. In August 1991, he noted transient left knee swelling and within a month developed left wrist synovitis and a persistent left knee effusion, with decreased range of motion. Left knee synovial fluid yielded MAI; radiographs were unremarkable. The knee effusion did not recur after aspiration, and the left wrist symptoms improved with naproxen, although decreased wrist range of motion persisted. The patient developed severe midabdominal pain in October 1991. Endoscopy showed multiple gastric ulcers, and a biopsy culture yielded MAI. Clarithromycin was begun at 1,000 mg orally twice daily, with resolution of the abdominal pain. Over the following year, he experienced a few episodes of severe joint pain that lasted less than 24 hours without effusions. These episodes were attributed to the "painful articular syndrome" associated with HIV infection. 24 Clarithromycin was discontinued in February 1993 because of persistent hepatic transaminase elevation and development of ascites. Rheumatologic evaluation at that time showed no joint damage or synovitis and full range of motion of all joints, which persisted until his death in May 1993.

Case 1

A 29-year-old homosexual white man, known HIV-positive since 1986, had previous PCP and cytomegalovirus (CMV) retinitis infections. Zidovudine (ZDV) and PCP prophylaxis were begun in early 1990. Blood cultures were positive for MAI in June 1990, and rifampin, ethambutol, and clofazimine were begun. Dideoxyinosine (ddI) was substituted for ZDV in September 1990 because of bone marrow suppression,

Case 2

A 44-year-old homosexual white man, known HIV-positive since 1987, presented initially in October 1990 with weight loss, fever, polyarthralgias of the hands and feet, and tender subcutaneous nodules on the trunk and extremities. His T-cell subsets were CD4 7/mm 3 and CD8 606/ mm 3, and ZDV and PCP prophylaxis were begun. Initial nodule punch biopsy findings

ATYPICAL MYCOBACTERIAL ARTHRITIS IN HIV

349

Table 1: Atypical Mycobacterial Skeletal Infections in HIV: Clinical Features Patient

Reference

1 2 3 4

3 16 Case 11" 29

5

30

6 7 8

4 9 7

9

Organism

Septic Arthritis*

MAI MAI MAI

Osteomyelitis

Other Sites

Wrists, ankles L knee & wrist L knee & wrist Myobacterium kansa- None

Wrists, L ankle None None Calvareum

Blood Blood Blood, gastric mucosa Blood (MAI only)

28

sii/MAI Mkansasii/MAI M kansasii M kansasii Mkansasfi Mkansasii

None None None R elbow None

Calvareum R tibia L 4th finger None Calvareum

10 11

23 Case 31-

Mkansasfi Mkansasfi

R arm R ankle, proximal tibia

12 13 14

Case 51" Case 61" 20

None None None

None None Skin, biood

15 16 17

10 18 18,19

M kansasii M kansasii Myobacterium haemophilum M haemophi/um M haemophilum M haemophilum

None R knee & ankle, L elbow R knee R wrist, MCPs R knee

Sinus, blood Skin Sputum, liver None Sputum (MAC also in sputum & blood) Sinus Sputum

Ankles, L wrist None L knee

Blood Skin Skin

18

8

M haemophilum

None

None L anne R 3rd finger, R calcaneus L ankle and tibia

19

13

M haemophilum

R finger

None

20

14

Mhaemophilum

B knees

21 22 23 24

27 26 5 Case 41"

Mhaemophilum M haemophilum M haemophilum M haemophilum

R elbow None None Knees, ankles

Fingers, toes tibia, elbow, T9-10 vertebrae R olecranon L foot B tibia and fibula R ankle and tibia

25

Case 21

Myobacteriurn terrae

Knees,:l: ankles

B hands and tibia

Skin, tenosynovitis L ankle Soft tissue abscess, BAL Skin, lungs

Skin None Skin, sputum Skin, blood, lymph nodes Blood, skin, sputum, stool

Abbreviations: HIV, human immunodeficiency virus; MAI, mycobacterium avium intracetlulare; L, left; R, right; MAC, microbacterium arium complex; MCP, metacarpophalangeal; BAL, bronchoalveolar lavage; B, bilateral. *AFB present in at least one joint with clinical synovitis, except where otherwise noted. 1"Current report. 1:Clinical synovitis, AFB present in osteomyelitis sinus tract drainage.

were consistent with bacillary angiomatosis, and erythromycin was prescribed. Nodule cultures remained negative for aerobic bacteria and mycobacteria. A routine initial screening sputum smear was positive for acid-fast bacilli (AFB), despite a normal chest radiograph, and rifampin, ethambutol and ciprofloxacin were provided (isoniazid was avoided because of a possible neuropathy).

