Mycobaterium fortuitum disseminated infection in an immunocompetent patient without predisposing factors

Background

Mycobacterium fortuitum is a member of the rapidly growing mycobacteria (RGM). There are six groups of RGM representing about one half of all the mycobacterial species. RGM usually grow within 7 days. They are saprophytes, found in soils, dust, water, animals, hospital settings (tap water) and various solutions and instrumentation (responsible for nosocomial outbreaks). RGM are very difficult to eradicate as they survive in nutriment-poor environment, form biofilms and are resistant to standard disinfectants and high temperatures.1

M. fortuitum infections are rare, usually result from a direct inoculation (following surgery/catheters or trauma) and involve mainly wound infections. Most of the time, the presence of M. fortuitum in a respiratory specimen is considered to be ‘non-pathogenic’ but a few pulmonary infections have also been described, usually associated with a predisposing pulmonary disease. Rarely M. fortuitum is associated with central nervous system (CNS) infections but never without a prior breach.1

Case presentation

In August 2018, a patient from a sub-Saharan country consulted at the emergency department with a 1-month history of left eye ptosis and abduction limitation. He also had left hemicrania headache for the prior 6 months and a weight loss of 6 kg associated with asthenia.

His medical history included a schistosomiasis treated in 2016 and 2018 and a self-resolved hepatitis B infection. Since he arrived in Switzerland in 2015, he only travelled to Tchad once in 2018.

On admission (day 1), the patient was febrile (39°C). Neurological examination revealed an abduction, adduction and vertical gaze palsy of the left eye associated with a left ptosis. We also noted a hyperaesthesia of the left side of the face and a left hypoacusis. These signs combined suggested a cavernous sinus syndrome.

Laboratory findings were non-contributive. Notably, there was no inflammatory syndrome (C-reactive protein and blood cells count normal).

A brain CT scan demonstrated a tissular lytic lesion of the petroclival left synchondrosis, extending to the carotid canal and the cavernous sinus up to the orbital apex (figure 1A). On the upper pulmonary images, multiple bilateral pulmonary micronodules and nodules randomly distributed were visible. A brain MRI was performed and better characterised the perineural extension of the trigeminal nerve (figure 1B–F).

This patient had no prior immunosuppression. HIV test was negative twice.

These findings were at that time highly suspicious of a cerebral tumour process with pulmonary metastasis.

Investigations

We performed extensive cerebrospinal fluid (CSF) and blood infectious analyses and sputum examinations. Results are presented in table 1.

At day 3, we were informed that one out of two sputum cultures for mycobacteria was positive and M. tuberculosis PCR being negative, a non-tuberculous mycobacterium was assumed. After sequencing, it was identified as M. fortuitum. The second sputum remained sterile. The patient did not have any respiratory symptoms, only one sputum was positive for M. fortuitum and we had an alternative explanation for the pulmonary lesions with the suspicion of an oncological disease affecting the brain and lungs. For these reasons, we considered this germ non-pathogenic and decided initially not to treat. The infectious workup being negative, we suspected the mass to be oncological. The tumour board (composed of ear nose throat (ENT) surgeons, neurosurgeons and oncologists) evaluated the case and recommended an elective ENT endoscopy in search of a cavum tumour and, if possible, a transnasal diagnostic biopsy of the intracranial mass.

At day 31, while the patient was waiting for the endoscopic biopsy, he presented an acute neurological deterioration and a new MRI showed a progression of the mass with extension to the right cavernous sinus and a perineural infiltration of the fifth right cranial nerve (figure 2). The neurosurgeons performed a therapeutic and diagnostic craniotomy with removal of the mass in order to release the left optic nerve and obtain specimens. The surgeons described a white milk-like liquid.

Histopathological examination revealed an inflammatory tissue with a lymphocytic infiltrate and multiple granulomas, some with necrosis (figure 3). The Ziehl, Grocott and Gram stains were negative. There was no element suggesting a tumour. The PCR for M. tuberculosis was negative on the biopsy specimen (amplification sequence IS6110, includes M. tuberculosis, M. bovis, M. africanum, M. bovis var. BCG and M. microti detection). Cultures for bacteria and fungi remained sterile.

