INTERNATIONAL JOURNAL OF LEPROSY^ Volume 62, Number 4

Printed in the U.S.A.

Epidemiologic Characteristics of Leprosy Reactions'David M. Scollard, Trevor Smith, Lertlakana Bhoopat,

Choti Theetranont, Samreung Rangdaeng, andDavid M. Morens 2

Leprosy reactions are acute emergenciesin the otherwise generally indolent courseof human infection with Mycobacteriumleprae, and account for substantial morbid-ity, hospitalization, and difficulty in clinicalmanagement of leprosy ( 2, 22, 24 ) . Two typesof reaction are clinically differentiated: type1 reactions, often called "reversal reac-tions" (RR), appear as exacerbations of pre-existing lesions, and arc accompanied bysystemic symptoms; type 2 reactions, oth-erwise known as erythema nodosum lepro-sum (ENL), are characterized by the suddenappearance of crops of tender, erythema-tous nodules in areas of the body that hadnot necessarily been involved previously(I I. 16) .

Although leprosy reactions have been thesubject of several clinical and laboratory in-

9, 12 , 14 , 22 , ,vestigations ( 21 ) their etiologies areunknown and their pathogenesis poorly un-derstood. Several studies indicate that type1 reactions are associated with activation ofthe cellular immune system (I. 27, 30, 343 ,) butthe stimulus for this activation is not known.Type 2 reactions are generally consideredto be immune complex phenomena ( 32 ), al-though much evidence suggests that circu-lating complexes are not responsible (Is. 29 )and available data are consistent with butdo not convincingly implicate tissue-de-rived complexes ( 4 . 20 ).

To learn more about the epidemiology ofleprosy reactions, we therefore examined

' Received for publication on 30 December 1993;accepted for publication in revised form on 10 August1994.

= D. M. Scollard, M.D., Ph.D., Laboratory ResearchBranch, GWL Hansen's Disease Center at LouisianaState University, P. 0. Box 25072, Baton Rouge, LA70894, U.S.A. T. Smith, M.B.B.S., McKean Rehabil-itation Institute, Chiang Mai, Thailand. L. Bhoopat,M.D.; C. Theetranont, M.D.; S. Rangdaeng, M.D., De-partment of Pathology, Faculty of Medicine, ChiangMai University, Chiang Mai, Thailand. D. M. Morons,M.D., Schools of Medicine and Public Health, Uni-versity of Hawaii at Manoa, Honolulu, Hawaii, U.S.A.

their occurrence in a longitudinal, prospec-tive study of newly diagnosed leprosy pa-tients. We sought particularly to determinewhether temporal variables in the earlycourse of the disease (including age of onset,duration of illness prior to reaction, age offirst reaction, etc.) were associated with arisk of either reaction.

MATERIALS AND METHODSStudy subjects were enrolled from those

patients presenting for initial diagnosis atthe clinics of the McKean RehabilitationInstitute, Chiang Mai, Thailand. Patientswho had been previously diagnosed andtreated at other facilities were excluded; allnewly diagnosed patients were consideredeligible for study except those occasionalpatients from "hill tribes," for whom nosuitable translators were available or wholived at great distances and could not besuitably followed. Patients with reactions atthe time of diagnosis were included in thestudy. Otherwise, the outcome endpoint wasconsidered to be the first type 1 or type 2reaction experienced by each patient.

Enrollment began in the fall of 1984 andcontinued until the fall of 1989. Follow-upcontinued through fall 1992, so that eachpatient was followed a minimum of 3 years.

Initial histories by both the research teamand the attending physicians documentedthe patient's year of birth and age at onsetof first leprosy symptoms. A representativelesion was biopsied in each patient; eachwas classified as to clinical category of lep-rosy, according to the five-part scale of Rid-ley and Jopling ( 19), based on clinical andhistologic criteria.

