Paradoxical reaction in the form of pleural effusion after onset of anti-tuberculous medication for tubercular lymphadenitis

Discussion

IRIS was the term originally used to describe the inflammatory pattern, which follows initiation of highly active antiretroviral therapy (HAART) in patients infected with HIV. It is paradoxical in the sense that there is worsening of clinical features in spite of appropriate therapy.¹

A similar paradoxical inflammatory response, with an incidence of up to 20%, has also been reported following initiation of anti-tuberculous medication in patients infected with M tuberculosis.² Researchers believe this to be an exacerbation of the immune response to the M tuberculosis antigen when effective anti-tuberculous treatment is initiated.³ Constitutional symptoms like fever, malaise and weight loss can develop along with worsening of existing radiographic abnormalities, which can progress to severe respiratory distress and adult respiratory distress syndrome in rare cases. Often, the clinical pattern is dictated by the original site of the M tuberculosis infection, but it may affect sites not originally affected by the infection; for example, in extra-pulmonary tuberculosis, the clinical pattern may include worsening lymphadenitis (computerised tomography scan may show new necrosis in lymph nodes), worsening pleural effusion (or appearance of new effusion on the contralateral side) and expansion of previous intracranial tuberculomas (presenting with new onset/worsening headaches). The respiratory and central nervous system are the most commonly reported sites for development of paradoxical reaction; other sites that could be affected are the lymph nodes, skin, soft tissue, bone, tendons and abdomen.⁴

Paradoxical reaction following anti-tuberculous treatment is common in both HIV and non-HIV infected individuals. Patients with disseminated tuberculosis, extra-pulmonary tuberculosis or tuberculosis co-infected with HIV are more likely to develop paradoxical reactions. Risk factors for paradoxical reactions in patients without HIV include baseline anaemia, hypoalbuminaemia and lymphopenia.⁵ The mechanism for paradoxical reaction after starting tuberculosis treatment is not well understood but it is very likely immune mediated. At the time of paradoxical deterioration, a concomitant increase in the lymphocyte count and conversion of the tuberculin skin test is observed.⁴ Initiation of anti-tuberculous therapy and subsequent reduction in mycobacterial load leads to reversal of the immune response. The clinical severity of a paradoxical reaction is probably determined by the magnitude and timing of the immune response; an overwhelming response may produce excessive immunopathological damage at the tissue level. The median time to development of paradoxical reaction is 60 days (range 14–270 days) in HIV negative individuals.⁴

Differential diagnosis of a paradoxical reaction would include secondary infections, adverse drug reactions, drug resistance and poor compliance. Diagnosis of paradoxical reaction is by exclusion; therefore, investigations should be directed to exclude the above conditions. Gram staining, acid fast staining, as well as bacterial and mycobacterial cultures obtained from the involved organs in these cases are mostly negative; however, occasionally acid-fast bacilli might be seen. Although even then, there would be no evidence of resistance to the drugs used in that particular regimen on drug sensitivity testing.

Most of the non-severe paradoxical reaction does not require any specific treatment once the diagnosis is established. Patients need reassurance and anti-tuberculosis therapy needs to be continued. A short course of oral corticosteroids, which is tapered off, can be considered. Severe clinical deterioration is rare but has been reported; this can include obstructive hydrocephalus secondary to enlargement of tuberculomas, massive pleural effusion and development of deep-seated abscesses. In addition to systemic steroids, these patients might need surgical drainage procedures. Most patients will recover uneventfully with either conservative treatment or a combination of medical and surgical management. Only a few cases with central nervous system involvement result in residual neurological deficits.⁶