Clinical and laboratory characteristics in the retreatment of leprosy relapse

Abstracts

OBJETIVO: Comparar as características clínico-laboratoriais dos doentes de hanseníase durante o tratamento inicial e no retratamento por recidiva diagnosticada em unidades de saúde de referência no Estado de Mato Grosso MÉTODO: Estudo transversal de casos diagnosticados de recidiva em hanseníase em unidades de referência de 2005 a 2007 em cinco municípios do Estado. O tratamento inicial foi considerado t1 e a recidiva t2. Fontes de dados: Sistema de Informação de Agravos de Notificação, prontuários, exames laboratoriais, ficha de notificação individual e de avaliação de incapacidade física. Utilizou-se para a comparação e cálculo de proporções o teste do Qui-quadrado (c²) ao nível de significância de 5%. RESULTADOS: Verificou-se predomínio da forma clínica dimorfa em t2 quando comparada a t1 (39,6% versus 11,3%; p = 0,003); 20,8%, dos casos em recidivas apresentaram índice baciloscópico ≥ 4+ se comparados aqueles em t1 (p = 0,034); aumento (17%) dos casos de recidiva com grau zero de incapacidade quando comparados aos pacientes avaliados no momento do diagnóstico (58,5% versus 41,5%); aumento (7,5%) de recidivas com incapacidades grau 2 quando comparadas a t1 (9,4% versus 1, 9%); predomínio de casos não avaliados quanto a incapacidade física entre t1 (45,3%) e t2 (22,6%); (p = 0,040). CONCLUSÃO: Os casos de recidiva caracterizam o agravamento da doença indicadas pelo aumento do índice baciloscópico e do grau de incapacidade física. Recomenda-se maior atenção à confirmação diagnóstica de recidiva por meio de exames baciloscópicos, em especial nos multibacilares, e da avaliação neurológica sistemática de todos os pacientes de hanseníase.

Hanseníase; Recidiva; Epidemiologia; Estudos transversais; Prevenção e Controle; Notificação de Agravos

ORIGINAL ARTICLES

Clinical and laboratory characteristics in the retreatment of leprosy relapse

Silvana Margarida Benevides Ferreira^I; Eliane Ignotti^II; Mônica Antar Gamba^III

^IFaculdade de Enfermagem. Universidade de Cuiabá. Cuiabá, MT, Brasil. Secretária Municipal de Saúde de Cuiabá. Cuiabá, MT, Brasil

^IIDepartamento de Enfermagem. Universidade Estadual de Mato Grosso. Cáceres, MT

^IIIEscola Paulista de Enfermagem. Universidade Federal de São Paulo, SP

Correspondência

ABSTRACT

OBJECTIVE: To compare clinical and laboratory data of leprosy patients diagnosed in specialized services in the State of Mato Grosso, Brazil, during the initial treatment and the retreatment of relapse.

METHODS: A cross-sectional study of patients with diagnosis of leprosy relapse was conducted in specialized health services of five cities, between 2005 and 2007. Initial treatment was described as t1 and relapse treatment as t2.

DATA SOURCE:Sistema de Informação de Agravos de Notificação (Sinan - Reportable Diseases Information System), medical records, laboratory tests, and files of individual reports and of physical disability assessments. The chi-square test (c2) was applied at a significance level of 5%.

RESULTS: The clinical dimorphic form prevailed in t2 when compared with t1 (39.6% versus 11.3%; p = 0.003); 20.8% of relapse cases showed a bacilloscopy index ≥ 4+ in relation to those in t1 (p = 0.034)]; an increase in the number of (17%) cases of relapse with physical disability at level 0 was found, compared to patients evaluated during the diagnosis (58.5% versus 41.5%); an increase (7.5%) in the recurrence of disabilities at level 2 was observed, when compared to t1 (9.4% versus a 9%); and there was a higher prevalence of cases not evaluated for disability between t1 (45.3%) and t2 (22.6%) (p = 0.040).