By December 1990, he developed tenderness and swelling of several metacarpophalangeal joints and a sausage-shaped upper extremity digit, accompanied by diarrhea. A fecal AFB stain was positiwe. Repeat nodule punch biopsy in January 1991 showed noncaseating granulomata. Both fecal and nodule cultures yielded a mycobacterium that could not be identified. Pyrazinamide and clofazimine were begun, with

350

HIRSCH ET AL

Table 2: Laboratory Features, Treatment, and Outcome in HIV-Associated Mycobacterial Skeletal Infection

Patient

Reference

Organism

3

MAI

16

MAI

Case I t

CD4 Count (mm 3)

Synovial Fluid*

Antimicrobial Treatment

Outcome

NA

I, R, E, AN, ET, CY, CL

Progression

16

WBC 2335 49M, 47L

R, CL, CI

Synovitis persisted

MAI

40

WBC 3250/39S, 31L, 30H, gluc 97

R, E, A, CL, CLA, CI

Improvement

29

Myobacterium kansasii/MAI

16

NA

I, R, E, CL

Noncompliant, died several months later

30

Mkansasii/MAI

2

NA

A, I, R, E, CLA, CI, CL

Progressive bone destruction

4

Mkansasii

NA

R, I, ST, TMS

Died of opportnniatic infection soon after treatment began

9

Mkansasii

76

NA

"Antitubercutar therapy"

Resolution of symptoms

7

Mkansasii

12

WBC 6450 91S, 2L, 7H

I, R, E

Resolution

9

28

Mkansasfi

2

NA

I, R, CLA

Scalp lesions 1 month later

10

23

Mkansasfi

NA

I, R, P

Improvement, died of sepsis 2 months later

11

Case 3t

Mkansasfi

14

WBC 78,500 97S, 3L; gluc 12

R, I, E, A

Improvement

12

Case 51

M kansasii

12

NA

R,E,P

Improvement

13

Case 61

M kansasfi

189

NA

CLA, CI

Improvement, died 3 months later of HIV complications

14

20

Myobacterium haemophilum

95

NA

R,I, P, E

Improvement, stable at 19-month follow-up

15

10

M haemophilum

WBC 46,100 90S, 10L

R,I, P, E, ET

No improvement

16

18

M haemophilum

20

NA

R,I, P, E

Resolution of skin and joint symptoms

17

18, 19

Mhaemophilum

40

NA

R, I, E, A, CI, CL, CE, D

Resolution of symptoms

NA

NA

< 200~

NA

ATYPICAL MYCOBACTERIAL ARTHRITIS IN HIV

351

Table 2: Laboratory Features, Treatment, and Outcome in HIV-Associated Mycobacterial Skeletal Infection (cont'd)

Patient

Reference

Organism

CD4 Count (mm 3)

