Meningitis caused by Mycobacterium fortuitum mimicking tuberculous meningitis in an immunocompetent patient: a case report and literature review.

Background: Nontuberculous mycobacteria (NTM) are a large group of microorganisms that mainly affect persons who have immune deficiency. Mycobacterium fortuitum is one of them, which usually cause soft tissue or pulmonary disease. Meningitis caused by M. fortuitum is extremely rare and is often confused with tuberculous meningitis (TBM) due to its low prevalence. Case presentation: A 35-year-old woman was referred to our hospital with a history of headache, followed by fever, chills, cough, and vomiting. The results of mycobacterial culture and TSPOT. TB of her cerebrospinal fluid were positive. Therefore, she was diagnosed with tuberculous meningitis and was given anti-tuberculous chemotherapy. During the observation, the CSF results were not significantly improved. Finally, hsp65 gene PCR revealed that the real pathogen was M. fortuitum . The treatment therapy was changed and the patient recovered after one-year combined chemotherapy. Conclusions: In this case we described a patient with M. fortuitum meningitis who was immunocompetent with no trauma or surgical history. The wrong diagnosis with TBM was made due to positive results of both blood and CSF TSPOT. TB . The pathological evidence and microbiological analysis of hsp65 gene PCR suggested the real pathogen to be M. fortuitum . The diagnostic accuracy of blood and CSF TSPOT. TB in case of TBM is moderate. Infections of NTM cannot be excluded when the patient does not respond to anti-tuberculous therapy and it is of great significance to do molecular identification for clinical isolates of mycobacterium. VP LP WBC INH isoniazid, SD sulfadiazine, TGC tetracycline, PEN penicillin, CRO ceftriaxone, PMNs polymorphonuclear leukocytes, GPB gram-positive bacilli, CAZ ceftazidime, VAN vancomycin, RFP rifampin, CIP ciprofloxacin, IMI imipenem, LVFX levofloxacin, EMB ethambutol, RFB rifabutin, MEM meropenem, OFX ofloxacin, CFZ clofazimine.


Background
In the past few decades, infections caused by non-tuberculous mycobacteria (NTM) have attracted considerable attention with its increasing prevalence [1][2][3]. NTM is widely distributed in the environment such as water and soil [4,5]. M. fortuitum is one of the rapidly growing mycobacteria (RGM), which usually causes skin and soft tissue infection as well as pulmonary diseases in some cases [6]. In the past, people who are susceptible to NTM infection were thought to be immunodeficient [7], such as patients with HIV/AIDS or people with deficiencies in the IFN-γ-IL-12 axis [8], while reports of infection in immunocompetent individuals are rare.
We herein describe an immunocompetent patient with meningitis caused by M. fortuitum, which was to be confused with tuberculous meningitis. The correct diagnosis was made according to the results of hsp65 gene PCR, and the patient finally recovered after a long duration of combined chemotherapy.