All patients were given standard multipledrug therapy (MDT): 100 mg dapsone daily,100 mg clofazimine every other day, and1.2 g of rifampin monthly in two consecu-tive doses (if multibacillary), or dapsone andrifampin (if paucibacillary). Treatment wasusually continued until patients were skin-

559

• " A...SWAM a% 4

560^ International Journal of Leprosy^ 1994

Female^

Male

50^411^30^20^10^0^

10^20^

30^

40^

50

Number of PatientsChitong N1.11 Study Cohort, 1484-1502

FiG. I . Distribution of reactions among leprosy pa-tients. The distribution of incident, medically observedreactions is indicated in the cohort of I7(1 new patientsaccording to sex and leprosy classification I IN = inde-terminate). Ii = All patients of each classification inthe cohort: 0 type I reaction: l -= type 2 reaction.

smear negative for multibacillary (MB) pa-tients, and for at least 6 months for pauci-bacillary (P13) patients. Patients were seenat regular intervals, usually every 1 or 2months, and were encouraged to come tothe clinic or hospital if they experiencedworsening of local or systemic symptoms.

All reactions documented in this studywere severe enough to warrant hospital ad-mission. An attempt was made to biopsyall reaction lesions. However, due to thedifferent durations of reactions before di-agnostic presentation and the lack of uni-form criteria for histologic diagnosis, diag-nosis of reactions was ultimately based onthe clinical appearance of characteristic le-sions of type 1 or type 2 reactions. Type 1reactions were diagnosed when existing bor-derline lesions became inflamed, i.e., ery-thematous, swollen or raised, and tender,

combined with pain and/or tenderness ofinvolved peripheral nerves. The degree ofsystematic involvement varied, but mosthad low-grade fever with or without mal-aise. In patients who originally presentedwithout type 1 reactions, these findings rep-resented definite changes from the patient'sprevious status. Type 2 reactions were di-agnosed when small, inflammatory, red,swollen and highly tender nodules devel-oped suddenly in the skin or subcutis, ac-companied by fever and malaise. Most ofthese patients also had a mild leukocytosisand acute neuritis, with one or more of thefollowing: arthritis, orchitis, iritis, myalgia,and peripheral edema.

Patients with reactions were given stan-dard treatment with corticosteroids and/orthalidomide as considered appropriate inindividual cases by the attending physi-cians, and their MDT regimen for leprosywas not interrupted. All medication, as wellas the progression and regression of signsand symptoms, were charted on flow sheetsespecially designed for the study. Immu-nologic studies of reactions in the patientsreported here have been published previ-ousl y (3, 17, 26, 27) .

Statistical comparisons of proportionswere made using the two-tailed chi-squaredtest with Yates' correction for continuity.

RESULTSA total of 176 patients were prospectively

enrolled in the study between 1984 and1989. The distribution of patients by clas-sification of leprosy was as follows: 55 LL,64 BL, 16 BB, 31 BT, 9 TT, and 1 indeter-minate. When this distribution was furthercategorized by sex (Fig. 1), the preponder-

BI,

BB

BT

TT

IN

TABLE 1. Frequency of occurrence of reactions in leprosy.a

Reaction typeLL 13L 1313 BT All

class.M F Total M F Total M F Total M F Total

Type I (RR) 0 0 0 16 I0 26 2 3 5 3 1 4 35At risk 46 18 64 I0 6 16 25 6 31 111Frequency (%) 35, 56 41 20 50 31 12 17 13 32%

Type 2 (ENL) 23 6 29 11 4 15 0 0 0 0 0 0 44At risk 42 12 54 46 18 64 118Frequency (%) 55 50 54 24 22 23 37%

Data regarding type 1 (RR) and type 2 (ENL) reactions are presented according to clinical category of leprosyand sex of the patients from a cohort of 174 new patients seen at McKean Rehabilitation Institute, Chiang Mai,Thailand, from 1984-1989 and followed for a minimum of 3 years. No reactions were seen in 1 indeterminateor 9 TT patients.

