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Mycobacterium haemophilum Infection in Immunocompromised Patients: Case Report and Review of the Literature Mar Kristjansson,* Virginia M. Bieluch, and Peter D. Byeff

From the Department of Medicine, New Britain General Hospital, New Britain, Connecticut; and the University of Connecticut School of Medicine, Farmington, Connecticut

In recent years 16 cases of infection with Mycobacterium haemophilum have been reported in the world literature [1-14]. Most infections occurred in immunodeficient patients [1, 5, 7-13]. For many, acid-fast smears of material from the site of infection were positive, but the organism failed to grow under routine conditions used to isolate mycobacteria. Thus, the diagnosis is often delayed unless the clinician alerts the microbiology laboratory to the possibility of infection with M. haemophilum and appropriate modifications of culture techniques are made. We report a patient for whom the diagnosis of AIDS was made on the basis of infection with M. haemophilum that resulted in skin ulcers and presumably septic arthritis. The rest of this report describes the clinical and unusual growth characteristics of this organism. Earlier recognition of infection with M. haemophilum should result in decreased morbidity from infection with this organism.

Case Report During evaluation for mild thrombocytopenia, a 36-yearold homosexual man was found to be infected with the human immunodeficiency virus (HIV). He remained asymptomatic for 2 years until he developed painful, erythematous swelling of his right knee. Initial culture of aspirate from the joint was negative for bacteria, and the patient was treated symptom-

Received 31 August 1990; revised 27 December 1990. Reprintsandcorrespondence: Dr. VirginiaM. Bieluch, New Britain General Hospital, Division of Infectious Diseases, 100 Grand Street, New Britain, Connecticut 06050. * Present address: Section ofInfectious Diseases, Boston University Hospital, 88 East Newton Street, Boston, Massachusetts 02118. Reviews of Infectious Diseases 1991;13:906-10 © 1991 by The University of Chicago. All rights reserved. 0162-0886/91/1305-0041$02.00

atically with antiinflammatory and analgesic medications. Magnetic resonance imaging of the knee revealed a large joint effusion, disruption of the deep fibers of the medial collateral ligament, and partial disruption of the posterior cruciate ligament. Over the next 6 months the patient's symptoms continued, and he developed an erythematous area on his calf. Serous material drained from both areas, which became ulcerated. A biopsy revealed a perivascular neutrophilic infiltrate with few histiocytes. There were no granulomas. Acid-fast staining revealed intra- and extracellular organisms. A routine mycobacterial culture of the drainage from the posterior calf was obtained. Treatment with isoniazid, rifampin, ethambutol, and zidovudine was initiated. A blood specimen for culture of acidfast bacilli was obtained in an isolator (Du Pont, Wilmington, DE). This specimen was incubated on a Middlebrook 7HI0 agar slant and Lowenstein-Jensen medium at 35°C. Six weeks later the blood culture was positive for an acid-fast organism, but the wound culture was negative. The patient had minimal response to the antimycobacterial therapy; after an area of erythema and swelling developed on his right elbow, therapy was discontinued. A second specimen of drainage from the knee was obtained and plated on CDC anaerobic blood agar (BBL Microbiology Systems, Cockeysville, MD). This specimen was incubated at 30°C in a Campy Pak Plus jar (BBL). Because a diagnosis of M. haemophilum infection seemed likely, therapy with rifampin and p-aminosalicylic acid was initiated. The blood culture isolate was subsequently identified as M. haemophilum; the second culture of fluid from the wound was also positive for the organism. The patient's pain and drainage decreased, the range of motion in the knee improved, and the area of erythema on the elbow resolved over the ensuing months (figure 1). Follow-up cultures have not been performed, and the patient has had no other AIDSdefining illness during 19 months of follow-up. His CD4lymphocyte count after 19 months of therapy was 95/mm3 •

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Mycobacterium haemophilum, previously characterized as an unusual pathogen, is found primarily in immunocompromised hosts. This organism has stringent growth characteristics and may not be isolated using routine techniques. M. haemophilum infects the skin and underlying tissues, a circumstance which reflects the organism's propensity for growth in a cooler environment. Infections have been reported in renal transplant recipients, patients with Hodgkin's disease, and, more recently, patients with AIDS. The organism has also been isolated from children with cervical lymphadenitis in the absence of apparent immunodeficiency. Response to therapy has not been uniform, and in some instances improvement in immune status has been associated with regression of lesions. With proliferation of transplantation surgery, chemotherapy, and AIDS, the number of infections due to M. haemophilum is likely to increase.

