Dermatology Online Journal

Mycobacterium haemophilum: Cutanoeus nodules in a renal transplant patient
Anand Rajpara MD, Jennifer Sri MD, Marcia Driscoll MD
Dermatology Online Journal 16 (7): 3

University of Maryland

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Abstract

A 52-year-old male with a history of renal transplantation and chronic iatrogenic immunosuppression presented with a several-week history of hyperpigmented cutaneous nodules on bilateral upper and lower extremities. Biopsy showed inflammatory granulomatous dermatitis caused by acid-fast bacilli (AFB). However, tissue cultures for mycobacterium were repeatedly negative. The patient was diagnosed with Mycobacterium haemophilum based on PCR results and was placed on empiric antibiotic therapy.

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History

A 52-year-old male with a history of hypertension, Type 2 diabetes, and chronic tophaceous gout underwent renal transplantation in 2004. Since 2004, the patient had been on an immunosuppressive treatment regimen consisting of mycophenolate mofetil, prednisone, and sirolimus to prevent transplant rejection. The patient presented to the dermatology clinic with a several week history of painful and swollen dark “bumps” on his arms and legs. The patient reported that several of the bumps had “popped,” expressing a pus-like material. The patient denied fever, chills, weight loss, night sweats, cough, hemoptysis, odynophagia, nausea, vomiting, diarrhea, shortness of breath, and chest pain.

Physical Exam

Figure 1	Figure 2

Figure 3	Figure 4

There were multiple, somewhat tender, hyperpigmented cutaneous patches, plaques, and nodules scattered asymmetrically over the bilateral upper and lower extremities. Several of the hyperpigmented cutaneous nodules had areas of central hypopigmentation where the nodules had become suppurative or had ulcerated. The patient went on to develop similar lesions on his abdomen, chest, back, and face. The lungs were clear to auscultation bilaterally and a head and neck examination revealed no palpable lymphadenopathy. Our initial differential diagnosis included mycobacterial infection, deep fungal infection, viral infection, prurigo nodularis, calcinosis cutis, panniculitis, acquired perforating dermatosis, and vasculitis.

Laboratory data and histopathology

Figure 5	Figure 6

A biopsy of a cutaneous nodule from the left arm was sent for histopathology and tissue cultures. Histopathologic examination of the specimen using low power magnification (Figure 4) revealed an intact epidermis and inflammation in the deep reticular dermis. An examination of the deep reticular dermis using high power magnification (Figure 5) revealed a lobular proliferation of spindle cells coursing around distinct lobules of granulomatous inflammation containing lymphocytes, histiocytes, and multinucleated giant cells. Subsequent staining for acid-fast bacilli (AFB) highlighted innumerable slender elongated rods within the granulomatous infiltrate. The final diagnosis was an infectious granulomatous dermatitis due to AFB. However, tissue cultures for mycobacteria, fungi, and bacteria were all negative. The patient’s primary care doctor ordered a chest x-ray to evaluate for pulmonary tuberculosis and discovered a left lung pulmonary nodule. Accordingly, the patient was hospitalized for suspected tuberculosis. A subsequent chest CT, transbronchial lung biopsy, and bronchoalveolar lavage effectively ruled out pulmonary infection and malignancy. In addition, repeated biopsies by us continued to produce negative tissue cultures.

Diagnosis

Fresh tissue specimens were sent to the University of Washington microbiology lab, which specializes in the identification of non-tuberculosis mycobacterium (NTM). The lab extracted DNA directly from the biopsy tissue and amplified and isolated the mycobacterial RpoB gene via PCR and electrophoresis, respectively. They sequenced the mycobacterial RpoB gene from our specimen and compared it to reference RpoB gene sequences from over 40 NTM. They found that our specimen’s RpoB gene sequence matched 100 percent to the known RpoB gene sequence for Mycobacterium haemophilum.

Treatment and follow-up

With the diagnosis of M. haemophilum, we sent additional biopsies for culture in order to determine any antibiotic susceptibilities. Despite specific instructions that the organism required a temperature of 30-32°C and iron supplementation for growth, the cultures were again negative. Accordingly, we elected to treat the patient with empiric antibiotic therapy.

There are no standardized guidelines for the treatment of M. haemophilum infection. In a case series of 23 patients with M. haemophilum infection, in vitro antimicrobial susceptibility testing revealed that the mycobacterium had 100 percent sensitivity to ciprofloxacin and clarithromycin, and 94 percent sensitivity to rifampin [4]. Most authors recommend triple antibiotic therapy or at least a combination of two effective antibiotics for a duration of 12 to 24 months [2, 4, 7]. After discussing the treatment options with the patient’s nephrologist, we decided to empirically place the patient on ciprofloxacin 500 mg twice a day and clarithromycin 500 mg twice a day for 1 year [6].

The patient was seen for follow-up 7 months into his antibiotic therapy. He stated that he had been compliant with his antibiotic treatment and was tolerating the medications well. He reported that his skin lesions had been healing well and no longer were tender. He denied the appearance of any new skin lesions. On physical exam we noted that the majority of the patient’s hyperpigmented cutaneous nodules had regressed leaving behind hyperpigmented scars. Overall, we were happy with the patient’s progress and felt that his condition would fully resolve with 5 more months of antibiotic treatment.