CONCLUSION: Cases of relapse characterized the aggravation of the disease, indicated by the increase in the bacilloscopy index and level of physical disability. Attention should be paid to the diagnostic confirmation of relapse using bacilloscopy tests, especially in multibacillary cases, and systematic neurological assessment of all leprosy patients.

Keywords: Leprosy. Relapse. Epidemiology. Cross-Sectional Studies. Prevention and Control. Disease Reporting.

Introduction

Currently, there are 228,474 cases of leprosy worldwide. Brazil contributes to 92.4% of all cases recorded in the Americas and it ranks second in absolute number of cases, only surpassed by India¹.

Between 2004 and 2010, there were 2,596 cases of leprosy recurrence on a global level. In Brazil, in 2009 alone, there were 1,483 cases of recurrence, totaling 3.9% of the increase in cases during this period².

According to parameters of 2011 the state of Mato Grosso, in the Center-West region of Brazil, is a hyper-endemic area with 2,569 new cases and a general detection coefficient of 84.6/100,000 inhabitants, with significant differences among distinct areas of this state^3,4,5.

Since the 1980s, the World Health Organization (WHO) has recommended the use of polychemotherapy (PCT) and this measure has led to the treatment and cure of more than 14 million patients with leprosy⁶.

Although the recommended treatment is effective, there has been evidence of possible resistance to the existing chemotherapeutic drugs. This has been proved experimentally by Pettit and Rees (1964), using the inoculation technique with Mycobacterium leprae standardized by Shepard (1960). The result associated with the irregular use of the previously mentioned therapeutic scheme leads to low adherence to treatment and the possibility of occurrence of leprosy recurrence and, consequently, the permanence of the source of infection in the community^7-10.

The fact that M. leprae is not cultivated in vitro makes it difficult to define the parameters for laboratory confirmation of the initial diagnosis, treatment efficacy monitoring and leprosy recurrence^11-13.

There is no consensus on the criteria established for the diagnostic confirmation of recurrence. The following variations are included: reappearance of new lesions and/or nerve injuries with clinical and histopathological signs consistent with active forms (borderline-borderline/BB, borderline-lepromatous/BL and lepromatous/LL), according to Ridley-Jopling's classification (1966)^14,15; new skin lesions; increase in the bacilloscopy index (BI) >2+ in one or more areas; and viability of M. leprae through inoculation in mice paw¹⁶; reactivation after six months of regular treatment with multi-drug therapy; anesthetic lesions and/or exacerbation of previous lesions; bacteriological evidence with or without clinical activity; nerve lesions with or without neuritis in cases of paucibacillary leprosy; and diagnostic confirmation with biopsy¹⁷; reactivation and presence of new anesthetic lesions confirmed with bacilloscopy exam and skin biopsy¹⁸.

Studies aimed at the technical-scientific support and infrastructure available for professionals to accurately diagnose recurrence in health services are essential. The present study aimed to compare the clinical and laboratory characteristics of individuals with leprosy during the initial treatment and during new treatment of recurrence diagnosed in referral health clinics of the state of Mato Grosso.

Materials and Methods

A cross-sectional epidemiological study was conducted to analyze cases of leprosy recurrence diagnosed in referral health clinics of five cities of the state of Mato Grosso (Cáceres, Cuiabá, Diamantino, Rondonópolis and Várzea Grande) between 2005 and 2007. There are 1,032,523 inhabitants in these five cities, 36.2% of the total state population estimated to be 2,854,462 inhabitants at the time of this study¹⁹.

The criteria for the diagnosis of recurrence used in specialized health clinics are defined in the protocols adopted by the Brazilian Ministry of Health¹¹: patients who were discharged as cured subsequently had new lesions and/or the exacerbation of previous lesions, new neurological lesions with an unsatisfactory response after treatment with corticosteroids and/or thalidomide, and results of bacilloscopy/histopathological tests compatible with active forms.

