Leprosy reactions, classified as Type 1 or Type 2, occur before, during and after Multi-Drug Therapy (MDT), and may be triggered by different co-infections and/or antigens of Mycobacterium leprae (M. leprae) especially phenolic-glycolipid-1 (PGL-I) (1, 2).

Regarding to the time for leprosy reaction occurrence, a study reported that 9.5% of patient had late type 1 reaction up to 7 years after starting MDT (3).

The type 1 reaction (T1R), common between borderline tuberculoid (BT), borderline borderline (BB), and borderline lepromatous (BL), might be subdivided into upgrading and downgrading reaction (4).

A current study showed 27% of patients being affected by T1R with 63% ranging from moderate to severe cases (5). Furthermore, a study reported that 60% of patients developed T1R with 90% of cases presenting inflamed plaques as the main sign (6). The T1R presents cutaneous manifestations such as erythema, infiltration into the skin and edema in preexisting lesions, as well as arising of new skin lesions. As to the presence of neurological signs and symptoms, it is possible to highlight neural thickening (edema), pain in the peripheral nerve, sensory-motor changes with loss of muscle strength and consequent evolution to physical disabilities (7).

The type 2 reaction (T2R), whose main presentation is erythema nodosum leprosum (ENL), is systemic and associated with the formation of immune complexes (IC) in the blood such as found in serum samples, and are deposited inside tissues, especially skin, kidneys and joints, reported as extravascular complements, therefore being a type III hypersensitivity reaction (8–10). This type of reaction is considered an immunological complication for the clinical forms BL and lepromatous leprosy (LL) (8). The T2R affected 44% of BL and 71% of LL according to a study involving a period of 12 years of data collection. Furthermore, independent on clinical form, it was reported 26.8% of T2R in a referral center (11, 12). The systemic signs and symptoms that are commonly present in this type of reaction include malaise, loss of weight and injury to internal organs, which in turn may cause peripheral neuropathy, orchiepididymitis, glomerulonephritis, myositis, arthralgia, iridocyclitis, hepatomegaly, and ganglion infarction (13). Hematological and biochemical changes may be present in T2R as leukocytosis, neutrophilia, thrombocytosis, increased acute-phase proteins such as C-reactive protein, alkaline phosphatase, transaminases, fibrinogen, and elevated immunoglobulins of the IgG and IgM classes (14).

Studies analyzing prognostic factors in relation to the outcome of leprosy reactions are scarce. However, it is possible to find some research studies limited to risk factors associated with leprosy reactions.

Therefore, we aim to approach, by means of comparison among survival curves, the prognostic factors that may be associated with leprosy reactions across 10 years of follow-up.

This study was approved by the Research Ethics Committee at the Federal University of Uberlândia – Brazil under registration number 28931320.9.0000.5152. The written informed consent was not needed given that this research was to be carried out by means of secondary data.

Among leprosy reaction cases, the borderline group, BT, BB and BL, have predominated, being considered by several studies as a risk factor for T1R (4, 5). The proportion of the reactional LL clinical form was higher than LL reaction-free in agreement with previous studies (13, 18). The low proportion of the reactional T form was expected, due to the fact that these cases may be subpolar tuberculoid (TTs), rare and immunologically unstable, being able to migrate on the clinical spectrum of disease toward borderline forms (19). The MB operational classification was associated with high bacillary load, which results in risk of leprosy reaction occurrence as reported in a past study (8). The disability degree 2, associated with leprosy reactions, corroborated a recently study that indicated a dependent relationship between these two variables (20). The association between female sex and leprosy reaction was cited in another study as a risk factor, especially for T1R (21). The low prevalence of reactional individuals that belong to the 0–19 age group may be related to the operational classification and clinical form of them, since they were treated in early stage of disease (22). Moreover, the efficient immune response in this group, since these individuals have regular production of B and T cells from bone marrow and the thymus (23). On the other hand, elderly individuals present an increased number of regulatory T lymphocytes (Treg), which may cause excessive suppression of immune responses; furthermore, degenerative disease associated with polypharmacy may favor immunologic abnormalities in the elderly (24).

The positivity of anti-PGL-I serology was mentioned in this study as a risk factor for leprosy reactions. Thus, this result may contribute as a risk factor for leprosy reaction when compared with those seronegative. This important finding is supported by a study that reported a high positivity proportion of this antigen in reactional individuals (25). Our results from dermal-smear BI indicated high risk for manifesting leprosy reaction when the results to this test were positive at diagnosis, as found in other studies that showed that positive BI raises the chance of developing leprosy reactions as compared with negative cases (7, 26).

