Mycobacterium haemophilum
Authors: Mini Kamboj, M.D., Monika K. Shah, M.D.
Previous authors: Mini Kamboj, M.D., Timothy E. Kiehn, Ph.D.
MICROBIOLOGY
Mycobacterium haemophilum was first described in 1978 by Sompolinsky et al. (28) in a woman from Israel with Hodgkin’s disease. It is a fastidious, aerobic, slow-growing nontuberculous mycobacterium with an optimal temperature for in vitro growth between 30 and 32°C, and a requirement for supplementation of growth media with iron containing compounds such as ferric ammonium citrate or hemin. The organism is biochemically inert and colonies of M. haemophilum often show cord formation similar to that seen with Mycobacterium tuberculosis. The taxonomic relationship between M. haemophilum and other mycobacterial species is not completely clear (17).
EPIDEMIOLOGY
To date, over 200 patients with M. haemophilum infection have been described worldwide. The organism primarily causes cutaneous, synovial, and pulmonary infections in patients immunocompromised because of HIV infection, solid organ transplantation, hematologic malignancies, hematopoietic stem cell transplantation, or chronic conditions that require prolonged immunosuppressive therapy (8, 16, 17). The organism is also a cause of cervicofacial lymphadenitis in healthy children (1, 18, 25). M. haemophilum infections have been reported from several countries, and appear to be acquired from the environment, most likely from water and biofilms (9), and cutaneous infection acquired from coral injury has been reported (29). More recently, skin lesions with associated suppurative cervicofacial lymphadenitis was reported in a twelve immunocompetent patients who underwent permanent makeup of the eyebrows by the same makeup artist (10). The organism was recovered in the ink. A cluster of cases occurred in New York City beginning in 1990 (4). At Memorial Sloan Kettering Cancer Center (MSKCC) in New York City, there were 23 cases between 1990 and 2000; 14 patients had undergone bone marrow transplantation, 5 were infected with the human immunodeficiency virus, 3 had hematologic malignancies, and 1 had no known underlying immunosuppression (26). Clinical syndromes on presentation included skin lesions in 13 patients, arthritis or osteomyelitis in 4 patients, and lung disease in 6 patients. Two molecular epidemiologic studies of some of the New York City isolates suggested clonal clustering associated with underlying patient disease and location, but sources of infection have not been identified (15, 34). The genetic diversity of 128 isolates from different parts of the world was analyzed by amplified fragment length polymorphism (AFLP), and no clear clustering on the basis of continental origin was observed; however, types were restricted to geographical areas and not found on other continents (2). It is interesting to note that at MSKCC since 2000 there have been only 3 cases of M. haemophilum infection detected, with no apparent change in clinical or laboratory procedures that would suggest a reduction in susceptible patients. Two of the three patients had received alemtuzumab, a DNA-derived, humanized monoclonal antibody (14). There are reports of M.haemophilum infections in animal hosts, including a report of spinal intradural infection in an American Bison (12) and infection with granuloma in Zebrafish at a research facility (32).
CLINICAL MANIFESTATIONS
The most common clinical presentation in adults is cutaneous lesions including nodules, cysts and papules that may be erythematous, nodular or ulcerated, and can culminate in painful draining ulcers. Pyomyositis through direct extension from a cutaneous infection (13) and skin disease associated with nerve bundle involvement, mimicking leprosy, have been described (5). Septic arthritis, synovitis and osteomyelitis (7) are less common manifestations in immunocompromised patients, and when they do occur, skin disease may also be present. Several primary ophthalmologic infections have been reported: endophthalmitis in a male immunosuppressed following cardiac transplantation (23), filamentary keratopathy in a man with graft-versus-host disease (22), and chiasmitis in a patient with AIDS (27). Disseminated disease with multiorgan involvement and recovery of M. haemophilum from blood isolates has also been described in severely immunocompromised patients (16, 24). Pulmonary involvement in immunocompromised patients is associated with a higher mortality and progressive pulmonary disease can develop even while on effective antimicrobial treatment in severely immunosuppressed patients. Immunocompetent children usually present with cervicofacial lymphadenitis (11) and less commonly, inguinal lymphadenitis (20). Apparently immunocompetent adults with infection include a patient with subcutaneous nodules who had undergone coronary artery bypass grafting (21), a 62 year old woman from the Philippines with no apparent risk factors who developed a pulmonary nodular lesion due to M. haemophilum (33), and a cluster of women with suppurative cervicofacial lymphadenitis who had undergone the permanent application of eyebrow makeup (10).
LABORATORY DIAGNOSIS
Biopsy specimens from patients who are immunocompromised often reveal acid-fast bacilli, and a common histopathological feature is that of a mixed granulomatous and suppurative reaction. Biopsy specimens of skin lesions may also show granulomatous panniculitis and caseating or noncaseating and sometimes poorly formed granulomas (3). Microorganisms are not usually detected in stains of tissue from patients with normal immune responses. Laboratory media should contain ferric ions and be incubated at 30°C for several weeks. A practical method for culture is to inoculate Middlebrook 7H10 (or similar medium) agar plates with the clinical specimen and to place a hemin-containing paper strip (X factor) on the agar surface, with incubation of the plate at 30°C (26). M. haemophilum will form satellite colonies near the paper strip to provide, in conjunction with an acid-fast stain, a presumptive identification of the organism. Blood or other body fluids can be inoculated into blood culture bottles, with ferric iron supplementation. Growth is usually detected within 2 to 3 weeks. In recent years, molecular methods have been increasingly used for direct detection of M. haemophilum in clinical specimens Application of a Mycobacterium genus-specific real-time PCR in combination with amplicon sequencing and a M. haemophilum-specific PCR resulted in the recognition of M. haemophilum as the causative agent in several reports, including children and adults with cervicofacial lymphadenitis (1, 10), and PCR-restriction endonuclease analysis (PRA) has been used for direct identification of M. haemophilum in specimens from AFB smear-positive specimens from adults (31).