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M. haemophilum Infection in Immunocompromised Patients

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Given his HIV-positive status and the nontuberculous mycobacterial infection of his knee joint, this patient meets the current Centers fur Disease Control definition of AIDS [15]. Discussion Sixteen cases of infection with M. haemophilum have been reported in the literature [1-14], but few isolates have been obtained from patients with AIDS [16, 17]. No isolates of M. haemophilum were found in 104 patients with AIDS at the University of California, Los Angeles, from whom acid-fast bacilli were isolated between 1980 and 1985 [16]. Of the nontuberculous mycobacteria recovered, the Mycobacterium avium/Mycobacterium intracellulare complex predominated. Much less commonly isolated Mycobacterium species were M. gordonae, M. kansasii, M.fortuitum , M. smegmatis, and M. scrofulaceum. Cases of infection in humans have been reported in Australia [2-6, 8, 9], Canada [14], France [10, 13], Israel [1], and the United States [7, 11, 12], a distribution suggesting that this organism is ubiquitous. Despite attempts at culturing M. haemophilum from aquatic sources [7, 13], its environmental source remains unknown. In addition to cases in which M. haemophilum was definitively identified, 29 cases of skin infection caused by an acidfast bacillus species that could not be cultured have been reported from Minnesota and southern Manitoba [18]. It appears unlikely that M. haemophilum would be the pathogen, however, as these patients were not reported to have defects in their cell-mediated immune systems. Three immunocompromised patients have been reported with clinical presentations suggestive of M. haemophilum skin infection, but no definitive identification of the organism as M. haemophilum was made [5].

Table 1 details 17 patients in whom M. haemophilum infection has been reported, including 1 each with lymphocytic lymphoma and Hodgkin's disease, eight renal transplant patients receiving immunosuppressive therapy, and five patients with AIDS. In addition, cervical lymphadenitis has been noted in two apparently immunocompetent children. M. haemophilum infection has been reported in 10 men and seven women. The relatively young average age of these patients (39 years) probably reflects the occurrence of this infection in patients immunocompromised secondarily to AIDS and transplantation. No deaths have been attributed to infection with this organism. As shown in table 1, lesions of the skin and its underlying structures are the most common manifestations of infection with M. haemophilum. As in our patient, these lesions begin as painful erythematous or violaceous nodules that may progress to form an abscess. The lesions often exude purulent or serous fluid and progress to cutaneous ulcers [1, 7, 10-13]. The synovium of joints such as the knee, ankle, digits , and wrist [11, 12] as well as tendon sheaths [11] can be infected by this organism. M. haemophilum has been isolated from bronchoalveolar lavage fluid [12], blood [12], joint capsules and effusion [5, 11], skin ulcers [1, 2, 4, 7-10, 12-14], the eye [14], and lymph nodes [6, 14]. Lesions persisted despite antimycobacterial therapy in all patients with AIDS thus far reported [11, 12]. When our patient was given a combination of antimycobacterial and zidovudine therapy, his pain lessened, his lesions drained less, and the erythematous area over his elbow resolved. It is not clear whether the antimycobacterial therapy or improvement in his immune function due to zidovudine accounted for healing of the lesions. Our patient has had no other AIDS-defining disease, whereas some of the patients

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Figure 1. Lesions due to infection with M. haemophilum (A and B) on the leg of a patient with AIDS. The lesions were photographed after the patient was treated with zidovudine, rifampin, and p-aminosalicylic acid for 6 months . Therapy resulted in decreased drainage and pain and increased range of motion of the knee.

Kristjansson, Bieluch, and Byeff

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Table 1. Clinical characteristics of 17 patients infected with Mycobacterium haemophilum. Cause of immunodeficiency, gender, age (years) Renal transplant F,46

Site of infection

Source of culture specimen

Outcome

Reference

Resolved with decreased immunosuppression, reappeared several years later, and resolved again with decreased immunosuppression Skin lesions decreased; joints remained swollen during mycobacterial therapy; died 2 weeks after therapy started Healed after 6 weeks of mycobacterial therapy Improved with cotrimoxazole; progressed with folate and iron replacement, which resulted in increased hemoglobin concentration; improved again with sulfamethoxazole Lesions regressed with mycobacterial therapy; * decreased immunosuppression Resolved with surgery and minocycline; recurred and resolved with erythromycin Healed with minocycline

