Recurrent Immune Reconstitution Inflammatory Syndrome of Tuberculous Brain Infection in People Living with HIV/AIDS

Abstract

HIV infection has changed the scenario of infectious disease. HIV-associated immunodeficiency resulted in a wide spectrum of new opportunistic infections. After introduction of antiretroviral therapy (ART), immune reconstitution inflammatory syndrome (IRIS) became an important challenge in management of 10% to 25% of the patients. Meta-analyses of IRIS from various reports published worldwide by Monika Muller et al described 12% IRIS incidence and 15.7% IRIS tuberculosis. Among IRIS tuberculosis, central nervous system involvement with IRIS tuberculous meningitis forms only 7%. Only 9 cases of tuberculous brain abscess is reported in patients with AIDS so far. The IRIS tuberculous brain abscess is very rare, and so far only 1 case is reported as a paradoxical reaction after ART initiation. Here, we report a case of recurrent IRIS tuberculosis meningitis and brain abscess.

Case Report

A 41-year-old male agriculturist from a small town in Cuddalore district in Tamil Nadu in India was detected to be HIV-positive in December 2008. The patient was diagnosed as having AIDS with pulmonary tuberculosis (TB), a new case with sputum positive for acid-fast bacilli (AFB). All other baseline investigations were normal, and his CD4 count was 32 cells/mm³ (4%). He was started on with category I, antituberculosis therapy (ATT) under Revised National Tuberculosis Control Program (RNTCP) with rifampicin, isoniazid, ethambutol, and pyrizinamide thrice weekly directly observed treatment–short course (DOTS). After 2 weeks, antiretroviral therapy (ART) was started with regimen consisting of stavudine (d4T) + lamivudine (3TC) + efavirenz (EFV) as per National AIDS Control Organization, antiretroviral therapy guidelines, India. He completed ATT in June 2009 and the regimen changed to zidovudine (ZDV) + lamivudine 3TC + nevirapine (NVP) with improvement in hemoglobin (ZDV was substituted for d4T) and completion of ATT (NVP was substituted for EFV).

In December 2009, the patient developed severe headache and altered behavior and was admitted to the hospital. He was investigated for meningitis with lumbar puncture, which revealed elevated cerebrospinal fluid protein 300 mg and cerebrospinal fluid sugar 56 mg. Total number of cells in the cerebrospinal fluid increased and consisted of predominately lymphocytes. Cerebrospinal fluid was negative for AFB, negative with India ink preparation for Cryptococcus, and negative for culture for Cryptococcus. Grams stain of cerebrospinal fluid did not reveal any positive results. Computed tomography (CT) scan of the brain with contrast was normal. Other investigations were normal and CD4 count was 335 cells/mm³ (19%). Viral load was not done, as the patient was from an economically poor status. According to national program in India, viral load can be done only with immunological failure in patients with ART. With these investigations an IRIS tuberculous meningitis was diagnosed and category II of ATT under RNTCP with streptomycin, rifampicin, isoniazid, ethambutol, and pyrizinamide thrice weekly DOTS was started for this patient. The regimen was again changed to d4T + 3TC + EFV (stavudine, lamivudine and efavirenz) due to ZDV-induced anemia. Patient was discharged with this after complete symptomatic improvement.

In June 2010, the patient was again admitted with loss of consciousness. On examination, he was unconscious and no focal lesions were identified. The repeat lumbar puncture on June 2010 revealed cerebrospinal fluid protein 154 mg and cerebrospinal fluid sugar 54 mg. Total number of cells in cerebrospinal fluid showed increased lymphocytes. Cerebrospinal fluid was negative for AFB, negative for India ink for Cryptococcus, and negative for culture for Cryptococcus. Grams stain for cerebrospinal fluid was negative. His CD4 count was 992 cells/mm³ (40%). All other investigations were normal. With antiedema measures, the patient regained consciousness and had left hemiparesis and slurred speech. A CT scan of the brain (Figure 1) with contrast revealed multiple brain abscesses in temperoparietal lobe. The patient was treated in the neurosurgery department and the abscess was drained in 2 sittings and pus was sent for analysis. The pus was positive for Mycobacterium tuberculosis with Zheil Nielson stain. The repeat CT scan (Figure 2) showed good reduction in the abscess size, and the patient was discharged with advice to continue ATT and ART. After discharge, this patient had completed ATT and continues to be on ART with minimal residual neurological deficit in the form of titubation of head till date.

