Can baseline ML Flow test results predict leprosy reactions? An investigation in a cohort of patients enrolled in the uniform multidrug therapy clinical trial for leprosy patients in Brazil

For many years, leprosy patients were treated with dapsone monotherapy, and the development of ENL was reported in half of LL patients and in one-quarter of BL patients [24]. The introduction of MDT in the 1980s reduced the frequency and the severity of ENL, probably as a result of the anti-inflammatory activity of clofazimine that was included in the treatment regimen [25]. However, previous data from the U-MDT cohort showed that there was no statistical difference in the frequency of leprosy reactions among MB patients receiving R-MDT or U-MDT, indicating that six or 12 months of clofazimine treatment does not result in the prevention of leprosy reactions [26]. In the U-MDT/CT-BR, until 2014, 780 930 person-days, i.e. 2 139.5 person-years, with a maximum of 6.66 years of follow-up were evaluated [9]. In the current study, a comparable frequency of leprosy reactions and other clinical manifestations was observed in PB patients being treated with U-MDT or R-MDT. Findings from a previous report together with findings from the current investigation indicate that whether patients receive U-MDT or R-MDT does not have any impact on the incidence of leprosy reactions and other clinical manifestations such as neuritis.

In this cohort of leprosy patients, composed mainly of MB patients (~80 %), more than half developed at least one episode of a leprosy reaction. Moreover, the great majority of patients who developed reactions were MB patients with high BIs, and these variables have been previously associated with a high probability of developing leprosy reactions [2, 27, 28]. Our results confirm that MB patients have a higher risk of developing leprosy reactions as compared with PB patients. In addition, the study confirms that the most common reaction in both MB and PB patients is RR, and ENL occurs only in MB patients. While most MB patients developed reactions, the majority of PB patients remained reaction-free. Overall, more than half of the patients had a positive BI and reactions were more frequent in these patients as compared with patients who had a negative BI. The development of reactions was more common in the first year of follow-up compared to subsequent years. Our results are in accordance with other studies, which showed the predominance of RR over ENL and the higher incidence of reactions in MB patients with a positive BI as compared with patients with a negative BI [29, 30].

In this cohort, RRs were seen mainly in BL MB patients, a finding which is consistent with other studies [2, 14, 31]. The majority of patients who developed ENL had LL and high BIs. Other studies have reported that ENL is more often seen in LL patients than in BL patients [32, 33] and a higher BI is a known risk factor for developing ENL [34, 35]. Interestingly, MB patients who developed ENL were younger than reaction-free MB patients. Accordingly, a study that evaluated risk factors for developing ENL showed that patients older than 40 years were less likely to develop ENL [34]. Another study showed that patients whose first leprosy symptom occurred during adolescence had a greater chance of developing ENL than patients whose onset of leprosy occurred after adolescence [36]. In this study, PB patients who developed RR were older than reaction free-PB patients. Other studies have shown that older age was an important risk factor for developing both RR at diagnosis and developing sequelae after treatment [37, 38].

During MDT, bacillary death occurs resulting in a massive release of mycobacterial antigens favoring the formation of immune complexes, mainly among MB patients, and immune complexes are considered to play a role in the pathophysiology of leprosy reactions [39–42]. In this study, reactions were more frequent during the course of MDT, as previously reported [2, 27, 43]. However, patients mainly developed ENL during follow-up. The results of this study underline the importance of alerting patients about the possible development of reactions before, during, and even years after the conclusion of MDT, since reactions require immediate assistance and specific treatment to avoid irreversible nerve damage. Overall, neuritis was a common clinical manifestation that occurred in all clinical forms of leprosy, with higher frequencies observed in BT and BL forms. Similar to previously reported data, isolated neuritis with no other dermatological or clinical symptom was present in 20 % of cases, while less than half of the neuritis cases were associated with a reaction [44].

In this study, baseline positivity determined using the ML Flow test was associated with MB disease, a positive BI, and the development of reactions during follow-up, mainly ENL. Bacillary load is known to directly correlate with antibody levels and with the development of leprosy reactions [2, 16, 27, 28]. Moreover, antibodies, which are abundant in MB patients, probably play a role in the pathophysiology of ENL [15–17, 39]. However, little, if anything, is known about the role of antibodies in the development of RRs and other clinical manifestations such as neuritis. In this study, at baseline, patients with a negative BI who developed neuritis and RRs during follow-up had higher ML Flow positivity with a higher colour intensity compared with reaction-free patients who had a negative BI. Further studies on the immunopathogenesis of RRs are needed in order to clarify whether antibodies play a role in the development of RRs.

Our ROC analysis showed that the results of the ML Flow test at baseline had limited sensitivity and specificity to predict whether patients will develop leprosy reactions during follow-up (see Additional file 3: Figure S1). Additionally, high ML Flow seropositivity was not always associated with leprosy reactions and other clinical manifestations, as high positivity was also observed in reaction-free patients.