[2-4]

Skin lesions

Lesions

F,55

Arms, legs, breast, ankle, fingers

Skin lesions, joint aspirate

F,32 F,40

Leg Arm

Wound Aspirate of nodule

F,47

Toe, ankle

Biopsy

M,48

Finger, ankle, face

Drainage

M,51

Knee

Knee aspirate

Fingers, ankle, foot, face

Skin

M. haemophilum coexisted with Mycobacterium xenopi, isolated from urine and sputum; lesions healed with surgery, rifampin and minocycline therapy, and reduction in immunosuppression

[10]

Knee, skin Finger, ankle

Blood, wound BAL fluid, skin lesions Skin lesions

Improved with rifampin, PAS, zidovudine Died, cause unknown; lesions persisted despite mycobacterial therapy* Unknown

[PRJ [12]

Wrist, upper arm

Blood, biopsy

Lesions persisted despite mycobacterial therapy*; died of Kaposi's sarcoma

[12]

Wrist, ankles, knees

Synovial fluid

Lesions persisted until death despite mycobacterial therapy*

[11]

Knee, ankles, feet

Joint aspirate

Partial response to mycobacterial therapy; healed after surgical debridement

[3, 5]

Multiple lesions on extremities and trunk

Wound drainage

Spontaneous regression of lesions initially; later lesions responded to mycobacterial therapy*

[1]

Cervical lymph node Cervical lymph node

Lymph node Lymph node

Cured with surgery Unknown

[3, 5]

[7] [8]

[13]

[13]

+ Cytomegalovirus infection M,48

AIDS M,36 M,38 Mt

+

Legs, hand, lymph node, eye

Kaposi's sarcoma M,34

[14]

+ Kaposi's sarcoma and pneumocystis pneumonia M,32 Lymphocytic lymphoma M,58 Hodgkin's disease, steroids, radiation F,51

Unknown M,I F, 4 NOTE.

+

[6]

[14]

= in addition to; PAS = p-aminosalicyclic acid; PR == present report; BAL = bronchoalveolar lavage.

* Mycobacterial therapy consisted of administration of routine agents such as isoniazid, rifampin,

and ethambutol.

t Age not known.

with AIDS who were reported to be infected with M. haemophilum have had other more life-threatening infections or tumors [11, 12]. Lesions in some of the transplant recipients improved when immunosuppressive therapy was decreased [2, 9, 10]. For one patient, administration of iron and folate

supplementation and a resultant increase in hematocrit coincided with progression of infection [8], a circumstance suggesting that the increase in serum iron concentration provided a more permissive milieu for growth of this mycobacterium. Although our patient wastransfused several times, no progres-

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[9]

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M. haemophilum Infection in Immunocompromised Patients

for 5 % sodium chloride, urease activity, indole production, and presence of t1-galactosidase are negative for M. haemophilum strains [1, 3, 8-11, 13]. Positive reactions with neutral red stain, pyrazinamidase, and nicotinamidase havebeen noted [1, 8, 9, 11]. Results of tests for phosphatase activity have been reported as both negative and positive [1, 11]. M. haemophilum does not typically reduce nitrate [1, 8, 11], although nitrate reduction has been reported [3, 9]. Most studies have demonstrated in vitro susceptibility of M. haemophilum to rifampin and p-aminosalicylic acid [1, 3, 8-11, 13]. However, the correlation between in vitro susceptibility test results and results of antimycobacterial therapy is unclear. Experimental data suggest that iron compounds in medium may interfere with antimycobacterial activity of the agents being tested [3, 10]. Dawson and Jennis [3] have done susceptibility testing using Lowenstein-Jensen culture medium supplemented with the lowest concentration of ferric ammonium citrate that will support growth of this organism (5 mg/mL) in order to minimize the effect of drug inactivation by this compound. Other investigators have recommended using chocolate agar for susceptibility testing because this medium interferes less with drug activity [10]. Minocycline, administered as an adjunctive therapy with surgery or combined with rifampin, has been used in treatment of patients and produced some response [10, 13]. Improvement has also been noted with administration of cotrimoxazole and sulfamethoxazole alone [8]. Because of the limited number of patients with M. haemophilum infections, it is unlikely that a large amount of data concerning susceptibility of this organism and response to therapy will be acquired. Clearly, the status of a patient's immune system is an important determinant of outcome. Histologic examinations of biopsy specimens from immunosuppressed patients with renal transplants or Hodgkin's disease and who were infected with M. haemophilum have revealed granuloma (with or without caseation) and the presence of acid-fast bacilli [6, 7, 9]. In our patient and another patient with AIDS for whom histologic results were reported previously, granulomas were poorly formed [12]. This lack of granuloma formation is consistent with that seen with other mycobacterial infections in patients with AIDS, most notably infections due to the M. avium-M. intracellulare complex [17]. Abbott and Smith [20] infected prednisone- and nonprednisone-treated mice with M. haemophilum. Mice in both categories had acid-fast bacilli detected in spleen, liver, and lung tissues at necropsy. Skin lesions appeared on the ears and feet only in those treated with prednisone. Although those not treated with prednisone developed a low-grade fever and enlarged spleens, no skin lesions were detected. The findings of skin infection only in the immunocompromised animals correlates with the human experience, in which M. haemophilum infection has been detected primarily in immunocompromised individuals. It is unknown whether subclinical

