Central nervous system infection due to Mycobacterium haemophilum in a patient with acquired immunodeficiency syndrome

Introduction

Mycobacterium haemophilum is a non-tuberculous mycobacteria (NTM) associated with infections in immunocompromised hosts. Commonly-infected sites include skin, bone and joint, respiratory system and disseminated infections. ¹ Central nervous system (CNS) infections due to this organism have rarely been reported. We present here a case of CNS infection due to M. haemophilum in a patient with acquired immune deficiency syndrome (AIDS).

Case report

A 35-year-old Thai woman presented to our hospital with 4-week history of worsening diplopia, right-eye ptosis and intermittent fever. She was diagnosed with HIV 3 weeks prior with CD4+cell count of 12 cells/µl. On examination, body temperature was 38°C. There were no abnormal skin lesions. Neurological examination revealed complete right-eye ptosis with impaired eye movement in all directions, dilated right pupil (5 mm), decreased pinprick sensation over the areas supplied by the right fifth cranial nerve and right lower motor neuron facial palsy. Laboratory investigation revealed white blood cell count of 5400 cells/µl (76% neutrophils, 14% lymphocytes and 10% monocytes) and normal blood chemistry. Initial magnetic resonance imaging (MRI) of the brain is shown in Figure 1(a). There were hyperintensity lesions involving anterior aspects of medulla oblongata, pons and cerebellar peduncles, right midbrain and inferior parts of right basal ganglia and thalamus. Her computed tomography of chest and abdomen was normal. Lumbar puncture was performed with an opening pressure of 16 cmH₂O. Cerebrospinal fluid (CSF) was clear with lymphocytes of 2 cells/µl, protein of 145 mg/dl, glucose of 52 mg/dl and CSF-to-blood glucose ratio of 0.52. CSF acid-fast bacilli (AFB) stain, Gram's stain, polymerase chain reaction (PCR) for mycobacteria, fungal and mycobacterial cultures and cytology for malignant cells were negative. CSF PCR for JC virus was negative. Blood cultures for bacteria, mycobacteria and fungi revealed no growth. Serum cryptococcal antigen, toxoplasma immunoglobulin G and VDRL were negative. She was empirically treated for CNS toxoplasmosis with trimethoprim-sulfamethoxazole (TMP-SMX). Two weeks after the treatment, the patient had worsening extraocular movement of both eyes and new generalised muscle weakness (grade IV/V). The follow-up MRI of the brain showed progression of the lesions (Figure 1b). Stereotactic brain biopsy was performed at the inferior part of right basal ganglia. The histopathology revealed brain tissue extensively infiltrated with histiocytes and numerous AFB organisms. PCR for mycobacteria of the brain tissue was negative. The tissue specimen was cultured in both mycobacteria growth indicator tube (MGIT) and Lowenstein-Jensen medium without haemin supplementation. Anti-tuberculous drugs including isoniazid 300 mg/day, rifampicin 600 mg/day, pyrazinamide 1250 mg/day and ethambutol 800 mg/day were empirically initiated along with dexamethasone. Six weeks into treatment, her condition had not improved. The MGIT culture flagged positivity on day 40. The MGIT-positive specimen was subsequently identified as M. haemophilum by INNO-LiPA MYCOBACTERIA v2, using amplification of the 16S-23S ribosomal rRNA spacer region with the primer sequences TTGTACACACCGCCCGTCA and CGATGCCAAGGCATCCACC. ² The MGIT-positive specimen was also cultured in the Lowenstein-Jensen medium at the temperature of 30°C with haemin supplementation. Neither the brain tissue nor the MGIT-positive specimen cultured on the Lowenstein-Jensen medium grew any organism. Therapy was switched to the combination therapy with ciprofloxacin 1000 mg/day, azithromycin 500 mg/day, rifampicin 600 mg/day and amikacin 750 mg/day. After three weeks of treatment, there was no improvement in her conditions and she died of septic shock from urinary tract infection. OPEN IN VIEWER

Discussion

There have been just over 150 cases of M. haemophilum infection reported since 1996. ¹ The risk of these infections is increased in immunocompromised conditions, especially defective cell-mediated immunity, such as HIV infection, solid-organ and stem-cell transplantation or receiving immunomodulatory therapy. Cutaneous lesions were the most frequently reported manifestations, while bacteraemia and pulmonary infection were present less commonly but associated with poorer prognosis.^3,4 CNS infections due to NTM among AIDS patients are rare and were usually reported to be caused by M. avium intracellulare, M. fortuitum, M. kansasii and M. gordonae.^5–7 Most of these cases had concurrent disseminated infection and presented with altered mental status and seizure, while our reported case initially presented with focal neurological deficits.

Diagnosis of mycobacterial CNS infection is challenging. The yield of positive acid-fast staining in CSF is usually low. Although histopathology may show granulomatous inflammation with or without necrosis, definitive diagnosis requires growth of the organism. M. haemophilum requires appropriate culture conditions including lower temperature (30–32°C) and additional haemin supplementation in the Lowenstein-Jensen or Middlebrook medium. ⁸ A previous case report of disseminated infection and probable localised CNS infection caused by M. haemophilum demonstrates positive cultures of blood but negative cultures of the brain tissue for M. haemophilum. The authors attribute the discordant culture results to no supplementation of haemin or ferric ammonium citrate in the brain tissue cultures. ⁹ In our presenting case, the diagnosis of M. haemophilum infection could be easily missed if the MGIT had failed to grow the organism. Thus, haemin supplementation along with the appropriate culture temperature for mycobacterium broth media may be routinely required, especially among immunocompromised patients suspected of having NTM infections. Molecular identification methods for mycobacteria can be performed by sequencing method or commercial line probe assay which has high sensitivity (100%) and specificity (100%). ¹⁰ Our presenting case highlights the importance of CNS tissue procurement and molecular identification methods in facilitating the diagnosis of the infection.

The mainstay of treatment for M. haemophilum infection is combination of two or three active drugs, including clarithromycin, ciprofloxacin and one of the rifamycins with a prolonged course (range 12–24 months). ¹ Generally, cases with NTM-associated CNS infection have poor outcomes. A mortality rate of 45% was reported among M. abscessus complex-associated CNS infections in non-HIV-infected patients ¹¹ while M. avium complex-associated CNS infection in HIV-infected patients resulted in a 67% hospital mortality rate. ⁶ The unfavourable outcomes in NTM-associated CNS infections, including our case, may be due to the poor CNS penetration of recommended therapeutic agents including clarithromycin, macrolides, aminoglycosides and fluoroquinolones ¹² and the patients' underlying immunocompromised status. In addition, the definitive therapy for M. haemophilum was delayed for 6 weeks given that the initial PCR for mycobacteria of the brain tissue was negative and it took 40 days for MGIT to flag the positive result. These suggest that empiric treatment may be broadened to cover NTM, especially if there is no improvement after anti-tuberculous drugs. In conclusion, CNS infections due to NTM, including M. haemophilum should be included in the differential diagnosis in AIDS patients who present with neurological deficits and multifocal infiltrative brain lesions of the brain and fail to respond to toxoplasmosis and anti-tuberculous treatment.