62, 4^ Scollard, et al.: Leprosy Reactions^ 561

TABLE 2. Occurrence of type I (RR) reactions in males and females, by age at onset ofleprosy.

Decade ofonset ofleprosy

Totalmalesat risk

Totalmales

affected

% Malesaffected

Totalfemalesat risk

Total % Females Total no. Total no.females affected^at risk^affectedaffectedTotal °/oaffected

1 4 2 50 1 0 — 5 2 402 15 3 20 6 2 33 21 5 243 23 4 17 6 4 67 29 8 284 17 5 29 4 I 25 21 6 295 7 3 43 6 3 50 13 6 466+ 15 4 27 7 4 57 22 8 36

Total 81 21 26 30 14 47 111 35 32

ance of males and of MB patients is evident,as previously documented in this popula-tion. One patient in our cohort, a 28-year-old male with LL disease, died soon afterdiagnosis of an apparent dapsonc reaction,and he is not included in the calculations ofthe incidence of leprosy reactions since theduration of follow up was only a few months.None of the remaining 175 patients was lostto follow up during the study.

The study cohort equalled 45% (176) ofthe 388 new, untreated patients registeredat McKean during the study interval, in-cluding 79% of 171 MB (LL-BB) patientsand 32% of 97 BT patients. Twenty-threeof the new patients at McKean were inde-terminate, of whom one was enrolled in ourstudy. This sample thus may underestimatereactions in BT patients, but approximatesthe total population of new MB patients inthis population, whose greater acceptanceof a brief hospital admission (for relatedimmunologic studies) may have led to in-creased enrollment. Despite the differentproportions of study volunteers in eachgroup, a review of medical records of par-

TABLE 3. Frequency of occurrence of type2 (ENL) reactions by age at onset of leprosy.

Decade of onsetof leprosy

No.affected

Totalat risk

Affectedper onsetdecade

1 0 3 012 17 71

3 12 36 334 12 24 505 5 16 316 3 13 23

>6 0 9 0Total 44 118 37

ticipating and non-participating patients ineach clinical group revealed no differencesin age, gender, occupation, area of resi-dence, or severity of leprosy, except for pa-tients excluded because of inaccessibility tofollow up.

Of the 175 patients followed, 79 (45%)developed one or more reaction; 35 devel-oped type 1 reactions and 44 developed type2 reactions. Two patients developed bothtype 1 and type 2 reactions. Two additionalpatients who developed severe neuritis notassociated with typical reaction skin lesionswere excluded from analysis because the ba-sis for their neuritis could not be clearlydetermined.

The incidence of reactions in this cohortof new patients, unadjusted for duration offollow up, indicates the association of type1 reactions with borderline patients, and of

20

S 15

toLri

:

09-14^15-19^20-29^30-39^40-49^50-59^>59

Age at Onset of Leprosy

FIG. 2. Mean duration of leprosy before diagnosisand treatment (MDT). The duration of leprosy (in years)was determined by careful history at the time of di-agnosis; MDT was initiated at diagnosis. Dates areshown according to age at onset of leprosy. patients who developed ENL; --- = patients who didnot develop ENL. The two curves are not statisticallydifferent.

562^ International Journal of Leprosy^ 1994

TABLE 4. Incidence of type 2 (ENL) reactions, by age of leprosy onset and duration ofleprosy before and after initiation of treatment, per 100 person-years.

Age at leprosyonset No.

