Social transfigurations, gender, and imagined wellness: a qualitative case study of erythema nodosum leprosum in Indonesia and India

Reactions in leprosy represent sudden shift in the immunological response and are seen in 11-25% of affected patients. It can be seen before, during or after the completion of multidrug therapy (MDT).1 Two types of reactions are recognized; Type 1 reaction (T1R), seen in borderline leprosy, affecting mainly skin and nerves; type 2 reaction (T2R) or erythema nodosum leprosum (ENL), seen in lepromatous leprosy, characterized by systemic features in addition to cutaneous lesions. Trophic ulcers and ulcerating ENL are well known entities while cutaneous ulceration in T1R is extremely rare; we describe an immune-competent woman with cutaneous ulceration as a presenting feature to highlight the need to recognize this entity at the earliest opportunity.

Erythema nodosum leprosum (ENL), also known as type 2 reaction (T2R) is an immune complex mediated (type III hypersensitivity) reactional state encountered in patients with borderline lepromatous and lepromatous leprosy (BL and LL) either before, during, or after the institution of anti-leprosy treatment (ALT). The consequences of ENL may be serious, leading to permanent nerve damage and deformities, constituting a major cause of leprosy-related morbidity. The incidence of ENL is increasing with the increasing number of multibacillary cases. Although the diagnosis of ENL is not difficult to make for physicians involved in the care of leprosy patients, its management continues to be a most challenging aspect of the leprosy eradication program: the chronic and recurrent painful skin lesions, neuritis, and organ involvement necessitates prolonged treatment with prednisolone, thalidomide, and anti-inflammatory and immunosuppressive drugs, which further adds to the existing morbidity. In addition, the use of immunosuppressants like methotrexate, azathioprine, cyclosporine, or biologics carries a risk of reactivation of persisters (Mycobacterium leprae), apart from their own end-organ toxicities. Most ENL therapeutic guidelines are primarily designed for acute episodes and there is scarcity of literature on management of patients with chronic and recurrent ENL. It is difficult to predict which patients will develop chronic or recurrent ENL and plan the treatment accordingly. We need simple point-of-care or ELISA-based tests from blood or skin biopsy samples, which can help us in identifying patients who are likely to require prolonged treatment and also inform us about the prognosis of reactions so that appropriate therapy may be started and continued for better ENL control in such patients. There is a significant unmet need for research for better understanding the immunopathogenesis of, and biomarkers for, ENL to improve clinical stratification and therapeutics. In this review we will discuss the potential of neutrophils (polymorphonuclear granulocytes) as putative diagnostic and prognostic biomarkers by virtue of their universal abundance in human blood, functional versatility, phenotypic heterogeneity, metabolic plasticity, differential hierarchical cytoplasmic granule mobilization, and their ability to form NETs (neutrophil extracellular traps). We will touch upon the various aspects of neutrophil biology relevant to ENL pathophysiology in a step-wise manner. We also hypothesize about an element of metabolic reprogramming of neutrophils by M. leprae that could be investigated and exploited for biomarker discovery. In the end, a potential role for neutrophil derived exosomes as a novel biomarker for ENL will also be explored.

Background: Leprosy is a chronic granulomatous infectious disease caused by thebacterium Mycobacterium leprae. Leprosy "Type 1" reactions (T1R), reversalreactions, occur in 30–40% of borderline patients with cellular immune responses toM. leprae. "Type 2" reactions (T2R), also known as erythema nodosum leprosum(ENL), occur only in lepromatous (LL) and borderline lepromatous (BL) patients witha high bacterial load and little or no cellular immunity to M. leprae. Corticosteroidsalleviate symptoms in T1R and T2R, but many patients have multiple, recurrentepisodes. The Objective of the present study is to verify the validity of measuringchitotriosidase activity and neopterin level, products of activated macrophages,adenosine deaminase activity and monocyte chemoattractant protein-1 (MCP-1) asmarkers of leprosy and to detect their values in diagnosis of different types of leprosy.Methods: This study was conducted on 15 healthy subjects and 75 leprotic patientsthat were classified into 5 groups [tuberculoid leprosy (TT), borderline tuberculoid(BT), borderline borderline (BB), borderline lepromatous (BL), and lepromatousleprosy (LL)], each group formed of 15 patients, depending on clinical,bacteriological and histopathological pattern. Patients were further grouped with aBI≥2 as multibacillary (MB, n=45), whereas those with BI<2 were grouped aspaucibacillary (PB, n=30). Thirty-four of the aforementioned patients werediagnosed with reactions of which 17 had type II/erythema nodosum leprosum (ENL)and 17 had type I/reversal reaction (RR). Reactions were treated using prednisolonefor 12 weeks. Venous blood sample was collected from each subject and processed forestimation of the activity of chitotriosidase and adenosine deaminase, neopterin andMCP-1 levels. Results: both chitotriosidase activity and neopterin level were elevatedin leprosy patients with significant elevation in MB than PB leprosy with significantlowering in the patients with reactional leprosy after prednisolone therapy.Adenosine deaminase activity was significantly elevated in TT, PB and reactionalleprosy. MCP-1 was significantly elevated in LL, MB and ENL. Conclusion:chitotriosidase and neopterin could be considered as promising markers fordifferentiation of MB from PB patients and useful for determining the response ofreactional leprosy to therapy. Adenosine deaminase could be useful in distinguishingTT, PB and reactional leprosy. MCP-1 could be considered a fair marker in LL, MBand ENL. In addition, these findings may provide new clues to the pathogenesis ofleprosy reactions.