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sion of infection was noted. The one immunocompetent child with cervical lymphadenitis for whom the outcome is known was cured by surgical therapy alone [6]. Thus, cell-mediated immune dysfunction appears to be the factor most associated with infection with M. haemophilum. M. haemophilum is a short, slightly curved rod that occurs singly or in a cord-like formation. The organism is strongly acid-fast by Ziehl-Nielsen staining [1]. Although it is likely to be missed if samples are plated only on routine mycobacterial media, it has been grown on various media, including Lowenstein-Jensen culture medium supplemented with ferric ammonium citrate [1, 4-6, 10, 13]; Middlebrook 7H11, 7HI0, and 7H9 agar supplemented with hemin or hemin and OADC (oleic acid, bovine albumin, fraction V, glucose, catalase, and sodium chloride) [1, 8, 11, 12]; Bactec medium (Eastman Kodak, Rochester, NY) [12]; Mueller-Hinton medium with Fildes supplement [10]; chocolate agar [9-11]; lysed horse blood agar [9]; Columbia colistin-nalidixic acid agar with 5 % sheep red blood cells [10, 13]; and brain-heart blood agar [14]. In our laboratory, M. haemophilum grew on CDC anaerobic blood agar in the CO 2 atmosphere of a Campy Pak Plus jar at 30°C. CDC anaerobic blood agar contains trypticase soy agar supplemented with additional agar, yeast extract, vitamin K 1 , hemin, cystine, and 5 % sheep blood. Initial cultures became positive after 1'\J3 weeks of incubation, but subcultures required only 2-3 days for visible growth. Initially, M. haemophilum was isolated from our patient's blood culture. Growth from blood and synovial fluid may occur on routine mycobacterial media because of residual hemin from the source material [11]. Reports regarding optimal growth temperature are inconsistent. Most authors report that 3D-32°C is the optimal temperature [1-4, 6-8, 12]; others have observed adequate levels of growth at 28°C [10]. A lower optimal growth temperature probably explains this organism's predilection to infect cooler areas of the body rather than visceral organs. Two other atypical mycobacteria, M. ulcerans and M. marinum, also grow at cooler temperatures in the laboratory, and infection with these organisms also occurs in the extremities [19]. An increased hemin concentration and addition of 10% CO2 to the atmosphere improve conditions for culture of M. haemophilum, which may be able to grow at 37°C or on suboptimal media under these conditions [11]. Colonies differ in morphology depending on the culture medium and atmospheric CO2 concentration. For example, on Middlebrook 7HI0 agar with hemin in ambient air, strains ECMC and ATCC 33206 formed small colonies with vertical growth [11]. With the addition of 10% CO 2 , some strains produced larger, flatter colonies [11]. M. haemophilum does not produce pigment when exposed to light [1]. This characteristic distinguishes the organism from M. marinum, which can cause infection of periarticular tissues and ulceration [19]. Tests for catalase activity, niacin synthesis, polysorbate hydrolysis, presence of arylsulfatase, tellurite reduction, tolerance

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infection, as noted in the immunocompetent mice, occurs in healthy humans. Clinicians caring for immunocompromised patients should be familiar with M. haemophilum and should request that their microbiology laboratories seek this organism in appropriate clinical specimens. The organism may cause a debilitating disease, as in our patient. Among patients with malignancies or who have received transplants, manipulation of immunosuppressive regimens may help those infected with this organism. For others, palliative therapy may be beneficial in improving quality of life.

