First described by Sompolinsky in 1978, M. haemophilum is a rare yet increasingly recognized pathogen in immunocompromised patients that causes cutaneous, synovial, and, less frequently, pulmonary infections.1 Infections may also occur in healthy children, manifesting as chronic cervicofacial lymphadenitis.2,3
This 48-year-old white man developed gradual onset of pain involving his left ankle, both knees, and right elbow approximately 1 year after renal transplantation. He also developed a rash with nodular lesions in his distal upper and lower extremities. Other complaints included low-grade subjective fevers and chills and generalized weakness. Further history revealed that the patient had helped clean his recently deceased mother's house 1 month before presentation, during which time he was exposed to old dusty boxes in the attic as well as dust and other debris during the removal of old carpet. There was no environmental aquatic exposure or any history of trauma. His medical history was most notable for polycystic kidney disease, which progressed to end-stage renal disease necessitating living unrelated donor renal transplantation (from his spouse). At the time of presentation, he was maintained on chronic immunosuppressant medications including prednisone, mycophenolate mofetil, and tacrolimus.
His physical examination revealed diffuse tender erythematous plaques and nodular lesions in the soft tissues of his distal extremities, often overlying small joints or ligaments in his wrists, hands, ankles, and feet, frequently associated with evidence of synovitis (Fig. 1). He also had an erythematous macular lesion on his abdomen. He was afebrile, and at that time, the remainder of his physical examination was unremarkable. Initial laboratory investigations revealed a leukocyte count of 9.7 (Bil/L) with 6.4 (Bil/L) polymorphonuclear neutrophils and 1.9 (Bil/L) lymphocytes, along with a normal hemoglobin and hematocrit. Serum electrolytes were within normal limits. His initial calcium, alanine aminotransferase, alkaline phosphatase, and total bilirubin were within normal limits. His creatinine was 1.2 mg/dL, near the new baseline established after the transplant. Erythrocyte sedimentation rate and C-reactive protein were not elevated. Radiographs of all distal joints did not reveal any abnormalities.
The initial skin biopsy revealed a perivascular lymphocytic inflammatory dermatitis. His symptoms progressed, prompting a repeat skin biopsy, which revealed abundant acid-fast bacilli (AFBs) (Fig. 2). He was started on empiric antimycobacterial treatment with clarithromycin, rifabutin, and moxifloxacin to cover common nontuberculous mycobacterial pathogens, and his immunosuppressant regimen was reduced to only prednisone 10 mg daily. Given the acral manifestation of his infection, Mycobacterium haemophilum was included in the differential diagnosis of possible mycobacterial pathogens, and the specimen was thus also incubated at 30°C on ferric-supplemented media. Four weeks later, the culture grew this pathogen, and of note, an AFB blood culture incubated in the same fashion also grew M. haemophilum.
Although he initially did well on the empirical regimen and the reduction in his immunosuppressants, he later developed fevers, and his cutaneous lesions became more disseminated, including lesions on his back, malar area, nose, and forehead, and the arthralgia progressed to the point that he became wheelchair bound. His calcium levels increased to 14.2 mg/dL with ionized calcium of 7.38 mg/dL, requiring increased steroids and the use of bisphosphonates. There was also increase in 1,25-dihydroxyvitamin D levels corresponding to his increased calcium (Table 1). His progression on therapy was felt to be secondary to immune reconstitution, although antimycobacterial resistance was also considered. His regimen was temporarily modified to include amikacin; once the susceptibility results returned, his regimen was subsequently tailored to azithromycin, moxifloxacin, and rifabutin. His fevers and other inflammatory findings gradually diminished as did his hypercalcemia to the point that he could be discharged from the hospital. He remained on azithromycin, moxifloxacin, and rifabutin for approximately 18 months, with a gradual taper of his steroid dose over the initial several weeks and a corresponding reintroduction of tacrolimus and mycophenolate mofetil. He did develop evidence of allograft rejection 5 months into antimycobacterial treatment, which improved with enhanced immunosuppression, and his most recent creatinine level was 1.7 mg/dL (baseline, 1.2-1.5 mg/dL posttransplantation). He has remained symptom-free for 6 months since discontinuing the antibiotics.