Background: The Social Identity approach offers a unifying framework for understanding recovery from addiction as a process of identity change, associated with change in social network composition. This paper introduces Social Identity Mapping in Addiction Recovery (SIM-AR) — a visual method for capturing social group memberships, extended to integrate the substance use ‘status’ of group members as an indicator of group substance use norms. The aim here is to test theory-derived predictions focused on the relationship between changes in social identity and network composition reflected in groups' substance use norms in early recovery.Method: 155 therapeutic community (TC) residents in Victoria, Australia, completed the SIM-AR plus measures of substance-using and recovery identities and substance use shortly after admission, and 65% (N = 101) again 6 months later.Results: As predicted, substance use severity at follow up was associated with changes in both social identity and network composition. Furthermore, reduced strength of substance-using identity was associated with a decrease in the proportion of groups with heavy substance use norms, while increased strength of ‘recovery’ identity was associated with an increased proportion of non-using groups.Conclusion: SIM-AR proved useful in testing predictions about social identity and network changes in a residential treatment context. It captured key social identity constructs in recovery using a visual technique with value to both research and applied contexts. Findings highlight the clinical importance of assessing a person’s group-based relationships in treatment and early recovery, especially the influence of social group norms in relation to substance use.

Type 2 reaction (T2R) or erythema nodosum leprosum (ENL), a sudden episode of acute inflammation predominantly affecting lepromatous leprosy patients (LL), characterized by a reduced cellular immune response. This possibly indicates a close relationship between the onset of T2R and the altered frequency, and functional activity of T lymphocytes, particularly of memory subsets. This study performed ex vivo and in vitro characterizations of T cell blood subpopulations from LL patients with or without T2R. In addition, the evaluation of activity of these subpopulations was performed by analyzing the frequency of these cells producing IFN-γ, TNF, and IL-10 by flow cytometry. Furthermore, the expression of transcription factors, for the differentiation of T cells, were analyzed by quantitative real-time polymerase chain reaction. Our results showed an increased frequency of CD8+/TNF+ effector memory T cells (TEM) among T2Rs. Moreover, there was evidence of a reduced frequency of CD4 and CD8+ IFN-γ-producing cells in T2R, and a reduced expression of STAT4 and TBX21. Finally, a significant and positive correlation between bacteriological index (BI) of T2R patients and CD4+/TNF+ and CD4+/IFN-γ+ T cells was observed. Thus, negative correlation between BI and the frequency of CD4+/IL-10+ T cells was noted. These results suggest that CD8+/TNF+ TEM are primarily responsible for the transient alteration in the immune response to Mycobacterium leprae in ENL patients. Thus, our study improves our understanding of pathogenic mechanisms and might suggest new therapeutic approaches for leprosy.