Person-^No.^Inci-^Person-^No.^Inci-years ENL dence years type 2 dence

leprosy cases of type 2 followed reaction type 2pre-Rx' pre-Rxh pre-Rx post-Rxc post-Rx post-Rx

Totalperson- Totalyears type 2

followed

Totalinci-

dencetype

2/100person-years

9-14 8 103 0 41.1 1 2.4 144.1 1 0.715-19 12 51 4 7.8 58.7 7 11.9 109.7 11 10.0

Total, 9-19 20 154 4 2.6 98.8 8 8.1 253.8 12 4.7

20-29 36 160 3 1.9 165.0 9 5.5 325.0 12 3.730-39 24 97 7 7.2 132.1 5 3.8 229.1 12 5.240-49 16 37 0 78.3 5 6.4 110.3 5 4.550+ 22 43 0 119.8 3 2.5 162.8 3 1.8

Total, 20+ 98 337 10 3.0 490.2 22 4.5 827.2 32 3.9

Person-years of leprosy pretreatment is defined as the number of individuals multiplied by the number ofyears during which they had leprosy before treatment.

h Type 2 reaction pretreatment refers to observed reactions in patients at the first presentation to the clinic,i.e., those who had a reaction before they received treatment.

Post-Rx refers to the time after initiation of treatment." Number of patients with at least one type 2 reaction.

type 2 reactions with LL and I3L patients(Table 1). Thirty-two percent of patients atrisk for type 1 reactions (i.e., borderline pa-tients, BL-BB-BT) developed this reaction,and 37% of patients at risk for type 2 re-actions (i.e., MB patients, LL and BL) de-veloped this reaction.

Also noteworthy is the greater risk fortype 1 reactions in female patients, 47% vs26% overall, which appears independent ofclinical category (Table 1). Analysis of thefrequency of type 1 reactions by age at onsetof leprosy shows that the increased occur-rence is seen in women with onset ofleprosyat all ages (Table 2). These findings were notconfounded by duration of leprosy prior todiagnosis (data not shown).

The development of type 2 reactions ap-pears to be predicted by the age of onset ofleprosy rather than by patient age at the timeof the reaction (Table 3). Unadjusted forduration of follow up, patients whose firstsymptom occurred during adolescence hada much greater frequency (71%) of experi-encing a type 2 reaction than patients whoseonset of leprosy occurred after adolescence(p

62, 4^ Scollard, et al.: Leprosy Reactions^ 563

no evidence that treatment either protectsor precipitates type 2 reactions in patientsat risk.

Recurrence of type 1 and type 2 reactionsfollowed different patterns. The majority ofpatients (34/44) with type 2 reactions hadmultiple episodes of reaction, while only aminority of patients (11/25) with type 1 re-actions had multiple episodes (Table 5). Thisdifference was statistically significant (p

564^ International Journal of Leprosy^ 1994

mative if interpreted in the light of a pos-sible endocrine influence on either systemicor dermal immune mechanisms ( 2 '). An-other possibility is that the mechanisms in-volved in type 1 reactions may share somecommon determinants with other autoim-mune phenomena to which women are pre-disposed ( 31 ).

The observation that type 1 reactions typ-ically occur only once (or a very few times)suggests that in each individual only a lim-ited degree of "adjustment" in the immuneresponse to M. leprae can take place. If so,the permissible range of such change mightbe determined or limited by genetic or im-munologic factors which can be examinedin future studies.

The most interesting observation con-cerning type 2 reactions in this study is theapparently increased frequency of these re-actions in individuals whose onset of lep-rosy symptoms occur before adulthood.Other studies have noted that type 2 reac-tions are more often seen in patients be-tween 20 and 40 years old ( 6 ' 25 ), but theassociation with onset of leprosy in adoles-cence previously has not been noted. Anyhypothesis to explain this observation mustaccount for the fact that type 2 reactionsoccur after a variable duration of 4 monthsto 3 or more years after the onset of leprosy.If the later occurrence of type 2 reactions isrelated to onset during adolescence, the ini-tiating events must take a long and variabletime to become manifest.

Davey and Schenk ( 7 ) long ago cited stud-ies noting that puberty is associated withincreased risk of relapse of leprosy and ofthe development of lepromin sensitivity.The association of puberty with increasedsusceptibility to and mortality from tuber-culosis is also well documented ("), as isthe increase in the incidence of systemiclupus erythematosus in the decade follow-ing puberty ( 3 '). These clinical and epide-miologic phenomena remain unexplained.Neuroendocrine-immune interactions haverecently attracted interest ( 8 . 2 '), as have theirpossible effects on immunity to mycobac-teria (33 ), and the effects of infection-in-duced cytokines on neuroendocrine func-tion (23, 28, 33 , .) The possible role(s) of thechanges at puberty have not received asmuch attention, however, as the more ob-

vious mechanisms related to adrenal func-tion.