Synovial Fluid*

Antimicrobial Treatment

Outcome

18

8

Mhaemophilum

NA

NA

R, I, A, E, M, CI, CL

Resolution of symptoms

19

13

Mhaemophilum

NA

NA

I, R, E

No i m p r o v e m e n t

20

14

Mhaemophilum

NA

WBC 3900/82S

I, R, E

No i m p r o v e m e n t

21

27

Mhaemophilum

132

NA

R, I, P

22

26

Myobacteriurn haemophilum

NA

NA

F, CI, A, D, R

Resolved 9 mos later I m p r o v e m e n t in 10 wk

23

5

Mhaemophilum

43

NA

I, R, E, CI, CL, A

Initial improvement, relapse in 6 wk

24

Case 4 t

Mhaemophilum

5

WBC 24

R, I, P, E, A, CI, CL

No i m p r o v e m e n t

25

Case 2~

Myobacterium terrae

7

WBC 6550/85S, 5L, 8H; gluc 94

R, A, P, E, CI, CLA

Resolution on CLA

Abbreviations: HIV, human immunodeficiency virus; MAI, Mycobacterium avium-intracellular; NA, not available; I, isoniazid; R, rifampin; E, ethambutol; AN, ansamycin; ET, ethionamide; CY, cycloserine; CL, clofazimin; WBC, white blood cells; M, monocytes; L, lymphocytes; CI, ciprofloxacin; H, histiocytes; A, amikacin; CLA, clarithromycin; ST, streptomycin; TMS, trimethoprim/sulfa; S, polys; P, pyrazinamide; gluc, glucoase (mg/dL); CE, ; DE, doxycycline; F, flucloxacillin; D, doxycycline. *Synovial fluid leukocyte WBC counts per mms. 1"Current report. ~:CD4counts reported for a series of 19 HIV-positive patients with Myobacteriumkansasiias " < 200/ram3. ''

some adjustments in dosing because of fears of possible drug eruption. Over the subsequent 9 months, the patient developed bilateral knee and ankle effusions, a 3 x 4 cm soft tissue swelling over the proximal right tibia, osteomyelitis of the left hand and right tibia, and multiple draining sinuses over the upper and lower extremities. Knee and ankle synovial fluid, and sinus tract drainage from the tibial site, were negative for AFB and fungal stains and culture. Sinus drainage from the right fourth distal interphalangeal joint (DIP) had a positive AFB stain, but culture yielded no organisms. Amikacin, administered at 500 mg intravenously twice daily for 14 days, did not hinder skeletal infection progression. Subsequently, an organism from a sputum sample obtained in August 1991 was identified as Mycobacterium terrae. Therapy with clarithromycin, 500 mg orally twice daily, was begun in November 1991. Over the next 6 weeks, all draining sinuses closed and swelling resolved over the osteomyelitis sites. The patient had no

recurrence of joint symptoms up to his death of Serratia marcescens sepsis in May 1993. Case 3

A 49-year-old black man with a history of intravenous drug abuse was found HIV-positive in May 1989, with his first episode of PCP. ZDV and PCP prophylaxis were begun at that time. At his initial clinic presentation in March 1990, he complained of a 30-pound weight loss and oral thrush was noted. T-cell subsets were CD4 14/ram 3 and CD8 205/mm 3. In December 1990, he reported fever, night sweats, pain and swelling of the right knee and ankle, and additional weight loss. Examination showed an inflamed right knee with an effusion and limited range of motion and small effusions in the right ankle and left elbow. Right upper and lower lobe infiltrates were seen on chest radiograph, and the patient was hospitalized. Right knee and left elbow synovial fluid AFB stains were positive. Radiographs of the right knee showed no bony abnormalities; however, osteomyelitis was

352

present in the right talus, navicular, and first metatarsal bones. A bone scan was consistent with osteomyelitis of the proximal right tibia and right foot. Synovial fluid and sputum cultures grew M kansasii. Therapy with rifampin, isoniazid, ethambutol, and amikacin was begun, and the patient rapidly became afebrile. Synovitis and range of motion of all affected joints improved, although complete resolution of the left knee effusion required 4 months. Subsequently he became wheelchair bound because of severe muscle wasting and weakness, but suffered no recurrence of joint effusions; he died in January 1992. Case 4 A 49-year-old homosexual Hispanic man was HIV-positive since 1986. ZDV and PCP prophylaxis were started in December 1988 because of falling CD4 counts. He complained of weight loss and low-grade fevers and had a CD4 count of 68/mm 3 in October 1989. Results of a gallium scan were unremarkable, and blood, sputum, and bone marrow cultures were negative. ZDV was discontinued in February 1990 because of toxicity, and ddI was begun in May 1990. By then, a 3- to 4-cm nodular abdominal wall swelling below the umbilicus was noted. Abdominal computed tomography scan showed no other abnormalities. The nodules were excised and consisted of chronically inflamed lymphoid tissue with positive AFB stains. Rifampin, isoniazid, ethambutol, and ciprofloxacin were begun, with clofazimine added later. He developed drug-induced hepatitis, and isoniazid was changed to pyrazinamide. Multiple additional subcutaneous nodules appeared on the upper and lower extremities by July 1990. He was empirically treated with vancomycin and ceftriaxone, but the lesions ulcerated and developed draining sinus tracts. Cultures from the sinus tracts, the abdominal wall lesions, and blood all subsequently grew M haemophilum. A 2-week course of amikacin at 500 mg intravenously twice daily had no apparent effect. In October 1990, he developed bilateral ankle synovitis and was referred to a rheumatology clinic, where multiple draining lesions over upper and lower extremity joints, thickened right wrist synovium, a sausage-shaped upper extremity digit, and slightly diminished spinal flexion were noted. Radiographs of the hands