Erythema nodosum leprosum in a patient with lepromatous leprosy: A case report

BackgroundThe ILEP Nerve Function Impairment in Reaction (INFIR) is a cohort study designed to identify predictors of reactions and nerve function impairment in leprosy. The aim was to study correlations between clinical and histological diagnosis of reactions.Methodology/Principal FindingsThree hundred and three newly diagnosed patients with World Health Organization multibacillary (MB) leprosy from two centres in India were enrolled in the study. Skin biopsies taken at enrolment were assessed using a standardised proforma to collect data on the histological diagnosis of leprosy, leprosy reactions and the certainty level of the diagnosis. The pathologist diagnosed definite or probable Type 1 Reactions (T1R) in 113 of 265 biopsies from patients at risk of developing reactions whereas clinicians diagnosed skin only reactions in 39 patients and 19 with skin and nerve involvement. Patients with Borderline Tuberculoid (BT) leprosy had a clinical diagnosis rate of reactions of 43% and a histological diagnosis rate of 61%; for patients with Borderline Lepromatous (BL) leprosy the clinical and histological diagnosis rates were 53.7% and 46.2% respectively. The sensitivity and specificity of clinical diagnosis for T1R was 53.1% and 61.9% for BT patients and 61.1% and 71.0% for BL patients. Erythema Nodosum Leprosum (ENL) was diagnosed clinically in two patients but histologically in 13 patients. The Ridley-Jopling classification of patients (n = 303) was 42.8% BT, 27.4% BL, 9.4% Lepromatous Leprosy (LL), 13.0% Indeterminate and 7.4% with non-specific inflammation. This data shows that MB classification is very heterogeneous and encompasses patients with no detectable bacteria and high immunological activity through to patients with high bacterial loads.Conclusions/SignificanceLeprosy reactions may be under-diagnosed by clinicians and increasing biopsy rates would help in the diagnosis of reactions. Future studies should look at sub-clinical T1R and ENL and whether they have impact on clinical outcomes.

Chronic recalcitrant erythema nodosum leprosum (ENL) or type 2 reaction (T2R) is a severe condition found in approximately 50% of multibacillary leprosy subjects. T2R is associated with important morbidities and may lead to several disabilities, not only due to nerve damage but also due to the prolonged use of corticosteroids, thalidomide, or immunosuppressors. We describe here four leprosy patients with chronic recalcitrant ENL treated with cyclophosphamide pulse therapy. All subjects had been on prednisone and thalidomide therapy for at least 30 months but showed inflammatory activity when doses were reduced. Pulse therapy with 1.0 g of cyclophosphamide was used every 4-6 weeks for a minimum of three applications. After pulse therapy, all cases presented total or partial regression of symptoms, and we were able to taper thalidomide and prednisone doses, with better control of ENL, avoiding further hospital admissions and disabilities. No side effects were observed during or after infusion therapy. Cyclophosphamide pulse therapy may be useful and safe to control chronic recalcitrant ENL.

A 26-year-old male presented with recurrent episodes of evanescent erythematous nodules over the face, abdomen, and limbs, associated with fever and joint pain for 3 years. He had received multi-bacillary multi-drug treatment (MB-MDT: monthly rifampicin 600 mg and clofazimine 300 mg, and daily dapsone 100 mg and clofazimine 100 mg) for borderline leprosy for 2 years from a local center. His bacillary index (BI) at baseline was unavailable. He had recurrent episodes of type-2 reaction, which were managed with oral corticosteroids. However, despite completing MB-MDT, the episodes of reaction persisted, resulting in chronic type-2 reactions. He had not been given thalidomide, clofazimine, or any steroid-sparing agent for controlling the recurrent type-2 reactions at the local center. When the patient came to our hospital, it was found that his BI was zero after 2 years of MB-MDT. The patient complied with the treatment, and no triggering factors could be identified for the recurrent reactions. Routine hemogram, peripheral smear, liver and renal function test, chest X-ray, and ultrasonogram of the whole abdomen were unremarkable. He was not initiated on thalidomide or clofazimine for recurrent reaction. A skin biopsy was sent for screening for drug resistance. Using the lysis method of DNA extraction with polymerase chain reaction (PCR) amplification targeting genes rpoB, folP, and gyrA with DNA sequencing, a mutation imparting rifampicin resistance was found in rpoB at codon 439: TTC—CTC (Phe → Leu) [1]. The treatment was modified to second-line MDT (oral ofloxacin 400 mg/day, minocycline 100 mg/day, and clofazimine 50 mg/day). He did not experience new episodes of type-2 reaction after 7 months of follow-up. Rifampicin is a broad-spectrum antibiotic that is effective against leprosy. Resistance to rifampicin in leprosy, which is reported to be 3.8% globally, is due to mutation in the rpoB gene, which encodes the β-subunit of bacterial RNA polymerase [2]. Studies have emphasized that mutation in the drug-resistance-determining region (codon 439–459) of the rpoB gene results in resistance to rifampicin. The most frequent mutation is seen in codon 456 (Ser → Leu). In the present case, the mutation was observed in codon 439 (Phe → Leu), a novel mutation reported from India [1, 2]. The major focus of drug resistance in global studies has been on the newly diagnosed and relapsed cases; however, patients presenting with recurrent or chronic leprosy reactions have largely been overlooked [1-4]. Such patients often become steroid-dependent, resulting in significant morbidity and mortality. It has also been shown that the host inflammatory response to phenolic glycolipid-1 (PGL-1) is significantly reduced in patients with chronic erythema nodosum leprosum (ENL) after prolonged corticosteroid treatment [3]. This contributes to the persistence of M. leprae and perpetuates the multiplication of resistant bacilli that leads to recurrent type-2 reactions and increased risk of relapse. Additionally, corticosteroids facilitate other infections that can act as potential triggers for inciting type-2 reactions (Figure 1) [3]. Drug resistance in leprosy is an emerging concern. Recurrent episodes of leprosy reactions and, more specifically, chronic reactions despite completion of MB-MDT could be a potential clinical manifestation of drug resistance. It is imperative to establish robust drug resistance surveillance, careful monitoring of recurrence and relapse, thorough investigation of patients with chronic or recurrent leprosy reactions, and early identification of drug resistance strains, especially in endemic countries, in order to achieve the global goal of leprosy elimination by 2030 [5]. The authors declare no conflicts of interest.