The prognostic was poor among seronegative patients, due to half of seronegative individuals presented leprosy reaction up to 5 months, while those seropositive developed the event at 9 months after MDT (Figure 1). In this current research, the highest proportion of patients with negative anti-PGL-I serology at diagnosis, among reactional cases, belong to T and BT clinical forms (data not shown). These clinical forms exhibited T1R, cell-mediated immunity, with macrophage activation under the influence of cytokines such as tumor necrosis factor-α (TNF-α), interferon gamma (IFN-γ), IL-2 and Lymphotoxin-alpha (LT-α) (24). We hypothesized that early occurrence of this type of reaction in this seronegative to PGL-I IgM is associated with MDT action on M. leprae that after bacillus fragmentation releases antigens into the bloodstream activating Th1 response, predominant in these individuals (27). The humoral immune response prevailed in those cases with positive anti-PGL-I IgM serology, such as BL and LL, characterized by production of the cytokines L-4, IL-5 and IL-10, manifesting, therefore, T2R, which provokes an increase in circulating levels of TNF-α and IL-10 in some of them. It is important to highlight that IL-10 cytokine may favor bacillus survival and delay an efficient response against this mycobacterium (28, 29).

We emphasized in this present study that, 33 months after t₀, there was a change in the prognostic-factor profile related to anti-PGL-I serology, evidencing poor prognosis for those seropositive, which may indicate a persistent of bacillary load in cases with higher dermal-smear BI. In relation to dermal-smear BI, a change in the prognostic factor was also observed 28 months after the t₀. This previous finding might be related to the persistence of bacillary load, which is as common in MB as in BL and LL, which consequently, will present a time-dependent bacillary clearance (30). The bacillary clearance also depends on the immune competence of these clinical forms, given that, as reported previously, a longer duration was necessary to eliminate the bacilli from tissues in those with T2R when compared to those without T2R (30).

Leprosy patients classified as T and BT have developed reactions in less time when compared with BB and BL (Supplementary Table 1). This difference among clinical forms regarding the time-to-event may be associated with effective immune response against M. leprae in those individuals with low bacillary load, an immunological event, according to other authors, that occurs within 6 months (31). Half of LL individuals developed a leprosy reaction within 6 months after t₀, corroborating a previous study that reported more than 70% of LL being affected by this reaction in the first 6 months after starting MDT treatment (32). The higher percentage of LL affected by T2R in the first 6 months after t₀ is in accordance with risk factors associated with this clinical form, since BI > 4, and hypothetically related to activation of immune complexes and release of TNF-α by macrophages in these individuals with high BI (33).

The idea about the presence of immune complexes during T2R/ENL episodes may be reinforced by other research that assessed genic expression in peripheral blood mononuclear cell (PBMC) from T2R/ENL patients, demonstrating the high expression of components from the classical complement pathway, such as C1qA (34).

With respect to anti-PGL-I translational application, we recommend the use of this marker as prognostic factor in order to screening patients according to clinical forms and median time for the first leprosy reaction as shown in this research. This serology test may be suitable for creating an assistance flowchart involving esthesiometry, electroneuromyography, and medical assessment in a short period of time among evaluations to prevent nerve damage. The use of steroid such as prednisolone 20 mg/day during the first 4 months after MDT was pointed out in another research for leprosy reaction prevention. However, this strategy is controversial and more studies should be performed (35). The use of steroid associated with positivity of PGL-I after treatment with the goal to prevent leprosy reactions should be avoided, since the bacillary load of dermal-smear positive falls 1 log per year what may indicate the persistence of positivity of anti-PGL-I titers after treatment for multibacillary forms (36). Even though we did not focus on data after MDT, the positive anti PGL-I showed to be, in another study of our group, a predictive factor for peripheral nerve impairment demonstrated by electroneuromyography evidencing 4-fold chance of nerve damage for positive households contact as compared with seronegatives (17).

Finally, this study showed that the anti-PGL-I should be considered the main prognostic factor for leprosy reactions prediction after MDT and pointed out a median time of 5 and 9 months for this event in seronegatives and seropositives, respectively. These data may facilitate the monitoring and follow-up of these patients in order to prevent potential peripheral neural damage.

The principal limitations of this study are related to the difficulty of testing cytokines and lipoarabinomannan (LAM) as prognostic factors for leprosy reactions in a large sample of patients, due to the high cost of these laboratory supplies.

The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding authors.

The studies involving human participants were reviewed and approved by Research Ethics Committee at the Federal University of Uberlândia. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

DA, IG, LG, and DS designed the study. ML, LC, MC, EM, and NC collected data on reporting. The lab protocol was standardized and performed by ML, LC, MC, EM, and NC. DA performed the data analysis. DA and DS wrote the manuscript. Critical review was performed by IG and LG. IG and LG directed the research. All authors read and approved the manuscript.

The authors thank the Brazilian funding agency CNPq for providing financial support to the National Institute of Science and Technology in Theranostics and Nanobiotechnology – INCT-TeraNano (CNPq-465669/2014-0).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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