HIRSCH ET AL

and ankles showed no bony lesions. T-cell subsets were CD4 5/mm 3 and CD8 76/mm 3, and HLA-B27 was positive. Bacterial culture and AFB stain of left ankle synovial fluid were negative. Indomethacin, started for possible HIV-associated Reiter's syndrome, gave significant symptomatic relief even though his left ankle aspirate subsequently grew M haemophilum. A bone scan in December 1990 suggested osteomyelitis of the right tibia and medial malleolus. Over the next several months, he developed bilateral knee and right elbow effusions, despite multidrug antimycobacterial regimen; disseminated multifocal cutaneous herpes; CMV retinitis; and mental status deterioration. He died in May 1991, before clarithromycin was available. Case 5 A 42-year-old white man, HIV-positive since 1987, was hospitalized previously in December 1991 for what was thought to be viral pneumonia. Kaposi's sarcoma was diagnosed in December 1992, and ZDV therapy and PCP prophylaxis were initiated in January 1992. ZDV was discontinued in August 1992 because of inefficacy. Therapy with ddI was begun and discontinued in April 1993 because of peripheral neuropathy. By January 1993, his CD4 count had decreased to 12/mm 3. He was referred to a rheumatology clinic in May 1993 with a 3-week history of pain and swelling in his right knee, and a 1-year history of right wrist pain. A massive right knee effusion was noted. Synovial fluid was cloudy, and cultures yielded M kansasi# radiographs and a bone scan were unremarkable. Treatment with rifampin, pyrazinamide, and ethambutol resulted in resolution of the arthritis within a few months, but he died in February 1994. Case 6 A 52-year-old African American man with a history of end-stage renal disease on maintenance hemodialysis since April 1992, when he presented after a gunshot wound and was found to be in renal failure and also HIV-positive, which was attributed to intravenous drug abuse. CD4 count was 62/ram 3, and ZDV was begun. In March 1994, ZDV was discontinued because of anemia, and zalcitabine prescribed. Within 2 months, the CD4 count had risen to 189/mm 3.

ATYPICAL MYCOBACTERIAL ARTHRITIS IN HIV

The patient presented to the rheumatology clinic in June 1994 with a 2-month history of pain and swelling in his right wrist. Swelling of the right wrist and synovitis of the third and fifth metacarpophalangeal and third proximal interphalangeal joints was noted. Radiographs showed soft tissue swelling and evidence of demineralization of the carpal and metacarpal bones. Aspiration of the right wrist yielded 0.5 mL turbid fluid that grew M kansasii. The patient was treated with clarithromycin and ciprofloxacin with rapid symptomatic improvement. On follow-up 1 month later, the pain and swelling had completely resolved. Nevertheless, the patient's overall status continued to deteriorate, and he died in November 1994.

Incidence of Atypical Mycobacterial Infection Table 3 summarizes the frequency of mycobacterial infections in HCHD patients during a 10-month period in 1991, when three of the six cases were diagnosed. Among 1714 HIV clinic patients, 139 were colonized or infected with atypical mycobacteria, a rate of 811/10,000; comparable data for the general HCHD patient population were 24 of 202,432 for a rate of 1.2/10,000, 676-fold lower than for the HIV clinic patients (statistically significant difference). Rates of infection with Mycobacteriurn tuberculosis were also statistically significantly higher among HIV clinic patients than among the general patient population, 303 versus 8.6 per 10,000, respectively, a 35-fold difference. The latter emphasizes the need for strict attention to tuberculosis control measures within HCHD, especially at the HIV clinic. Comparison of the rates cited above shows that mycobacteria recovered from the HIV clinic patients are more than twice as likely to be atypical mycobacteria than M tuberculosis. However, this ratio is reversed for the general patient population, with mycobacterial isolates more than six times more likely to be Mtuberculosis. Sites of mycobacterial infection in the body also differ for the two patient populations. Infections with both atypical mycobacteria and M tuberculosis are much more likely to be extrapulmonary among HIV clinic patients than among the general patient population (data not shown). Regarding mycobacterial joint infections, HIV-infected patients more likely will have an atypical organism, whereas the general