Leprosy could be best understood as two conjoined diseases. The first is a chronic mycobacterial infection that elicits an extraordinary range of cellular immune responses. The second is lepra reaction, whose course and sequelae often extend many years beyond the cure of the infection and may have severely debilitating physical, social, and psychological consequences. Type-2 lepra reaction is also termed Erythema nodosum leprosum (ENL) regardless of the site of involvement, which is in turn a Coomb and Gell Type III hypersensitivity reaction. The paradox of ENL is that it can be a life-threatening disorder and requires control with immunosuppression which may itself pose life-threatening risks for patients Indian studies found its prevalence rate of almost 50% in those with LL and 9% in BL cases and the mean time to presentation with ENL was 3.7 months after starting multi-drug therapy (MDT). Hitherto we report a severe and steroid dependent case of chronic ulcerated ENL, not only occurred sixteen years after successful treatment of lepromatous leprosy, but also had an unusual initial presentation of arthritis. To the best of our knowledge, ENL for such a prolonged period of 15 years was not reported earlier. Â doi:10.3329/jom.v10i1.2002J Medicine 2009; 10: 31-33

BackgroundLeprosy reactions are a significant cause of morbidity in leprosy population. Erythema nodosum leprosum (ENL) is an immunological complication affecting approximately 50% of patients with lepromatous leprosy (LL) and 10% of borderline lepromatous (BL) leprosy. ENL is associated with clinical features such as skin lesions, neuritis, arthritis, dactylitis, eye inflammation, osteitis, orchitis, lymphadenitis and nephritis. ENL is treated mainly with corticosteroids and corticosteroids are often required for extended periods of time which may lead to serious adverse effects. High mortality rate and increased morbidity associated with corticosteroid treatment of ENL has been reported. For improved and evidence-based treatment of ENL, documenting the systems affected by ENL is important. We report here the clinical features of ENL in a cohort of patients with acute ENL who were recruited for a clinico-pathological study before and after prednisolone treatment.Materials and methodsA case–control study was performed at ALERT hospital, Ethiopia. Forty-six LL patients with ENL and 31 non-reactional LL matched controls were enrolled to the study and followed for 28 weeks. Clinical features were systematically documented at three visits (before, during and after predinsolone treatment of ENL cases) using a specifically designed form. Skin biopsy samples were obtained from each patient before and after treatment and used for histopathological investigations to supplement the clinical data.ResultsPain was the most common symptom reported (98%) by patients with ENL. Eighty percent of them had reported skin pain and more than 70% had nerve and joint pain at enrolment. About 40% of the patients developed chronic ENL. Most individuals 95.7% had nodular skin lesions. Over half of patients with ENL had old nerve function impairment (NFI) while 13% had new NFI at enrolment. Facial and limb oedema were present in 60% patients. Regarding pathological findings before treatment, dermal neutrophilic infiltration was noted in 58.8% of patients with ENL compared to 14.3% in LL controls. Only 14.7% patients with ENL had evidence of vasculitis at enrolment.ConclusionIn our study, painful nodular skin lesions were present in all ENL patients. Only 58% patients had dermal polymorphonuclear cell infiltration showing that not all clinically confirmed ENL cases have neutrophilic infiltration in lesions. Very few patients had histological evidence of vasculitis. Many patients developed chronic ENL and these patients require inpatient corticosteroid treatment for extended periods which challenges the health service facility in resource poor settings, as well as the patient’s quality of life.