Differential diagnosis

The presence of an intracranial mass with diffuse bilateral pulmonary nodules suggested a differential diagnosis including an oncological, infectious or immunological disease. According to radiologists and oncologists, the images were suggestive of a tumorous process. Because of the origin of the patient, a disseminated mycobacterial disease was also probable. Finally, considering the simultaneous pulmonary and cerebral involvement, the possibility of sarcoidosis was considered. The normal cellularity of the CSF and the absence of detection of any bacterial or viral pathogens despite a thorough microbiological workup did not support the possibility of other infectious aetiologies. The finding of M. fortuitum in only one sputum analysis was considered non-pathogenic because: (1) the patient had no pulmonary symptoms; (2) only one specimen was positive and (3) there was no prior report of an intracranial mass and a pulmonary infection caused by M. fortuitum without prior breach or associated risk factor. However, the biopsy of the mass showed no tumour cells and multiple granulomas. Two main diagnosis were favoured at that time: mycobacterial infection or sarcoidosis.

Treatment

Glucocorticosteroïds and a standard empirical antituberculous therapy (ethambutol 1000 mg once a day intravenous, pyrazinamide 1000 mg once a day per os, rifampicine 600 mg once a day intravenous, isoniazide 250 mg once a day intravenous) were introduced simultaneously. Additional biological testing for a possible sarcoidosis was inconclusive. The brain specimen was kept in culture for fastidious/slow-growing organisms including mycobacteria.

At day 48, we were informed that a mycobacterium was growing in the brain specimen (12th day of incubation). Until definitive identification was available, we continued rifampicin and isoniazid, stopped pyrazinamide and ethambutol and added amikacin, imipenem and ciprofloxacin (to cover a possible non-tuberculous mycobacteria).

About 10 days later, the mycobacterium was identified as M. fortuitum by sequencing and treatment was adapted accordingly: only amikacin, imipenem and ciprofloxacin were continued (figure 4). The resistance profile is shown in table 2.

The evolution was good under this regimen, both clinically and radiologically (figure 5).

After 4 weeks of targeted intravenous therapy, the patient was discharged on oral therapy composed of moxifloxacin, linezolid and doxycycline. The gaze palsy was at that time almost resolved and the patient did not have any other symptoms.

A follow-up brain MRI and lung CT scan were performed approximatively 10 weeks after discharge, showing improvement of the brain lesion and pulmonary nodules. At that time, we decided to stop linezolid in order to avoid neurotoxicity and we pursued moxifloxacin and doxycycline for a total duration of at least 1 year (figure 4).

Outcome and follow-up

To understand why this immunocompetent patient presented with a disseminated infection, we performed high throughput sequencing of a panel of genes involved in immune system disorders. The exome sequencing did not reveal any abnormality in the genes studied (panel of 473 genes).

During follow-up, symptoms improved: eye motility came back to normal and the patient only suffered from intermittent headaches. Brain MRI and lung CT scan were performed every 2–3 months, to ensure that evolution was satisfactory.

Tolerance to antibiotics was regularly assessed through clinical examination, ECG and blood tests. We did not notice any prolonged QT, tendinopathy or confusion, the main side effects of moxifloxacin. Regarding linezolid, cell counts and liver tests were assessed every 2 weeks. Due to a worsening thrombopenia, we reduced the dosage of linezolid from 2×600 mg/day to 1×600 mg/day 1 week after introduction. Platelets level improved and no further toxicity was noticed. The patient also had regular ophthalmological check-ups. The patient had intermittent abdominal discomfort, a possible side effect of doxycycline. As mentioned earlier, after 10 weeks of oral therapy and with satisfactory follow-up, we decided for a step down. In order to avoid an eventual linezolid-induced neuropathy, we chose to stop linezolid first.

However, despite what we considered as a positive clinical response, the patient spontaneously interrupted his treatment for approximatively 4 weeks. On the MRI performed 8 months after the beginning of the treatment (including the interruption and the ‘lost to follow-up’ period), the residual collection was easier seen than on the previous MRI. We therefore decided to reintroduce linezolid 600 mg once a day (in addition to moxifloxacin and doxycycline). We continued to monitor tolerance as previously described. No further toxicity was noticed. The treatment was stopped after a total of 13 months with a favourable radiological and clinical evolution (figure 4). A clinical follow-up was scheduled every 6 months with a brain MRI and chest CT scan for a 2-year period.