In addition to the major endocrinechanges that occur in both sexes during pu-berty, this also may be an important phasein the maturation of the immune system.This has not been the subject of substantialresearch, however, and little is known aboutit beyond the oft-repeated maxim that thefunction of the immune system "peaks"around the time of puberty ( 1 "). Our datado not provide a basis to select from anendocrine or an immune-maturation hy-pothesis in explaining the pathogenesis ofENL, but suggest that further studies of ENLshould consider both possibilities.

The characteristics of both type 1 and type2 reactions identified in this study may as-sist in distinguishing between them: type 1reactions occurred predominantly in wom-en who had onset at all ages, and type 2reactions were more common in males andfemales who had leprosy onset in adoles-cence. Future studies of immunologic pa-rameters of these reactions may benefit fromthe stratification of data by sex and age ofonset of leprosy in addition to the routineclassification of results by leprosy classifi-cation.

SUMMARYAn 8-year prospective study of a cohort

of 176 newly diagnosed leprosy patients wasconducted to examine the possible influenceof age, sex, multidrug therapy (MDT), andduration of illness on the risk of either type1 or type 2 reactions. Patients were enrolledover a 5-year period (1984-1989) and fol-lowed for a minimum of 3 years. All reac-tions studied were severe enough to warranthospital admission. Overall, 45% of this co-hort developed a reaction; 32% of patientsconsidered at risk developed type 1 reac-tions, and 37% of patients considered at riskdeveloped type 2 reactions. Despite the pre-dominance of men among the leprosy pa-tients, type 1 reactions occurred with sig-nificantly greater frequency in women, anddid not appear to be influenced by age ofonset of leprosy. Individuals experiencingone type 1 reaction were not likely to ex-perience a recurrence, suggesting that theimmunologic mechanisms of this reaction

62, 4^ Scollard, et al.: Leprosy Reactions^ 565

may be limited or regulated by genetic orimmunologic factors.

Type 2 reactions, on the other hand, oc-curred with equal frequency in both malesand females, but were highly associated withonset of leprosy in the second decade of life.Individuals who experienced type 2 reac-tions often had one or more recurrence ofthe reaction. No increased risk was seen foreither reaction with longer duration of lep-rosy or longer duration of treatment. Themechanisms by which these differences re-late to the pathogenesis of leprosy reactionsremains unclear, but future studies of clin-ical and immunological parameters of lep-rosy reactions may benefit from stratifica-tion of data by gender and age of onset ofleprosy in addition to the routine groupingof results by leprosy classification.

RESUMENSe hizo un estudio prospcctivo en un grupo de 176

pacientes con lepra rccien diagnosticada apra examinar

la influencia de la edad, el sex°, el tratamiento conpoliquimioterapia (PQT) y la duraciOn de Ia enfer-

medad, en el desarrollo de reacciones leprosas de lostipos I 6 2. Los pacicntes se cnrolaron en el estudio alo largo de 5 atios (1984-1989) y se estudiaron duranteun periodo minimo de 3 aims. Todas las rcaccioncs

leprosas estudiadas fucron lo suficientemente severas

como para justificar la hospitalizaciOn de los pacientes.El 45% de los pacientes desarrollaron algUn tipo de

reacciOn; 32% de los pacientcs considerados en riesgo

desarrollaron rcaccioncs del tipo I, y 37%, reaccionesdel tipo 2. No obstantc el predominio de hombres en

el grupo de pacientes, las rcaccioncs de tipo 1 fucron

mas frecuentes entre las mujeres. Las rcaccioncs noestuvieron asociadas con la edad de apariciOn de Ia

cnfermedad. Los individuos con reacciOn de tipo I nofucron propensos a experimentar rccaidas, sugiricndo

que los mecanismos inmunolOgicos de esta reacciOn

pueden estar sujetos a regulaciOn por factorcs geneticoso inmunolOgicos.