Leprosy reactions are acute immunological events that occur during the evolution of chronic infectious disease causing neural damage and disabilities. A study using blood samples of 17 leprosy reaction patients and 17 reaction-free was carried out by means of associations between antigens, receptors, and expression of cytokines, using path analysis providing new insights into the immunological mechanisms involved in triggering leprosy reactions. Toll-like receptors (TLR) such as TLR1 and TLR2, presented balanced expression in the reaction-free multibacillary (MB) group (TLR1: 1.01 ± 0.23, TLR2: 1.22 ± 0.18; p = 0.267). On the other hand, downgrading type 1 reaction (T1R) (TLR1: 1.24 ± 0.17, TLR2: 2.88 ± 0.37; p = 0.002) and erythema nodosum leprosum (ENL) (TLR1: 1.93 ± 0.17, TLR2: 2.81 ± 0.15; p = 0.004) revealed an unbalance in relation to the expression of these receptors. When the path analysis was approached, it was noted that interleukin 10 (IL-10) expression showed a dependence relation with phenolic glycolipid I (PGL-I) in downgrading T1R (direct effect = 0.503 > residual effect = 0.364), whereas in ENL, such relationship occurred with lipoarabinomannan (LAM) (direct effect = 0.778 > residual effect = 0.280). On the contrary, in the reaction-free leprosy group, interferon-gamma (IFN-γ) levels were dependent on the association between TLR2 and TLR1 (0.8735). The high TLR2 expression associated with IL-10 levels, in the leprosy reaction groups, may be hypothetically related to the formation of TLR2/2 homodimers and/or TLR2/6 heterodimers linked to evasion mechanisms in downgrading reactions and pathophysiology of ENL.

The enormous social, economic and political transformation South Africans have experienced especially over the past 12 years, since the systematic dismantling of apartheid in the era of social and economic reconstruction, has brought about numerous societal and social identity changes. Due to these changes in social identity, societal norms and power shifts, major changes are occurring in the workplace, and societal level identity crises and conflicts are increasingly spilling over into the workplace. This article unpacks these social identity changes and power shifts on the political, social, economic and management levels, by employing social identity theory, self-categorisation theory and embedded intergroup theory, and highlights some resultant workplace implications.

Background: Erythema nodosum leprosum (ENL) is an acute immunologic complication of multibacillary leprosy (MB) that causes systemic inflammation in various organs. It is a major factor contributing to morbidity, mortality, and financial hardship. ENL is diagnosed clinically, and objective indicators for severe conditions remain unexplored. Simple blood biomarkers that differentiate between different ENL disease severity levels are required. Neutrophilto-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have been widely studied as severity biomarkers of numerous neoplastic and inflammatory disorders. Objective: We examined NLR and PLR values at various ENL severities and their role as severe disease indicators for ENL. Methods: This cross-sectional retrospective study examined 246 patients with multibacillary leprosy—with and without ENL reactions and aged 18 and above—and calculated their NLR and PLR values. Then, we compared patients with mild and severe disease states to those without ENL. The severity classification was based on the ENLIST ENL Severity Score (EESS). To determine the NLR and PLR cutoff points of mild and severe ENL, a receiver operating characteristic (ROC) curve was constructed. Results: The NLR value for severe ENL was significantly higher than that for mild ENL (p &lt; 0.05), with a severe disease cutoff point of 5.71 (95.7% sensitivity, 68.7% specificity). No significant differences were found in PLR between patients with mild and severe ENL. Conclusion: While PLR is not an effective assay for evaluating ENL severity, NLR is a potential biomarker for severe ENL reactions in patients with multibacillary leprosy.

Leprosy is known for its diverse pathophysiologic involvement and resulting multisystemic manifestation and morbidities. Despite global efforts to eliminate this public health illness, it is still prevalent in some Asian and European countries. Perioperative management of a leprosy patient is challenging owing to the indirect and direct involvement of the airway, respiratory, and cardiac systems; treatment-related side-effects involving the hepato-renal systems affecting the anesthesia techniques and drugs pharmacokinetic and pharmacodynamics. While anaesthesiologists are aware of such happenings and often tailor the anesthesia management for the concerning issues, immunological aspects of the disease and drug-related adverse events are less enquired about, such as type-2 lepra reaction, i.e., erythema nodosum leprosum (ENL), etc. Further, data on perioperative ENL management and prevention are still being determined. We report one case of a 52-year-old female who underwent gynecology surgery and developed ENL on the third postoperative day, which was managed using Steroids. Unfortunately, the patient had a surgical site infection, which required another surgery within the month, while the patient was still under the steroid successfully without any adverse events. Although a single case cannot provide causation or association, the case is presented to highlight the probable preventive action of steroids on the occurrence of postoperative ENL, where surgical stress is considered a risk factor.