Case Presentation
A 35-year-old woman had a continuous pulsatile headache, followed by fever, chills, cough, and vomiting. Her body temperature was 39.8 °C. At her local hospital, she was given cephalosporins for about a week. Her temperature returned to normal shortly afterwards until she got fever and headache again a few days later. She was re-admitted to her local hospital. Laboratory testing of her cerebrospinal fluid (CSF) revealed a glucose concentration of 2 mmol/L, a chlorine concentration of 118.0 mmol/L, and a protein concentration of 835 mg/L. During the hospitalization period, her symptoms got worsened, and she developed confusion and sleepiness. Blood tests showed a leucocyte count of 6.6 × 10 3 cells/µL, a neutrophil percentage of 89.8%, and a C-reactive protein concentration of 3.19 mg/L. All antinuclear antibody tests were negative. She was diagnosed with viral encephalitis. Acyclovir was administered as a single-agent antiviral therapy, together with mannitol for lowering the intracranial pressure (ICP). Despite these treatments, the patient showed no sign of improvement and was referred to our hospital on Day 20 since disease onset.
On admission, her ICP was 230 mm H 2 O. CSF test showed a leucocyte count of 127 × 10 6 /L with 60% monocytes and 40% multinucleate cells, a glucose concentration of 1.60 mmol/L, a chlorine concentration of 111.0 mmol/L and a protein concentration of 1427 mg/L (Table 1). Standard bacterial and fungal cultures of her CSF were negative. Cranial magnetic resonance imaging (MRI) suggested a clear enhancement of the meninges and abnormal signals in bilateral frontal lobes and the periventricular area, consistent with the imaging changes of meningoencephalitis caused by infection (Fig. 1a). The results of T-SPOT.TB assay of her blood and CSF were both positive (Fig. 2). Assuming tuberculous meningitis (TBM), the patient was given anti-tuberculosis therapy with a combination of drugs including isoniazid, rifampicin, pyrazinamide, ethambutol and linezolid. Her Clopidogrel and dexamethasone were administered, along with the previous anti-tuberculosis regimens continued. After that, her consciousness was improved. However, her temperature was still higher than normal, and the results of CSF tests remained abnormal (  Fig. 1c). She was then discharged on oral maintenance therapy. The oral administration was continued for one year, after which the patient recovered with no symptoms of TBM, but some sequelae of cerebral infarction. A Gantt chart was used to summarize the the process of diagnosis and treatment of the patients (Fig. 4).
Patients who are normal immunocompetent usually have a history of trauma or surgery in the brain or spine [18], which enables M. fortuitum from the environment to enter into the central nervous system.
However, in our case, we did not find predisposing factors as such in our patient, who was a normal immunocompetent woman without a trauma or surgical history. At onset, the patient presented with fever, headache, nausea and vomiting. According to previous studies, the common symptoms of TBM in adult patients were non-specific malaise, weight loss, lowgrade fever, anorexia, and gradual onset of headache [19][20][21]. Subsequently, patients may develop more severe headache, vomiting, altered mental status, or stroke, leading to coma and death if left untreated [20]. Body signs of clinical significance include neck stiffness of variable degrees, cranial nerve palsies which develop as disease progresses along with confusion and coma deepening [19].
Confirmation of the diagnosis of TBM can be difficult. Often, the diagnosis is made with a delay of several weeks or months due to non-specific symptoms. The Vietnam diagnostic rule for the diagnosis of TBM in adults focuses on age, white blood cell counts, history of illness and CSF findings [22]. A number of studies up to date have evaluated the diagnostic value of blood and CSF T-SPOT.TB assays on TBM. A meta-analysis published in 2016 revealed the overall sensitivities for blood and CSF interferon gamma release assay (IGRA) were respectively 0.78 and 0.77, and the specificities were 0.61 and 0.88 [23]. In a prospective study by Kim et al, which included 276 patients, the reported sensitivity and specificity of the PBMC ELISPOT assay for diagnosing TBM from non-TBM were respectively 96% and 58%. The ELISPOT assay of CSF has a sensitivity of 68% and a specificity of 95% [24]. Indeed, the diagnostic specificity of blood and CSF T-SPOT.TB for TBM is relatively high.
Therefore in our case, given positive results of both the mycobacterial culture and the T-SPOT.TB of CSF, we falsely assumed that the diagnosis was TBM and prescribed empirical anti-tuberculosis treatment to our patient. The CSF laboratory tests were reviewed several times after the initiation of anti-tuberculosis treatment and showed no significant improvement, which leads to our reevaluation of the diagnosis of TBM.
M. fortuitum is generally sensitive to multiple oral antimicrobial agents, such as sulfonamides, fluoroquinolones, minocycline, and doxycycline [25]. The ATS/IDSA guidelines recommend treatment of pulmonary disease caused by NTMs with at least two active agents for 12 months of culture negativity. However, there are currently no guidelines for meningitis caused by NTM, and high-level clinical evidence from randomized controlled trials or prospective cohort studies is lacking [26]. Upon the confirmation of M.fortuitum infection, we changed the regimens as described above. After one year of chemotherapy, the patient finally recovered with only a few sequelae caused by cerebral infarctions.

Consent for publication
Written informed consent was obtained from the patient for publication of this case report and all accompanying images.

Availability of data and materials
All the data supporting our findings is contained within the manuscript.

Competing interests
The authors declare that they have no competing interests    The alignment result of the hsp65 gene by online tool BLAST.

Figure 4
The Gantt chart that illustrates the course of the patient's disease.

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