The authors thank the staff of the microbiology laboratory, New Britain General Hospital, for research into methods of isolating M. haemophilum; Joan Lively for secretarial assistance; and Joseph G. Garner for comments.

References 1. Sompolinsky D, Lagziel A, Naveh D, YankilevitzT. Mycobacterium haemophilum sp. nov., a new pathogen of humans. Int J Syst Bacteriol 1978;28:67-75 2. Abbott MR, Smith DD. Mycobacterial infections in immunosuppressed patients. Med J Aust 1981;1:351-3 3. Dawson DJ, Jennis F. Mycobacteria with a growth requirement for ferric ammonium citrate, identified as Mycobacterium haemophilum. J Clin Microbiol 1980;11:190-2 4. Walder BK, Jeremy D, Charlesworth JA, Macdonald GJ, Pussell HA, Robertson MR. The skin and immunosuppression. Aust J Dermatol 1976;17:94-7 5. Mezo A, Jennis F, McCarthy SW, Dawson DJ. Unusual mycobacteria in 5 cases of opportunistic infections. Pathology 1979;11:377-84 6. Dawson DJ, Blacklock ZM, Kane DW. Mycobacterium haemophilum causing lymphadenitis in an otherwise healthy child. Med J Aust 1981;2:289-90

7. Davis BR, Brumbach J, Sanders WI, Wolinsky E. Skin lesions caused by Mycobacterium haemophilum. Ann Intern Med 1982;97:723-4 8. Moulsdale MT, Harper JM, ThatcherGN. Infection by Mycobacterium haemophilum, a metabolically fastidious acid-fast bacillus. Thbercle 1983;64:29-36 9. Ryan CG, Dwyer BW.New characteristics of Mycobacterium haemophilum. J Clin Microbiol 1983;18:976-7 10. Branger B, Gouby A, Gules R, Balducchi JP, Mourad G, Fourcade J, Mion C, Duntz F, Ramuz M. Mycobacterium haemophilum and Mycobacterium xenopi associated infection in a renal transplant patient. Clin Nephrol 1985;23:46-9 11. Males BM, West TE, Bartholonew WR. Mycobacterium haemophilum infection in a patient with acquired immune deficiency syndrome. J Clin Microbiol 1987;25:186-90 12. Rogers PL, Walker RE, Lane HC, Witebsky FG, Kovacs JA, Parrillo IE, Masur H. Disseminated Mycobacterium haemophilum infection in two patients with the acquired immunodeficiency syndrome. Am J Med 1988;84:640-2 13. Gouby A, Branger B, Oules R, Ramuz M. Two cases of Mycobacterium haemophilum infection in a renal-dialysis unit. J Med Microbial 1988;25:299-300 14. Thibert L, Lebel F, Martineau B, Chicoine L. Mycobacterium haemophilum in Quebec. Can Dis Wkly Rep 1988;14:196 15. Revision of the CDC surveillance case definition for acquired immunodeficiency syndrome. Council of State and Territorial Epidemiologists; AIDS Program, Center for Infectious Diseases. MMWR 1987;36(Suppl 1):lS-15S 16. Young LS, Inderlied CB, Berlin OG, Gottlieb MS. Mycobacterial infections in AIDS patients, with an emphasis on the Mycobacterium avium complex. Rev Infect Dis 1986;8:1024-33 17. Jacobson MA. Mycobacterial diseases. Tuberculosis and Mycobacterium avium complex. Infect Dis Clin North Am 1988;2:465-74 18. Feldman RA, Hershfield E. Mycobacterial skin infection by an unidentified species: a report of 29 patients. Ann Intern Med 1974; 80:445-52 19. Woods GL, Washington JA II. Mycobacteria other than Mycobacterium tuberculosis: review of microbiologic and clinical aspects. Rev Infect Dis 1987;9:275-94 20. Abbott MR, Smith DD. The pathogenic effects of Mycobacterium haemophilum in immunosuppressed albino mice. J Med Microbiol 1980;13:535-40

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Acknowledgments

RID 1991;13 (September-October)

Mycobacterium haemophilum infection in immunocompromised patients: case report and review of the literature.

Mycobacterium haemophilum, previously characterized as an unusual pathogen, is found primarily in immunocompromised hosts. This organism has stringent...
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