Mycobacterium haemophilum is considered an opportunistic pathogen, and to date, less than 100 cases have been reported.4 This blood-loving aerobe has distinctive culture requirements for laboratory isolation, requiring supplementation of growth media with ferric-containing compounds. It is a fastidious organism, growing at 30°C to 32°C, and it is an important consideration in culture-negative, acid-fast-positiveinfections.5,6 Because of its unique culture requirements, cases of M. haemophilum infection have likely been underreported.4
The natural habitat, incidence, and mode of acquisition of M. haemophilum are unknown.7 Although M. haemophilum is thought to be ubiquitous, no specific environmental reservoir has been identified. Evidence from other case reports point to an environmental reservoir, possibly aquatic, but attempts to recover the organism from environmental sampling have been unsuccessful. A few patients have reported antecedent trauma at the site of infection.8 Although the pathophysiology is not well understood, cell-mediated immunity appears to play a key role in disease pathogenesis and outcome. Injection of M. haemophilum into steroid-treated mice results in the development of ear lesions similar to the skin lesions observed in humans.9
Cutaneous and subcutaneous manifestations are most commonly reported in literature.10 Skin biopsy specimens reveal AFB, granulomatous panniculitis, and mixed suppurative reaction. However, infections may involve multiple sites, are frequently associated with septic arthritis or synovitis potentially with overlying cutaneous infection, and may involve the bones of the foot, ankle, knee, elbow, and fingers. These and other sites may be involved via contiguous spread or via hematogenous dissemination from a pulmonary or cutaneous source.11
Optimal therapy for M. haemophilum infections remains unknown.12,13 It is susceptible in vitro to fluoroquinolones, rifamycins, amikacin, and macrolides. Duration of treatment is individualized but is usually at least 12 months. The organism is usually resistant to isoniazid, ethambutol, and pyrazinamide.7,13,14
Hypercalcemia caused by extrarenal production of 1,25-dihydroxyvitamin D by granulomatous infiltrates has been reported in various granulomatous diseases, but its association with M. haemophilum infection has been documented only once in the English-language literature, to our knowledge.15 The mechanism of hypercalcemia in granulomatous infections is due to endogenous overproduction of 1,25-dihydroxyvitamin D by disease-activated macrophages.15,16 However, in immunosuppressed patients, hypercalcemia may be delayed until immunosuppression is reduced and treatment is initiated, as was observed in this case.16 This delayed response is believed to be due to an immune reconstitution that develops as the immunosuppressants are reduced, in particular, calcineurin inhibitors.16 This reconstitution of the immune response leads to increased interferon γ levels, which in turn promote a rebound granulomatous response as well as increased monocyte synthesis of 1,25-dihydroxyvitamin D, both potentially leading to hypercalcemia.16
Mycobacterium haemophilum has recently been recognized as a cause of disease in immunocompromised patients, presenting predominantly as cutaneous lesions, arthritis, and, rarely, pneumonia.7 Because this organism is fastidious and difficult to grow without the use of special media and conditions, this case reflects the possibility that M. haemophilum is likely an underrecognized cause of cutaneous lesions in this population and should be considered, particularly in cases where smears for acid-fast bacteria are positive but cultures are negative.5,6 When this pathogen is suspected, it is essential that the treating clinician communicates directly with the microbiologist to ensure appropriate media and conditions are used to best facilitate its growth.
1. Sompolinsky D, Lagziel A, Naveh D, et al. Mycobacterium haemophilum
sp. nov. A new pathogen of humans. Int J Syst Bacteriol
2. Armstrong D, Kiehn T, Boone MW. From the Centers for Disease Control. Mycobacterium haemophilum
infections-New York City metropolitan area, 1990-1991. JAMA
3. Bruijnesteijn van Coppenraet LE, Kuijper EJ, Lindeboom JA, et al. Mycobacterium haemophilum
and lymphadenitis in children. Emerg Infect Dis
4. Shah MK, Sebti A, Kiehn E, et al. Mycobacterium haemophilum
in immunocompromised patients. Clin Infect Dis
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. Clin Infect Dis
6. Lefkowitz RA, Singson RD. Considering Mycobacterium haemophilum
in the differential diagnosis for lytic bone lesions in AIDS patients who present with ulcerating skin lesions. Skeletal Radiol
7. Kiehn TE, White M. Mycobacterium haemophilum
: an emerging pathogen. Eur J Clin Microbiol Infect Dis
8. Armstrong KL, James RW, Dawson DJ, et al. Mycobacterium haemophilum
causing perihilar or cervical lymphadenitis in healthy children. J Pediatr
9. Abbott MR, Smith DD. The pathogenic effects of Mycobacterium haemophilum
in immunosuppressed albino mice. J Med Microbiol.
10. Tan HH, Tan A, Theng C, et al. Cutaneous Mycobacterium haemophilum
infections in immunocompromised patients in a dermatology clinic in Singapore. Ann Acad Med Singapore
11. White DA, Kiehn TE, Bondoc AY, et al. Pulmonary nodule due to Mycobacterium haemophilum
in an immunocompetent host. Am J Respir Crit Care Med
12. White MH, Papadopoulos EB, Small TN, et al. Mycobacterium haemophilum
infections in bone marrow transplant recipients. Transplantation
13. Griffith DE, Aksamit T, Brown-Elliot BA, et al. An Official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med
14. Smith S, Taylor GD, Fanning A, et al. Chronic cutaneous Mycobacterium haemophilum
acquired from coral injury. Clin Infect Dis
15. Lin JH, Chen W, Lee JY, et al. Disseminated cutaneous Mycobacterium haemophilum
infection with severe hypercalcaemia in a failed renal transplant recipient. Br J Dermatol
16. Singh N. Hypercalcemia related to immune reconstitution in organ transplantation recipients with granulomatous opportunistic infections. Transplantation