Tuberculosis-Associated Immune Reconstitution Inammatory Syndrome Manifested As Multiple Central Nervous System Granulomas In Non-HIV Patient: A Case Report

Background: In addition to developed in HIV patient during highly active antiretroviral therapy, immune reconstitution inammatory syndrome (IRIS) has also been well recognized in non-HIV immunocompromised patients induced by latent viruses, untreated microorganisms, or treating microorganisms. Mycobacteria tuberculosis is one of the most common pathogens inducing IRIS. Case presentation: Here, we report a tuberculosis patient progressed with IRIS that additional central nervous system (CNS) granuloma occurred during the anti-tuberculosis treatment (ATT) process with her pulmonary symptoms improved after quadruple anti-tuberculosis. This case highlights the need to increase the awareness of IRIS in non-HIV immunocompromised patients. Conclusions: TB-IRIS must be considered when the condition deteriorates or development of new lesions at distant sites in the course of ATT. Early identication and diagnosis help to handle timely and correctly.


Background
Immune reconstitution in ammatory syndrome (IRIS) refers to a phenomenon that clinical manifestation become exacerbated or diseases developed in HIV patient during highly active antiretroviral therapy when the immune response recovers with the restoration of CD4 count. However, IRIS has also been well recognized in non-HIV immunocompromised patients after organ transplantation, recipients of tumor necrosis factor antagonist or neutropenic patients [1] . Besides, immune suppressed condition can also be induced by latent viruses, untreated microorganisms, or treating microorganisms [1] . Mycobacteria tuberculosis is one of the most common pathogens inducing IRIS [2] . In non-HIV patients, Tuberculosisassociated IRIS (TB-IRIS) can present with a variety of clinic-radiological presentations that are not easy to distinguish from drug resistance and treatment failure [2] , the awareness of IRIS in non-HIV immunocompromised patients need to be increased.
Here, we report a tuberculosis patient progressed with IRIS that additional central nervous system (CNS) granuloma occurred during the anti-tuberculosis treatment (ATT) process with her pulmonary symptoms improved after quadruple anti-tuberculosis.

Case Presentation
A 20-year-old girl suffered from painless lumps in her left neck in 2016-10. The lump progressed in lower jaws and the size increased gradually. In 2017-09, she was diagnosed of tuberculosis with multiple sputum smears test of Mycobacterium tuberculosis and treated with quadruple ATT of rifampicin, isoniazid, pyrazinamide and ethambutol. Her pulmonary symptoms improved, but from 2018-02, she had headache with dysuria, weakness and numbness of lower limbs, no fever, chills, jet vomiting, hemoptysis, unconsciousness and speech disturbance. Muscle strength of bilateral upper limbs was grade 5, while grade 3 in bilateral lower limbs with decreased muscle tension and hyper-active tendon re exes. Bilateral Babinski signs were positive. The sensation below level of the lower end of the sword was disturbed.

Repeated sputum smears and cultures, and cerebrospinal uid (CSF) smears, culture and PCR test of
Mycobacterium tuberculosis were negative. Erythrocyte sedimentation rate, soluble interleukin II receptor, angiotensin-converting enzyme and other laboratory examinations produced unremarkable ndings. MR scan showed multiple space-occupying lesions in right frontal gyrus, right anterior of pontine, suprasaddle and in the spinal cord of T3, T5 and T6 vertebral level (Fig. 1). Space-occupying lesion resection was performed to relieve spinal cord compression and con rmed to be in ammatory granulomatous ( Fig. 1). IRIS was diagnosed. On 2018-04-19 and 2018-05-16, two courses of methylprednisolone (1000 mg, VD, qd) was applied for 5 days and decreased gradually. Muscle strength in bilateral lower limbs improved gradually to grade 4+ and the urine function returned to normal. After discharge, prednisone (12mg, p.o., qd) was treated for 3 months along with ATT with rifampicin and isoniazid. Follow up was performed in 2018-09 and 2019-03, she could walk normally, CSF tests and MR scan results also improved obviously (Fig. 1 Acid-fast stain ---

Discussion And Conclusions
Typically, IRIS usually developed in HIV patient during highly active antiretroviral therapy. However, IRIS has also been well recognized in non-HIV immunocompromised patients induced by latent viruses, untreated microorganisms, or treating microorganisms [1] . Mycobacteria tuberculosis is one of the most common pathogens inducing IRIS [2] . The prevalence of TB-IRIS is still unclear and is estimated 2%-23% in non-HIV patients in a few studies [2] . It may occur during or even after completion of ATT [3] and represents an adverse clinical consequence of the restoration of immunity in the patient suffering from a serious systemic infection. TB-IRIS patients may experience development of new tuberculous lesions or paradoxical worsening of pre-existing tuberculous lesions despite on effective ATT [3] , such as initial or worsening radiological features of TB, initial or enlarging lymph nodes, initial or worsening serositis, initial or worsening CNS, other tissue involvement or cold, abscesses [2,4] . However, new neurological lesion as the paradoxical reaction of TB-IRIS is uncommon, especially in patients with drug resistant tuberculosis [5] .
However, the diagnostic criteria and guidelines of IRIS in non-HIV patients have not been established.
Some authors proposed draft diagnostic criteria according to the clinical courses of in ammatory disorders of various organs triggered by pre-existing antigens and pathogenic microorganisms [1] .
Glucocorticoids, tumor necrosis factor inhibitors or anti-IL-6 antibodies, and statins are the commonly used agents for non-HIV IRIS patient [1] . For TB-IRIS, although some patients improve spontaneously with continuation of ATT regimens in a few weeks, glucocorticoids are required with condition deteriorates [6][7][8] .
In this case, the CNS granuloma occurred during the ATT with pulmonary symptoms improved. Results of CSF examination of tuberculosis by various methods were negative, the lesion in the spinal cord did not show caseous necrosis and Langerhans cells, but in ltrated with a large number of acute and chronic in ammation cells including CD4 (+) lymphocytes. Eventually, she was cured after systematic approach of corticosteroid therapy. In addition, there was no TB drug resistance, no drug toxicity or reaction, no another opportunistic infection or neoplasm. Therefore, TB-IRIS should be considered.
In short, in the course of ATT, once the condition deteriorates or development of new lesions at distant sites, after excluding new opportunistic infections or drug tolerance, malabsorption and drug reactions, TB-IRIS must also be considered. Early identi cation and diagnosis help to handle timely and correctly. The lesion biopsy showed nodular locally, patchy necrosis was observed at the center of the nodule, brous tissue was observed in the peripheral with small vascular hyperplasia. Multiple acute, chronic cells in ltration and scattered polynuclear giant cells were also observed (J: HE 40x, K: HE 100x). CD4(+) (L, 100x) and CD68(+), PAS (-), CD1α(-), Langerin(-), S100(-) , acid stain (-) (not showed).