Figure 1.

Computed tomography (CT) scan with brain abscess before drainage.

Figure 2.

Computed tomography (CT) scan with brain abscess after drainage.

Discussion

The antiretroviral therapy has revolutionized the HIV treatment. The cause of mortality and morbidity before ART was due to opportunistic infections. The immune reconstitution due to ART resulted in a new entity of IRIS. The frequency of occurrence of IRIS may be between 10% and 25%. ¹ The IRIS is more common in TB than any other opportunistic infections in India. The severity of the IRIS depends on the location of the TB. The IRIS in the central nervous system will be very difficult to manage with high morbidity and mortality ² in short term but have good long-term prognosis after survival.

The IRIS can occur when (1) ART started for naive patients,

(2) ART restarted after default, (3) when substitution is made with new drug, and (4) when switched to second-line ART after treatment failure. The IRIS can also occur (1) when there is exacerbation of existing opportunistic infection, also called as paradoxical reaction, (2) occurrence of new opportunistic infection not treated before, (3) recurrence of already completely treated opportunistic infection, and (4) recurrence of incompletely treated opportunistic infection. In this case, we see IRIS with substitution of drugs and occurrence and recurrence of TB with ART.

The most common IRIS with TB is tuberculous lymphadenitis. ³ Exacerbation of tuberculous radiological opacities in the chest X-ray is the next common manifestation. Various case reports showed all the organs involved with TB in IRIS. The exacerbation of tuberculous meningitis is also commonly seen. Tuberculous brain abscess is a very rare presentation of IRIS. ^{4 –6}

It is important to diagnose or rule out TB before starting ART. To avoid paradoxical IRIS, it is ideal to treat TB for 2 to 8 weeks. Waiting until the symptoms subside before we start ART but not more than 8 weeks is the guideline by National AIDS Control Organization. The earliest is better to prevent mortality and morbidity due to IRIS, especially if CD4 count is less than 50 cells/mm³. ¹

In this case, the CD4 has increased from 32 cells/mm³ (4%) in December 2008 to 335 cells/mm³ (19%) in December 2009, after the regimen changed to ZDV + 3TC + NVP in June 2009. Here, the substitution with ZDV + 3TC + NVP has increased the CD4 count 10 times. This resulted in first IRIS TB meningitis.

Then, the CD4 count still raised 3 times to 992 cells/mm³ (40%) in June 2010 from 335 in December 2009. In spite of completing treatment for TB, he developed a tuberculous brain abscess after 6 months with a steep increase in CD4 count to 992 cells/mm³. This is the second IRIS of tuberculous brain abscess, a recurrence of already fully treated tuberculosis.

According to French et al criteria for IRIS diagnosis, ⁷ in this case 1 major criteria of atypical presentation of opportunistic infections with ART and 2 minor criteria are seen. A localized inflammatory response with brain abscess and organ dysfunction being the major criteria and increased CD4 count and spontaneous response to ART being minor criteria to call this as IRIS.

As per Robertson et al criteria for IRIS, ⁸ the required criteria of relationship with ART and worsening of inflammation and infection were noted. Supportive criteria of increase in CD4 count and demonstration of AFB were also seen to confirm IRIS.

According to the guidelines of Colebunders et al TB IRIS, to confirm IRIS TB⁷ we have a new and worsening radiological sign of brain abscess, a good increase in CD4 count, good adherence of ART, and ATT in this case. There is also no other new infection or treatment failure noted in this case.

With respect to the International network for the study of HIV-associated IRIS [INSHI] guidelines, antecedent requirement of diagnosis of TB and response to ATT were seen. Clinical criteria of new central nervous system tuberculous brain abscess and new radiological lesions were seen. There was also good response to treatment and no other opportunistic infection seen.

Here, the atypical mycobacteria and drug-resistant tuberculosis were not considered, as we saw clinically good response to first-line antituberculous drugs in all the 3 tuberculous infections of this patient.

Usually, IRIS occurs within 3 to 6 months, though late manifestations are reported. Tuberculosis manifesting as recurrent IRIS at 2 different periods of time, with continuous increase in CD4 count is very rare. The treating physician must look for IRIS when recurrent opportunistic infections occur with raise in CD4 count.