PATHOGENESIS
The pathophysiology of M. haemophilum infection is not well understood, however cell mediated immunity appears to play a significant role. Patients who presented with and died from pulmonary infection had severely depressed cell mediated immunity as measured by CD4 cell counts, compared to patients with less severe immunosuppression and cutaneous, joint or bone involvement whom had a favorable outcome (26).
SUSCEPTIBILITY IN VITRO AND IN VIVO
There is no standardized procedure for determining the in vitro antimicrobial susceptibility patterns of M. haemophilum. Methods reported include a proportional method involving Middlebrook 7H10 agar supplemented with hemin; a disk elution method with round-well cell culture plates, Middlebrook 7H10 broth, commercial antimicrobial disks, and commercial hemin disks; a micro-dilution method involving various concentrations of antimicrobials in Middlebrook 7H9 broth with and without hemin; and agar or broth dilution methods involving Middlebrook 7H11 agar or 7H12 broth with added hemin. Results are usually available after incubation of media at 30°C for 1 to 3 weeks. The organism appears to be most susceptible in vitro to the quinolones, macrolides, rifamycins, and amikacin; and resistant to the anti-tuberculosis drugs ethambutol, isoniazid and pyrazinamide (26).
ANTIMICROBIAL THERAPY
Based on in vitro susceptibility results and clinical outcomes, a 3-drug regimen containing a macrolide, a rifamycin, and a quinolone appears to be reasonable treatment. M. haemophilum does not respond to treatment with isoniazid or pyrazinamide (Table 1 and Table 2). The duration and amount of therapy should be guided by the patient’s underlying disease presentation and degree of immunosuppression. Immunocompromised patients may require several months of treatment, even upwards of 12-24 months. Rarely, resolution of cutaneous manifestations has been reported in HIV patients receiving antiretroviral therapy alone. For more invasive forms of disease in this subgroup multi drug treatment is required. Immune reconstitution syndrome as described in HIV patients with M. tuberculosis andMycobacterium avium has been observed with M. haemophilum as well (30). Prompt recognition and early treatment with steroids is necessary. In non-HIV patients, decreasing the amount of induced immunosuppression may enhance treatment (26). Recurrent disease despite long courses of anti-microbials in severely immunosuppressed patients has been described (6). For children and adults with lymphadenitis, surgical excision, if possible, is the preferred treatment option (10, 19).
ADJUNCTIVE THERAPY
For children with lymphadenitis, surgical excision of the affected lymph nodes is considered the treatment of choice.
ENDPOINTS FOR MONITORING THERAPY
Duration of antimicrobial therapy should be guided by the patient’s underlying disease presentation and degree of immunosuppression.
VACCINES
No vaccines are currently available.
PREVENTION OR INFECTION CONTROL MEASURES
Preventative measures probably cannot be implemented, as the means of acquisition is not well understood. However, increased awareness of the infection and the organism’s unusual growth requirements, and communication with the diagnostic laboratories regarding these issues is the most likely means to improve outcome. At Memorial Sloan Kettering Cancer Center all skin, joint or lymph node specimens sent to Mycobacteriology, all specimens that stain positive for acid-fast bacilli, and any lower respiratory specimen identified as coming from a transplant recipient are cultured for M. haemophilum (25).
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Tables
Table 1: Recommended Treatment for M. haemophilum infection
| Host Status | Clinical Syndrome | Treatment |
|---|---|---|
| Immunocompetent | Cervicofacial lymphadenitis | Surgical excision only |
| Immunocompromised | Cutaneous, synovial, pulmonary | Rifampin + Clarithromycin or Azithromycin daily + Fluoroquinolone or Amikacin. |
Table 2: Recommended dosages of antibiotics used for treatment of M. haemophilum
| Drug | Route and Dosage |
|---|---|
| Rifampin | 600 mg oral daily |
| Rifabutin | 300 mg oral daily |
| Clarithromycin | 500 mg oral twice daily |
| Azithromycin | 500 mg oral once daily |
| Amikacin | 7.5 mg/kg twice daily |
| Ciprofloxacin | 500 mg oral twice daily |
| Moxifloxacin | 400 mg oral once daily |
What's New
Winthrop KL, Chang E, et al. Nontuberculous Mycobacteria Infections and Anti-Tumor Necrosis Factor-Alpha Therapy. EmergInfect Dis. 2009 Oct;15:1556-61.
Deresinski S et al. Natural History of Lymphadenitis due to Nontuberculous Mycobacteria (NTM). Clin Infect Dis. 2009 Jan 15;48(2):iv.
Lutwick, LI and Shah, NS Ironic Exorcise. Infect Med 2009:10-12.
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Adhikari P, Mietzner T. Cell Mediated Immunity. 2008.
An Official ATS/IDSA Statement: Diagnosis, Treatment, and Prevention of Nontuberculosis Mycobacterial Diseases. Am J Respir Crit Care Med 2007:175;367-416.