353

patient population more likely will have M tuberculosis. The atypical mycobacterial skeletal infections occurred significantly more often in HIV-positive individuals than in the general patient population; however, M tuberculosis skeletal infection rates did not signNcantly differ between the populations. DISCUSSION

In the HlV-negative host, systemic dissemination of atypical mycobacteria is uncommon, so skeletal disease is rare. 31 In HIV-positive patients, three atypical mycobacterial species have been reported to cause skeletal infection: M kansasii, MAI, and M haemophilum. Herein we Table 3: Mycobacterial Infections in the Harris County Hospital District Populations From January Through October 1991 All Other

County HIV Clinic

County Medical Facilities

1,714

202, 432

Cases

Cases

Active, unreduplicated patient census t h r o u g h 10/91 Atypical m y c o b a c t e rial o r g a n i s m s : (all sites)

M avium-intrace//ulare M kansasii M gordonae M fortuitum M terrae M che/onei M fluorescens M simie M marinum M scrofulaceum Total (all sites) Skeletal infection

I OO

6

20

4

9 5 2 0 1 0 1 1

7 4 2 2 0 1 0 0

139"

24

3*

0

52*

175

IV/. tuberculosis cases All sites Skeletal infection

0

2

NOTE. The HIV-positive patient in the current report with M

haemophilum septic arthritis (case 4) was not seen at a Harris County Hospital District facility and therefore was not included in the statistics above. Likewise, case 5 was seen after the above period and was not included. *P < .0001 based on a Poisson distribution of disease occurrence.

354

report a possible infection by an additional species, M terrae. Tables 1 and 2 summarize the clinical features of 25 of the 31 documented cases (including our cases 1 through 6) of atypical mycobacterial skeletal infection in HIVpositive individuals.3-5,7-10,13-16,18-20,23,26-30 Insufficient information was available on six cases for inclusion in the tables2,~5; however, skin involvement and treatment response was noted in most and is included in the Discussion. M kansasii Of the nine documented cases of M kansasii skeletal infection in HIV-positive individuals, two had involvement of multiple skeletal sites. Synovial fluid, when evaluated, tended to be inflammatory (Table 2). Skin involvement was seen in only one case; however, this patient had a concomitant Salmonella blockley bacteremia, and there was no mention of skin lesion cultures. 4 Seven of the eight with treatment information responded readily to standard antimycobacterial therapy (one patient died of an opportunistic infection before treatment response could be determined4). MAI Two of the three HIV-positive patients with MAI septic arthritis had a nondestructive, relatively indolent course (6 to 12 months from initial symptoms to diagnosis) involving two joints. The patient reported by Vinetz and Rickman 16 with a nondestructive infection of the wrist and knee had resolution of constitutional symptoms on antimycobacterial drugs, but underwent open synovial biopsy for recurrent wrist pain and effusion. Our patient (case 1) also had nondestructive involvement of the knee and wrist. His culture-proven arthritis improved with antimycobacterial therapy plus naproxen, even while a nonarticular site of MAI infection (gastric mucosal granulomata) developed. The latter responded to treatment with clarithromycin, but subacute arthritis persisted. The third patient, reported by Blumenthal et al, 3 had a rapidly progressive course (over several months) involving multiple sites, including both wrists and ankles, associated with osteomyelitis. This patient did not respond to a five-drug antimycobacterial regimen. Progressive wasting and joint destruction occurred, and he died several months thereafter.

HIRSCH ET AL

MAI /M kansasii Two individuals had both MAI and M kansasii documented osteomyelitis of the calvareum with multiple lytic lesions. 29,3° Neither responded to antimycobacterial therapy. M haemophilum

