Tuberculosis-associated immune reconstitution inflammatory syndrome: case definitions for use in resource-limited settings

Abstract

The immune reconstitution inflammatory syndrome (IRIS) has emerged as an important early complication of antiretroviral therapy (ART) in resource-limited settings, especially in patients with tuberculosis. However, there are no consensus case definitions for IRIS or tuberculosis-associated IRIS. Moreover, previously proposed case definitions are not readily applicable in settings where laboratory resources are limited. As a result, existing studies on tuberculosis-associated IRIS have used a variety of non-standardised general case definitions. To rectify this problem, around 100 researchers, including microbiologists, immunologists, clinicians, epidemiologists, clinical trialists, and public-health specialists from 16 countries met in Kampala, Uganda, in November, 2006. At this meeting, consensus case definitions for paradoxical tuberculosis-associated IRIS, ART-associated tuberculosis, and unmasking tuberculosis-associated IRIS were derived, which can be used in high-income and resource-limited settings. It is envisaged that these definitions could be used by clinicians and researchers in a variety of settings to promote standardisation and comparability of data.

Figure 1. Illustrative case of paradoxical tuberculosis-associated IRIS

A 36-year-old HIV-infected man was diagnosed with culture-positive pulmonary tuberculosis (sensitive to rifampicin and isoniazid) without evidence of extrapulmonary involvement. His CD4 count was 39 cells per μL and HIV-1 viral load 1 300 000 copies per mL. He commenced antiretroviral therapy (ART; stavudine, lamivudine, and efavirenz) 7 weeks after initiating antituberculous therapy. 1 week later he presented with a recurrence of tuberculosis symptoms and cervical node enlargement. Paradoxical tuberculosis-associated IRIS was diagnosed. Over the next 18 months he presented with several tuberculosis-associated IRIS manifestations that sequentially emerged, despite corticosteroid therapy, then resolved. Photographs show development of massive cervical lymphadenitis (A), a chest wall cold abscess (B, arrows), and a massive right psoas abscess shown here on CT scan (C, arrow) from which over 2 L of pus was aspirated (D). Repeated mycobacterial cultures of aspirates from these collections have been negative. After 6 months on ART his CD4 count was 181 cells per μL and viral load undetectable. After 12 months his CD4 count was 448 cells per μL and viral load 35 copies per mL. This was an unusually prolonged course for paradoxical tuberculosis-associated IRIS given that the median duration of symptoms is reported to be 2 months (see text).

Figure 2. Illustrative case of unmasking tuberculosis-associated IRIS

A 48-year-old HIV-infected man with a CD4 count of 10 cells per μL presented with low-grade fevers, retrosternal chest pain, and a dry cough. Examination was non-contributory. He could not produce sputum and his chest radiograph showed no features of active tuberculosis (A). No other investigations for tuberculosis were available in this resource-limited setting (Uganda). Antiretroviral therapy (ART) was started (zidovudine, lamivudine, and efavirenz). 10 days later he returned acutely unwell with a productive cough. His temperature was 38·7°C and he was in respiratory distress. Chest radiograph now showed left mid-zone consolidation (B) and his sputum was positive for acid-fast bacilli. The unusual rapidity and clinical severity of his tuberculosis presentation was attributed to unmasking tuberculosis-associated IRIS. He responded well to continued ART and tuberculosis treatment.

Figure 3. Schematic representation showing the different forms of tuberculosis-associated IRIS and ART-associated tuberculosis

ART=antiretroviral therapy.