Discussion

M. haemophilum was first described in 1978 by Sompolinsky, who isolated the organism from the cutaneous lesions of a 51-year-old woman with Hodgkin Lymphoma [1]. M. haemophilum, a non-tuberculosis mycobacterium (NTM), is an aerobic, slow growing acid-fast bacilli (AFB) [2]. The epidemiology of this organism including its reservoir and mode of transmission is currently unknown. To date, less than 250 cases of M. haemophilum infection have been documented in the medical literature worldwide [3]. M. haemophilum is known to cause disease in two distinct clinical groups: immunocompromised adults and immunocompetent children [4].

Like other NTM, M. haemophilum mainly causes disease in immunocompromised populations. M. haemophilum infection has been documented in HIV/AIDS patients, transplant recipients, patients with hematological malignancies, and patients with chronic diseases requiring immunosuppression [2, 4]. In these patients, M. haemophilum infection usually presents as cutaneous nodules, cysts, and papules. Typically, the skin lesions progress from papules to painless nodules that may grow in size and become tender, erythematous, suppurative, or ulcerative [2]. Although skin lesions may remain localized, they tend to be diffuse and most often involve the extremities followed by the chest, back, and occasionally the face [2, 4]. Importantly, the lesions are not sporotrichoid in appearance because they do not follow lymphatic channels [5].

Less commonly, in immunocompromised patients, M. haemophilum can present as septic arthritis, osteomyelitis, or pulmonary infection with or without cutaneous lesions. Cutaneous lesions alone portend a good prognosis, whereas pulmonary infections often result in death [4]. In immunocompetent children M. haemophilum is known to cause benign cervical, sub-mandibular, or peri-hilar lymphadenopathy. This condition is generally curable with surgical excision of the affected lymph node(s), which is the treatment of choice [4].

The differential diagnosis for M. haemophilum includes other NTM infections, bacterial infections, deep fungal infections, panniculitis, lymphoma, and vasculitis. The initial step in the diagnosis of M. haemophilum infection begins with a biopsy of the cutaneous lesion(s), collection of infected synovial fluid, or collection of sputum samples, with or without a lung biopsy depending on the clinical presentation. Acid-fast staining of the tissue typically reveals numerous AFB, either singly or in a cord-like formation. Histopathologic examination of the tissue usually reveals poorly formed granulomas with small foci of necrosis, which may be accompanied by neutrophilic or mixed cellular infiltrates [2, 4].

Culturing M. haemophilum from tissue is notoriously difficult because of the organism’s unique in vitro growth requirements. M. haemophilum requires a temperature of 30-32°C for optimal growth and ferric ion supplementation of the growth media with substances such as hemin [6]. Accordingly, M. haemophilum will not grow in the lab using standard mycobacterial culture methods. M. haemophilum should be suspected in cases in which histopathology reveals a positive AFB stain, but tissue cultures are repeatedly negative.

Although culture remains the standard method for diagnosis of M. haemophilum and is needed to determine antibiotic sensitivities, the process is difficult and takes 3-5 weeks. Many laboratories are now using PCR followed by nucleotide sequencing or restriction enzyme analysis to directly detect M. haemophilum DNA in clinical samples [7]. This can produce a rapid diagnosis, which allows the physician to start empiric treatment and communicate special culture requirements to the microbiologist.

There are no standard guidelines for the treatment of M. haemophilum infection. Published literature generally agrees that patients should be placed on multiple antibiotics that include some combination of ciprofloxacin, clarithromycin, and one of the rifamycins [2, 4, 6, 7] for a duration of 12 to 24 months [4, 7]. Therapy should be tailored to the individual patient based on his or her disease presentation and underlying degree of immunosupression.

References

1. Sompolinsky, D., A. Lagziel, and I. Rosenberg. Further studies of a new pathogenic mycobacterium (M. haemophilum sp. nov.). Can. J. Microbiol. 1979; 25:217-226. [PubMed]

2. Saubolle, A. et al. Mycobacterium Haemophilum: Microbiology and Expanding Clinical and Geographic Spectra of Disease in Humans. Clinical Microbiology Reviews 1996;9(4):435-447. [PubMed]

3. Mata, O. et al. The diagnosis of two cases of cutaneous ulcer caused by infection with Mycobacterium haemophilum: direct identification in a clinical sample by polymerase chain reaction-restriction endonuclease analysis. International Journal of Dermatology 2008;47:820-823 [PubMed]

4. Shah, M. K., A. Sebti, T. E. Kiehn, S. A. Massarella, and K. A. Sepkowitz. Mycobacterium haemophilum in immunocompromised patients. Clin. Infect. Dis. 2001; 33:330-337. [PubMed]

5. Straus, W. L., S. M. Ostroff, D. B. Jernigan, T. E. Kiehn, E. M. Sordillo, D. Armstrong, N. Boone, N. Schneider, J. O. Kilburn, V. A. Silcox, V. LaBombardi, and R. C. Good. 1994. Clinical and epidemiologic characteristics of Mycobacterium haemophilum, an emerging pathogen in immunocompromised patients. Ann. Intern. Med. 120:118-125. [PubMed]

6. Lott, J. et al. Cutaneous Mycobacteria haemophilum infection in iatrogenically immunocompromised patients without transplantation. JAAD 2008; 59(1):139-142. [PubMed]

7. Jang, E. et al. Case of Pyomyositis Due to Mycobacterium haemophilum in a Renal Transplant Recipient. Journal of Clinical Microbiology 2007; 45(11):3847-3849 [PubMed]

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