M haemophilum is an emerging pathogen in humans, primarily in hosts immunocompromised because of organ transplantation, lymphoma, or HIV infection. The first report of M haemophilum infection in an HIV-positive patient was in 1987.l° Since then, most new M haemophilum cases reported have been in HIVpositive individuals.5,8,13-15,18-2~,26,27,32-35 Skin nodules, ulcers, and abscesses are the most common features, 5,14,15 although septic arthritis 1°,1315,19,20,27,33,36 (our case 4), and osteomyelitis5,8,14,15,18,26,27,35,36 ( o u r case 4) have each been documented. The joints most often involved are the ankles, knees, and wrists. 2° Most skeletal infections with M haemophilum occurred in HIV-positive individuals. At least nine of the septic arthritis cases (Table 1) 15 and all but two of the osteomyelitis cases 5,8,14,15,18 (our case 4) were in HIV-positive individuals. An HIV-positive individual with presumptive septic arthritis has also been reported. 21 Improvement with antimycobacterial therapy was noted in 6 of the 11 HIV-positive patients with skeletal infection noted in Table 2 and in three of the five cases not included in the table. 15 M terrae

Mterrae is a rare human pathogen. Only a few cases of skeletal infection in HIV-negative hosts have been reported previously. The wrists and upper extremity digits and knee were the sites of involvement.3739 Our patient (case 2) varied from these other cases because of multiple infected sites. The diagnosis of M terrae septic arthritis was presumptive in this case, because the microorganism was never cultured from the joint fluid (at the time arthrocentesis was performed, he had been on antimycobacterial drugs for 12 months). However, a smear of drainage from a sinus tract over a site of osteomyelitis was positive for AFB, and specimens from such sites are considered reliable. 31 Skeletal infection with atypical mycobacteria appears to be a late complication of HIV infection. As seen in Table 2, CD4 counts, when

ATYPICAL MYCOBACTERIAL ARTHRITIS IN HIV

355

obtained near the time of presentation with skeletal infection, were markedly depressed. Case 6 in our series had a higher CD4 count (189/mm 3) at presentation, although his chronic renal failure probably contributed a further immunosuppressive effect. Among six patients without CD4 data, it can be inferred that most were in the late stages of HIV infection because four had histories of PCP, and two of the latter also had Candida esophagitis. 3,t°,13,14 The severely compromised status of these HIVpositive patients may account for the increased extent and severity of their skeletal infections with atypical mycobacteria (namely, polyarticular involvement and osteomyelitis) and a more rapid progression of the infection (months instead of years) when compared with the HIVnegative host. 31,4° Cutaneous lesions, frequently extensive, were noted in 15 of the 31 cases of atypical mycobacterial skeletal infection in HIV-positive patients ( T a b l e 1) 4,5,8,14,15,18-20,27 (our cases 2 and 4), especially among those infected with M haemophilum. Of interest, four patients also had other dermatologic conditions, including three with Kaposi's sarcoma, one with bacillary angiomatosis, and one with cutaneous herpes 14,~8(our case 4). It is important, therefore, to obtain cultures of suspicious lesions, especially draining sinus tracts, nodules, or ulcers over a symptomatic joint, even if the patient has another documented dermatologic condition. Because HIV-positive patients have increased susceptibility to disseminated mycobacterial infection from impaired cellular immunity, the differential diagnosis of skeletal infection should include atypical mycobacteria, including species

previously thought less pathogenic in humans, such as M haemophilurn and M terraeo Although MAI is the most common systemic mycobacterial infection in AIDS patients, 41 it is not the most frequent to infect joints. M kansasii, the second most common atypical mycobacterial infection in AIDS patients, 42 was responsible for almost one fourth of the cases of skeletal infection reported. Three of these cases were from the south central United States, a particularly endemic area for M kansasii infection. 43 The emerging human pathogen, M haemophilure, was responsible for more than half the atypical mycobacteriat skeletal infections in HIV-positive patients. In summary, most atypical skeletal infections in HIV-positive hosts are due to M haernophilum and M kansasii, in that order. In contrast, in HIV-negative hosts, atypical mycobacterial infections are due to M marinum, Mkansasii, and MAI, in that order. 44 Based on the 25 well-documented cases of atypical mycobacterial skeletal infection in HIVpositive patients reported to date, several general features emerge: (1) it is usually a late complication of HIV infection; (2) it often involves several joints or skeletal sites; (3) septic arthritis may coexist with osteomyelitis; and (4) it often is associated with cutaneous lesions. Response to treatment is variable, although clarithromycin appears promising for MAI infection 45,46 and provided a dramatic response for the single patient with presumed M terrae osteomyelitis and diffuse cutaneous disease. ACKNOWLEDGMENTS The authors are grateful to Grace L. Griffin for her assistance in the preparation of this manuscript.