Por otro lado, las reacciones de tipo 2 ocurricron

con igual frecuencia tanto en hombres como en mu-

jeres, pero fucron inns frecuentes en los casos dondcla enfermedad apareciO en Ia scgunda decada de la vida.

Los individuos que desarrollaron reacciones de tipo 2,

frecuentemente presentaron una o mAs recurrenciasrcaccionales. El riesgo de apariciOn de Ia reacciOn Ic-prosa no cstuvo asociado ni con una mayor duraciOnde la enfermedad, ni con un mayor tiempo de trata-

micnto de Ia misma.

Los mecanismos de relaciOn entre las rcaccioncs le-prosas y los parAmetros analizados permanecen obs-

curos, pero los cstudios clinicos c inmunolOgicos de las

reacciones leprosas, podrian, en un futuro, bcneficiarse

si los datos se presentaran en forma estratificada en

funciOn del sexo del paciente y de Ia edad de apariciOnde la enfermedad.

RÉSUMÉ

Une etude prospective d'une duree de 8 ans dune

cohorte de 176 malades de la lepre nouvellemcnt dia-

gnostiques a Le realisee pour etudier l'influence pos-sible de Page, du sexc, de Ia polychimiotherapie (PCT)

et de Ia duree de Ia maladie sur lc risque de developperdes reactions de type I ou de type 2. Les patients ont

etc enroles dans ('etude au cours d'une periode de 5ans (1984-1989) et suivis pour un minimum de 3 ans.

Toutes les reactions etudiees &talent suffisamment se-vexes pour meriter l'hospitalisation. Au total, 45% des

patients de cette cohorte ont developpe unc reaction;32°h des patients consideres a risque ont devcloppe

unc reaction de type 1 et 37% des patients consideres

A risque une reaction de type 2. En &pit de la pre-

dominance masculine parmi les malades de la lepre,les reactions de type 1 sont apparues avec une frê-

quence significativement plus elevec chez les femmes,

et nc paraissaicnt pas etre influencees par l'Age a l'ac-quisition de Ia lepre. Les personnes chez qui survenait

une reaction de type I avaient pcu de risque de pre-senter une recidive, ce qui suggere que les mecanismes

immunologiques de cette reaction pcuvent etre limites

ou controlês par des facteurs genetiques ou immuno-logiques.

Les rections de type 2 apparaissaient, quant A elks

avec unc frequence semblable chez les hommes et les

femmes, mais it y avait unc forte relation avec lc de-veloppement de la lepre au cours do la deuxieme de-

cennie de vie. Les personnes qui avaient Cu une reac-tion de type 2 avaient souvent unc ou plusieurs recidivesde la reaction. On n'a pas observe d'augmentation du

risque d'aucun des types de reaction pour une lepre delongue duree ou un traitement de longue duree. Les

mecanismes par lesquels ces differences sont reliCes

la pathogenese des reactions lepreuses reste peu Clair,mais des etudes futures de parametres cliniques et im-

munologiques des reactions lépreuses pourraient be-neficier de Ia stratification des donnOes par sexc et age

A ('acquisition de Ia lepre, en plus du groupement ha-

bitue' des resultats scion le type de lepre.

ACKNOWLEDGMENTWe arc indebted to the nursing and technical staff

of McKean Rehabilitation Institute for their generous

cooperation and excellent patient care, and to the staffof the Research Institute for Health Sciences, ChiangMai University, Chiang Mai, Thailand, for providing

years of technical and administrative support. These

studies were supported by grants from USAID and by

a Research Strengthening Grant from the World Health

Organization.

566^ International Journal of Leprosy^ 1994

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