The comparative analysis of the investigated groups included the cases diagnosed as recurrence, which were described as time 2 (t2) and recorded in the databases of the Sistema de Informação de Agravos de Notificação (Sinan/MT - State of Mato Grosso Information System for Notifiable Diseases) between January 1^st 2005 and December 31^st 2007, in the cities selected for this study. Of all 82 cases of recurrence reported in this period, 53 (64.6%) were considered to be occurrences of leprosy recurrence with the validation of the information found in the medical records available in the specialized treatment units. The exclusion of 29 individuals was due to transfers to other states and diagnostic errors. The initial treatment group or time 1 (t1) included the records of leprosy cases that had been discharged as cured before the recurrence under study occurred. The sources of data were as follows: Sinan/leprosy/MT, medical records, laboratory tests, individual report files and physical disability assessment. Laboratory tests of bacilloscopy and histopathology were performed in the state and municipal Laboratório Central de Saúde Pública (Central Laboratory of Public Health) and in the Instituto Lauro de Souza Lima de Bauru - São Paulo (ILSL), respectively. The study variables were the following clinical/laboratory characteristics: clinical form, number, type and location of leprosy lesion, nerve thickness, reactive state, adverse effects, bacilloscopy and histopathology, and level of physical disability as assessed during diagnosis.

The non-inclusion of ill patients diagnosed as recurrence in all state health clinics is justified by the fact that 80% of these diagnoses are made in primary health clinics, which do not have appropriate technical resources. Consequently, the inclusion of such cases could create selection bias and thus affect the study⁵.

The SPSS 15 software program was used to manage and analyze data. Double data entry was used to check data consistency. The chi-square test (c²) and a significance level of 5% were used to compare proportions.

The present research project was assessed and approved by the Research Ethics Committee of the Hospital Universitário Júlio Muller (CEP/HUJM - Júlio Muller University Hospital - process 321 of April 2007).

Results

Of the 53 cases of recurrence reported in the state of Mato Grosso between 2005 and 2007, the majority were males (66.0%, n=35) with a mean age of 46.3 years (±16.8; minimum age of 18 and maximum age of 82 years). The mean time interval between the initial treatment and the occurrence of leprosy recurrence was seven years and six months (Table 1).

Table 2 shows the results of the comparative analysis of the proportion of leprosy cases between initial treatment (t1) and recurrence (t2), according to clinical form, bacilloscopy, histopathology and level of physical disability. The group of cases in this study revealed a higher proportion of cases of recurrence with the dimorphic clinical form (39.6%), whereas these represented 11.3% of all cases in t1. In contrast, 9.4% and 13.2% of individuals in t2 were categorized in the undetermined and tuberculoid clinical forms, respectively, and of these, 13.2% and 20.8% were in the same categories in t1 [c² = 16.06 (p= 0.003)]. With regard to the characteristic of the bacilloscopy tests, 54.7% of individuals had this test performed when they were cases of recurrence, whereas 66% did so in the initial treatment; 20.8% (n=11) of cases of recurrence showed a BI ≥ 4+ when compared to those in the initial treatment [c² = 8.69 (p = 0.034)]. Of all individuals who had a histopathological test performed, 49% (n=26) did so to have a diagnostic confirmation of recurrence [c² = 14.64 (p = 0.001)]. Among the cases assessed for physical disability, there was an increase of 17% in the number of cases of recurrence with physical disability at level 0, when compared to patients assessed at the moment of diagnosis (58.5% versus 41.5%). In addition, there was an increase of 7.5% of physical disability at level 2 between t1 and t2 (9.4% versus 1.9%). There was an increase in the proportion of cases not assessed for physical disability between t1 (45.3%) and t2 (22.6%) [c² = 8.29 (p = 0.040)].

There were no statistically significant differences between proportions of treatments according to the following variables: number, type and location of leprosy lesions, nerve thickness, presence and type of reactive state and adverse effect (Table 3).

Discussion

The identification of cases of leprosy recurrence with the analysis of clinical and laboratory characteristics is key in the adoption of more effective measures to diagnose and monitor such cases in specialized health clinics.

The comparison made in this study enabled researchers to observe that the dimorphic clinical form was more frequent in cases of recurrence, although tuberculoid and undetermined clinical forms were more frequent during the initial treatment. Cases of recurrence were manifested as more advanced or severe clinical forms of the disease, when compared to those in the initial treatment. The majority of cases of recurrence were diagnosed with histopathological tests. A higher proportion of cases of recurrence with physical disability at level 0 was found, although data also show recurrence with physical disability at level 2 and patients without neurological assessment.