REFERENCES 1. Goldenberg DL: Septic arthritis and other infections of rheumatotogic significance. Rheum Dis Clin North Am 17:149-156, 1991 2. Bamberger DM, Driks MR, Gupta MR, et al: Mycobacterium kansasii among patients infected with human immunodeficiency virus in Kansas City. CID 18:395-400, 1994 3. Blumenthal DR, Zucker JR, Hawkins CC: Mycobacterium avium complex-induced septic arthritis and osteomyelitis in a patient with the acquired immunodeficiency syndrome. Arthritis Rheum 33:757-758, 1990 4. Crawfurd EJP, Baird PRE: An orthopaedic presentation of AIDS: Brief report. J Bone Joint Surg Br 69:672-673, 1987 5. Dever LL, Martin JW, Seaworth B, et al: Varied presentations and responses to treatment of infections

caused by Mycobacterium haemophilum in patients with AIDS. CID !4:1195-1200, 1992 6. Edelstein H, McCabe R: Candida albicans septic arthritis and osteomyelitis of the sternoclavicular joint in a patient with human immunodeficiency virus infection. J Rheumatol 18:110-111, 1991 7. Friedman AW, Ike RW: Mycobacterium kansasii septic arthritis in a patient with the acquired immunodeficiency syndrome. Arthritis Rheum 36:1631-1632, 1993 8. Gupta l, Kocher J, Miller A J, et al: Mycobacterium haemophilum osteomyelitis in an AIDS patient. N Engl J Med 89:201-202, 1992 9. Hughes RA, Rowe IF, Shanson D, et al: Septic bone, joint and muscle lesions associated with human immunodeficiency virus infection. Br J Rheumato131:381-388, 1992 10. Males BM, West TE, Bartholomew WR: Mycobacte-

356

rium haemophilum infection in a patient with acquired immunodeficiency syndrome. J Clin Mierobiol 25:186-190, 1987 11. Munoz Fernandez S, Quiralte J, Del Arco A, et al: Osteoarticular infection associated with the human immunodefciency virus. Clin Exp Rheumatol 9:489-493, 1991 12. Rodriguez-Barradas MD, Claridge J, Darouiche R: Disseminated Mycobacterium fortuitum disease in an AIDS patient. Am J Med 93:473-474, 1992 13. Rogers PL, Walker RE, Lane CH, et al: Disseminated Mycobacterium haemophilum infection in two patients with the acquired immunodeficiency syndrome. Am J Med 84:640-642, 1988 14. Sabbagh M, Meyer O, Debandt M, et al: Bone manifestations associated with the acquired immunodeficiency syndrome. Ann Intern Med 143:50-56, 1992 15. Strauss WL, Ostroff SM, Jernigan DB, et al: Clinical and epidemiologic characteristics of Mycobacterium haemophilum, an emerging pathogen in immunocompromised patients. Ann Intern Med 120:118-125, 1994 16. Vinetz JM, Rickman LS: Chronic arthritis due to Mycobacterium avium complex infection in a patient with the acquired immunodeficiency syndrome. Arthritis Rheum 34:1339-1340, 1991 17. Woods SM, Gernaat H: Gonococcal osteomyelitis in a Zambian patient with AIDS. Trop Doct 22:47-48, 1992 18. Yarrish RL, Shay W, LaBombardi VL, et al: Osteomyelitis caused by Mycobacterium haemophilum: Successful therapy in two patients with AIDS. AIDS 6:557-561, 1992 19. Kiehn TE, White M, Pursell KJ, et al: A cluster of Mycobacterinm haemophilum infection. Eur J Clin Microbiol Infect Dis 12:114-118, 1993 20. Kristjansson M, Bieluch VM, Byeff PD: Mycobacterium haemophilum infection in immunocompromised patients. Rev Infect Dis 13:906-910, 1991 21. Becherer P, Hopfer RL: Infection with Mycobacterium haemophilum. CID 14:793, 1992 22. Nahar H, Peters B: Mycobacterium Kansasii-Serum der Haut bei HIV-Infektion. Hauteret 43:361-363, 1992 23. Levine B, Chaisson RE: Mycobacterium kansasii: A cause of treatable pulmonary disease associated with advanced HIV infection. Ann Intern Med 114:861-868, 1991 24. Berman A, Reboredo G, Spindler A, et al: Rheumatic manifestations in populations at risk for HIV infection: The added effect of HIV. J Rheumatol 18:1564-1567, 1991 25. Lawrence JM, Osborn TG, Paro R, et al: Septic arthritis caused by Hemophilus influenza type B in a patient with HIV-1 infection. J Rheum 18:1772-1773, 1991 26. Sowden D, Kemp R, Dawson D: Osteomyelitis due to Mycobacterium haemophilum in a patient with AIDS. Pathology 25:308-309, 1993 27. Soubani AO, Al-Marri M, Forlenza S: Successful treatment of disseminated Mycobacterium haemophilum infection in a patient with AIDS. CID 18:475-476, 1994 28. Weinroth SE, Pincetl P, Tuazon CU: Disseminated Mycobacterium kansasii infection presenting as pneumonia and osteomyelitis of the skull in a patient with AIDS. CID 18:261-262, 1994

