Several case reports have demonstrated that the immune reconstitution inflammatory syndrome induces reversal reaction in HIV and leprosy-coinfected patients. The present study describes 10 cases of immune reconstitution inflammatory-associated reversal reaction. The patients evolved satisfactorily despite presenting a more severe form of the disease and the fact that three required an additional use of corticoids. The present study, the largest case series published to date, demonstrates that leprosy reaction is a manifestation of immune reconstitution.
aLeprosy Laboratory, Oswaldo Cruz Institute, Brazil
bDepartment of Infectology, Evandro Chagas Clinical Research Institute, Brazil
cLaboratory of AIDS and Molecular Immunology, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil.
Received 16 September, 2008
Revised 7 November, 2008
Accepted 23 December, 2008
Correspondence to Euzenir Nunes Sarno, MD, Leprosy Laboratory, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Av. Brazil 4365, CEP 21040-360 Manguinhos, Rio de Janeiro, Brazil. Tel: +55 2122709997; fax: +55 2122709997; e-mail: email@example.com
Although HIV infection has been reported to have little impact on leprosy, initiation of antiretroviral treatment has been associated with activation of subclinical Mycobacterium leprae infection and exacerbation of existing leprosy lesions . Since the introduction of HAART for AIDS treatment, 17 cases of leprosy reaction associated with immune reconstitution inflammatory syndrome (IRIS) have been described in the literature [2–12]. The present study describes 10 cases of IRIS-associated reversal reaction in a cohort with 28 coinfected HAART patients diagnosed with leprosy from 1996 to 2007 at the Oswaldo Cruz Foundation, Rio de Janeiro, Brazil. Pertinent data on these patients were collected from patient charts. Case reports of two of these patients have been published ; but since additional data were added, they were maintained in the cohort.
Leprosy was diagnosed and classified according to Ridley–Jopling criteria . The histopathological definition of reversal reaction was primarily based on the presence of epithelioid-cell granuloma. Reversal reaction treatment and HIV diagnosis followed the Brazilian Ministry of Health regulations [14,15]. HAART was initiated when the CD4 cell count was 200 cells/μl or less or if an opportunistic infection was diagnosed. IRIS was defined as the presence of reaction during the first 6 months of HAART in association with a decrease of more than 1 log in the HIV-1 viral load , or when naive patients with no laboratory test data previous to HAART initiation were found to have an undetectable HIV-1 viral load at the onset of reversal reaction.
Among the 28 patients experiencing leprosy reversal reaction under HAART, 10 (36%) met the predetermined IRIS criteria. Demographic, clinical, and laboratory data of these 10 IRIS patients are presented in Table 1. Eight patients were initially diagnosed with HIV. Significantly, HAART induced reaction in seven patients who had not been diagnosed with leprosy. The mean time the patients presented reversal reaction after starting HAART was 7.8 weeks.
The clinical or laboratory findings of all patients showed immune suppression prior to reversal reaction diagnosis. Moreover, by the time reaction occurred during HAART treatment, all patients had an increased CD4/CD8 T-lymphocyte rate, mainly due to an increased CD4 cell count mean of 170 cells/μl (92–357 cells/μl). Seven patients had an undetectable viral load when reaction developed and three had a mean viral load reduction of 2.4 log (1.4–4.6 log). All patients were treated for HIV with regimens containing two nucleoside reverse transcriptase inhibitors in combination with a protease inhibitor (10%), a boosted protease inhibitor (40%), or a nonnucleoside reverse transcriptase inhibitor (50%).
All patients presented erythematous-infiltrated plaques. The histopathological features observed in the skin biopsies ranged from heavy infiltration, necrosis foci, and extensive epidermal involvement to mild infiltration with small, well formed granulomas. Four biopsies showed evidence of fragmented acid-fast bacilli.
Eight patients received standard treatment for reaction in addition to the multidrug therapy for leprosy. Three patients required prolonged use of prednisone for up to 11 months.
As observed in the present case series, in the HAART era, leprosy reaction associated with IRIS appears to be a frequent event in coinfected patients. The 36% reversal reaction rate in coinfected patients undergoing HAART is similar to that estimated for tuberculosis as a manifestation of IRIS [17,18]. Interestingly, HAART triggered reversal reaction in 88% of the patients not previously known to have leprosy. As likewise seen in the literature, most of the present IRIS cases associated with leprosy had the predominantly borderline-tuberculoid form [2–12]. The borderline forms are considered the most unstable in that the immunological capability of the patient to restrain the infection is only partial. During reversal reaction, high amounts of inflammatory cytokines such as interferon-γ and tumor necrosis factor are produced, reflecting the immune activation characteristics of skin lesions with a tuberculoid pattern .
Furthermore, immune restoration by HAART does appear to worsen reversal reaction. In the present series, 60% of the patients had numerous lesions, 30% had skin ulcers, and 30% needed extended corticoid therapy, demonstrative of a more intense inflammatory process. This type of presentation is more commonly seen in type II leprosy reactions, which are more frequent in multibacillary patients and which have never been referred to in the context of IRIS. On the other hand, patients with the tuberculoid forms, who tend to display a strong cellular response to M. leprae, are more often found to have neuritis. Therefore, it is surprising that only one patient in this series was diagnosed with neuritis.
The histological findings observed in all patients were typical of reversal reaction. Disorganized and disperse granulomas could be seen in some cases, thus making it difficult to classify them according to the Ridley and Jopling leprosy spectrum. The presence of necrosis only occurred during severe reaction, either in small foci or when causing liquefaction of the granuloma followed by fibrosis, as seen in one case. The presence of a small number of acid fast bacilli has already been described in borderline tuberculoid lesions .
It is worth noting that in the present series, patients treated with prednisone as standard reversal reaction therapy had a favorable evolution despite disease severity. Thus, the results of this study clearly indicate that no modification of the standard reversal reaction therapy appears necessary in leprosy patients with IRIS.
In countries like Brazil, where both epidemics overlap and HAART has been broadly administered, leprosy reaction associated with IRIS is prone to occur. It might be posited, therefore, that the appearance of clinical signs of M. leprae infection in HIV-infected individuals is not a manifestation of immune suppression but rather of immune reconstitution. However, further prospective studies are required to more adequately evaluate the association of leprosy reaction and IRIS so as to more precisely characterize the pathology and immunology of this worrisome coinfection.
We would especially like to thank Judy Grevan for editing the text.
E.S. supervised this work. M. M. generated the CD4+ cell count and viral load data. A. M. generated the histopathologic data. X. I. carried out the statistical analysis. A. S., M.C.G., J.A.N., and V.M. were treating physicians of the patients and collected clinical data. All coauthors contributed to the development and critical revision of the article.
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