The higher proportion of males at an economically productive age was similar to other studies^{5,12,16,20,21}. The risk of development of leprosy is two times higher in men than women²². This characteristic is probably associated with the cultural values of self-care and environmental factors involved in the function performed by an individual²³.

Diagnoses of recurrence observed in the early and late periods, when compared to the time interval between the initial treatment and occurrence of leprosy recurrence, are in agreement with findings from other studies^15,24-27. Certain factors may influence the time interval until recurrence, such as clinical form, therapeutic scheme, reactions, irregular treatment and bacillary load^15,28-30 .

The higher proportion of diagnoses of recurrence categorized in the dimorphic clinical form suggests a relationship with an individual's immune response to M. lepra and the severity of the disease. A study on the interactions between pathogens and the immune system in patients with infectious diseases has contributed to the investigation of the basic regulatory mechanisms of the human immune response^13,31. In the case of leprosy, there is a variety of symptoms that are manifested as distinct clinical forms and its main characteristic is the type of immune response between host and pathogen³¹. For this reason, an individual's resistance to M. leprae is specific and suggests a genetic component^32,33. It is estimated that the majority of individuals have natural resistance to M. leprae (80 to 95%). The remaining individuals would be in a borderline state of anergy (5%) and could develop the severe forms of this disease. In this case, the small number of prime-infected individuals develop the disease due to endogenous reactivation or due to their receiving a new bacillary load (exogenous reactivation)^13,31.

It should be emphasized that higher percentages were found in the tuberculoid and undetermined clinical forms in the initial treatment. The clinical forms and, consequently, the operational classification of the first treatment could have been erroneously adopted, which may have led to recurrence^12,29,30. Thus, if a multibacillary patient is initially categorized as paucibacillary and is treated with PCT/6 instead of PCT/12 as a result, the probability of occurrence of leprosy recurrence is increased. Serological tests could function as an alternative tool to classify paucibacillary and multibacillary leprosy in the first treatment and to confirm suspected cases of recurrence^34,35.

Histopathological tests are diagnostic criteria of recurrence in the majority of studies, similarly to the present study^{15,17,18,24,28}. Although this procedure is important as diagnostic support for the confirmation of recurrence, bacilloscopy tests are also essential, especially in previous multibacillary cases¹¹. Bacillary persistence indicates a factor of development of recurrence and resulting detection of drug resistance^9,21,26,28.

Due to the lack of a test considered to be the gold standard to diagnose this disease³⁶, referral treatment units need to have other resources to accurately diagnose recurrence, such as serological tests, morphological indices and inoculation tests in mice feet. The latter tests, although difficult to be performed, enable the viability of M. leprae to be observed, tests with chemotherapeutic drugs to be monitored, levels of resistance to drugs to be verified, and cases of recurrence to be confirmed^9,10,34,35.

Despite the higher proportion of recurrence with physical disability at level 0 at the moment of diagnosis showing an improvement in this indicator, the higher frequency of patients with physical disability at level 2 reveals an aggravation of the disease and its consequences. However, the data found emphasizes the higher prevalence of cases ignored/not evaluated for neurological assessment. These data suggest the inefficiency of the health service with regard to systematic dermato-neurological test monitoring. The reappearance of neural impairment is a diagnostic suspicion of the occurrence of leprosy recurrence^11,12,17. Studies indicate that the number of nerves affected in the beginning of the treatment, combined with other factors, determines the chances of occurrence of physical disabilities³⁷.

In conclusion, cases of recurrence characterize the aggravation of the disease, indicated by the increase in the bacilloscopy index and level of physical disability. It is recommended that more attention should be given to the diagnostic confirmation of recurrence, using bacilloscopy tests, especially in multibacillary cases, and systematic neurological assessment of all leprosy patients.