HIRSCH ET AL

29. Gallant JE, Alwood K, Chaisson RE: Osteomyelitis due to Mycobacterium kansasii and Mycobacterium avium complex in an HIV-infected patient. Infect Dis Clin Pract 3:297-299, 1994 30. Naguib MT, Byers JM, Slater LN: Paranasal sinus infection due to atypical mycobacteria in two patients with AIDS. CID 19:789-791, 1994 31. Hoffman GS, Sentochnik DE: Mycobacterial and fungal infections, in Kelley WN (eds): Textbook of Rheumatology (Ed 3). Philadelphia, PA, Saunders, 1989, pp 15891590 32. Armstrong KL, James RW, Dawson D J, et al: Mycobacterium haemophilum causing perihilar and cervical lymphadenitis in healthy children. J Pediatr 121:202-205, 1992 33. Gouby A, Branger B, Oules R, et al: Two cases of Mycobacterium haemophilum infection in a renal-dialysis unit. J Med Microbiol 25:299-300, 1988 34. Holton J, Nye P, Miller R: Mycobacterium haemophilum in a patient with AIDS. J Infect Dis 23:303-306, 1991 35. Thibert L: Mycobacterium haemophilum infection in Canada. Can Dis Wkly Rep 17:25-26, 1991 36. Mezo A, Jennis F, McCarthy SW, Dawson D J: Unusual mycobacteria in 5 cases of opportunistic infections. Pathology 11:377-384, 1979 37. Edwards MS, Huber TW, Baker CJ: Mycobacterium terrae synovitis and osteomyelitis. Am Rev Respir Dis 117:161-163, 1978 38. Fournie B, Dabernat H, Vandet B, et al: Arthritis of the knee caused by mycobacterium terrae. Rev Rheum Mal Osteoartic 54:49-51, 1987 39. Rougraff BT, Reeck CC Jr, Slama TG: Mycobacterium terrae osteomyelitis and septic arthritis in a normal host. Clin Orthop 238:308-310, 1989 40. Sutker WL, Lankford LL, Tompsett R: Granulomatous synovitis: The role of atypical mycobacteria. Rev Infect Dis 1:729-735, 1979 41. Young LS: Mycobacterium avium complex infection. J Infect Dis 157:863-867, 1988 42. Horsburgh CR Jr, Selik RA: The epidemiology of disseminated nontuberculous mycobacterial infection in the acquired immunodeficiency syndrome (AIDS). Am Rev Respir Dis 139:4-7, 1989 43. Carpenter JL, Parks JM: Mycobacterium kansasii infections in patients positive for human immunodeficiency virus. Rev Infect Dis 13:789-796, 1991 44. Yangco BG, Espinoza LR, Germain BF: Nontuberculous mycobacterial joint infections, in Espinoza L (eds): Infections in the Rheumatic Diseases. San Francisco, CA, Grune & Stratton, 1988, pp 142-148 45. Dautzenberg B, Truffot C, Legris S, et al: Activity of clarithromycin against Mycobacterium avium infection in patients with the acquired immune deficiency syndrome. Am Rev Respir Dis 144:564-569, 1991 46. Neu HC: New macrolide antibiotics: Azithromycin and clarithromycin. Ann Intern Med 116:517-519, 1992