References

• ¹
  World Health Organization. Leprosy update, 2011. (WHO) Weekly Epidemiological Record; 2011; 36(86): 389-400.
• 2. World Health Organization. Global leprosy situation, 2010. (WHO) Weekly Epidemiological Record; 2010; 35(85): 337-48.
• ³
  Secretaria de Saúde do Estado de Mato Grosso. Setor de vigilância epidemiológica. Dados sobre Hanseníase no Estado de Mato Grosso por municípios e Escritórios Regionais de Saúde (ERS/SES/MT); Mato Grosso (MT); 2011.
• 4. Ignotti E, De Paula RC. Situação epidemiológica da hanseníase no Brasil: análise de indicadores selecionados no período de 2001 a 2010. In: Saúde Brasil 2010: Uma análise da situação de saúde e de evidências selecionadas de impacto de ações de vigilância em saúde Ministério da Saúde. Secretaria de Vigilância em Saúde/MS; 2010: 186-202.
• 5. Ferreira SB, Ignotti E, Gamba MA. Recidivas de casos de hanseníase no Estado de Mato Grosso. Rev Saúde Pública 2010; 44(4): 1-7.
• 6. World Health Organization. Leprosy fact sheet. (WHO) Weekly epidemiological record 2010; 6 (85): 37-48.
• 7. Pettit JH, Rees RJ. Sulphone resistance in leprosy. An experimental and clinical study. Lancet 1964; 2(7361): 673-4.
• 8. Shepard CC. The experimental disease that follows the injection of human leprosy into food pads of mice. J Exp Med 1960: 112(3): 445-54.
• 9. Matsuoka M, Budiawan T, Aye KS, Kyaw K, Tan EV, Cruz ED et al. The frequency of drug resistance mutations in Mycobacterium leprae isolates in untreated and relapsed leprosy patients from Myanmar, Indonesia and the Philippines. Lepr Rev 2007; 78(4): 343-52.
• 10. World Health Organization. Drug resistance in leprosy: reports from selected endemic countries. Weekly Epidemiological Record 2009, 26(84): 261-8.
• ¹¹
  Ministério da Saúde. Portaria Nº 3.125 de 7 de outubro de 2010. Aprova as Diretrizes para Vigilância, Atenção e Controle da hanseníase. Gabinete do Ministro/MS. Brasília (DF); 2010.
• 12. Kaimal S, Thappa DM. Relapse in leprosy. Indian J Dermatol Venereol Leprol 2009; 75(2): 126-35.
• 13. Azulay RD, Azulay DR, Azulay-Abulafia L. Dermatologia 5. ed., rev. e atual. Rio de Janeiro: Guanabara Koogan; 2008. p. 322-46.
• 14. Ridley DS, Jopling WH. Classification of leprosy according to immunity; a Five group system. Int J Leprosy 1966; 34; 255-73.
• 15. Shetty VP, Wakade AV, Ghate SD, Pai VV, Ganapati RR, Antia NH. Clinical, histopathological and bacteriological study of 52 referral MB cases relapsing after MDT. Lepr Rev 2005; 76: 241-52.
• 16. Norman G, Joseph G, Richard J. Relapse in Multibacillary Patients Treated with Multi-drug Therapy until Smear Negativity: Findings after Twenty Years. Int J Leprosy 2004; (72): 11- 6.
• 17. Suite M. Relapse rates following leprosy multidrug therapy. West Indian Med J 2000; 49 (3): 210-211.
• 18. Rodriguez G, Pinto R, Laverde C, Sarmiento M, Riveros A, Valderrama J et al. Recidivas postratamiento de la lepra multibacilar. Biomédica 2004; 24: 133-9.
• ¹⁹
  Fundação Instituto Brasileiro de Geografia e Estatística. Contagem populacional 2007. População recenseada e estimada, segundo os municípios de Mato Grosso Rio de Janeiro; 2007.
• 20. Gelber RH, Balagon MVF, Cellona RV. The relapse rate in MB leprosy patients treated with 2-years of WHO-MDT is not low. Int J Leprosy 2004; 72(4): 493-9.
• 21. Shen J, Liu M, Zhang J, Su W, Ding G. Relapse in MB leprosy patients treated with 24 months of MDT in South West China: a short report. Lepr Rev 2006; 77: 219-24.
• 22. Bakker MI, Hatta M, Kwenang A, Mosseveld PV, Faber WR et al. Risk factors for developing leprosy - a population-based cohort study in Indonesia. Lepr Rev 2006; 77: 48-61.
• 23. El-Hassan LA, Khalil EA, El-Hassan AM. Socio-cultural aspects of leprosy among the Masalit and Hawsa in the Sudan. Lepr Rev 2002; 73: 20-8.
• 24. Cellona RV, Balagon MVF, Dela Cruz E, Burgos JA, Abalos RM, Walsh GP, et al. Long-term efficacy of 2-year WHO multiple drug therapy (MDT) in multibacillary (MB) leprosy patients. Int J Leprosy 2003; 71(4): 308-19.
• 25. Ali MK, Thorat DM, Subramanian M, Parthasarathy G, Selvaraj U, Prabhakar V. A study on trend of relapse in leprosy and factors influencing relapse. Indian J Lepr 2005; 77(2): 105-15.
• 26. Ximenes RAA, Gallo MEN, Brito MFM. Retreatment in Leprosy: a case-control study. Rev Saúde Pública, 2007; 41(4): 632-7.
• 27. Balagon MF, Cellona RV, Dela Cruz E, Burgos JA, Abalos RM, Walsh GP et al. Long-Term Relapse Risk of Multibacillary Leprosy after Completion of 2 Years of Multiple Drug Therapy (WHO-MDT) in Cebu, Philippines. Am J Trop Med Hyg 2009; 81(5): 895-9.
• 28. Girdhar BK, Girdhar A, Kumar A. Relapses in multibacillary leprosy patients: effect of length of therapy. Lepr Rev 2000; 71: 144-53.
• 29. Opromola DVA. Ação terapêutica das drogas anti-hansênicas e evidências de persistência microbiana nos casos paucibacilares. Editorial. Hansen Int 2004; 29(1): 1-3.
• 30. Ferreira SB, Ignotti E, Gamba MA. Fatores associados à ocorrência de recidiva em Mato Grosso. Rev Saúde Pública 2011; 45(4): 756-64.
• 31. Goulart IMB, Penna GO, Cunha G. Imunopatologia da hanseníase: a complexidade dos mecanismos da resposta imune do hospedeiro ao Mycobacterium leparae Rev Soc Bras Med Trop 2002; 35(4): 365-75.
• 32. Beiguelman B. Genética e hanseníase. Ciênc Saúde Coletiva 2002; 7(1): 117-28.
• 33. Franceshi DNA, Mazini OS, Rudnick CCC, Sell AU, Tsuneto LT, Ribas ML et al. Influence of TNF and IL10 gene polymorphisms in the immunopathogenesis of leprosy in the south of Brazil. Int J Infect Dis 2009; 13: 493-8.
• 34. Bührer-Sékula S, Cunha MGS, Foss NT, Oskam L, Faber WR, Klatser PR. Dipstick assay to identify leprosy patients who have an increased risk of relapse. Trop Med Int Health 2001; 6(4): 317-23.
• 35. Katoch VM, Lavania M, Chauhan DS, Sharma R, Katochi K. Recent advances in molecular biology of leprosy. Indian J Lepr 2007; 79(2-3): 151-66.
• 36. Bhatia AS, Katoch K, Narayanan RB, Ramu G, Mukherjee A, Lavania RK. Clinical and histopathological correlation in the classification of leprosy. Intl J Lepr Other Mycobact Dis 1993; 61: 433-8.
• 37. Gonçalves SD, Sampaio RF, Antunes CMF. Fatores preditivos de incapacidades em pacientes com hanseníase. Rev Saúde Pública 2009; 43(2): 267-74.

Publication Dates

• Publication in this collection
  18 Oct 2012
• Date of issue
  Sept 2012

History

• Received
  01 Oct 2010
• Accepted
  25 Apr 2012
• Reviewed
  26 Feb 2012