CLINICS 2012;67(10):1145-1148 DOI:10.

6061/clinics/2012(10)05

CLINICAL SCIENCE
Leprosy reactions: coinfections as a possible risk factor
Ana Carolina F. Motta, Karla Juliana Pereira, Daniela Chaves Tarqunio, Mariana Bellini Vieira, Karina
Miyake, Norma Tiraboschi Foss
University of Sao Paulo, Ribeirao Preto Medical School, Division of Dermatology, Departamento de Clnica Medica, Ribeirao Preto/SP, Brazil.

OBJECTIVE: This study aimed to determine the frequency of coinfections in leprosy patients and whether there is a
relationship between the presence of coinfections and the development of leprosy reactional episodes.

METHOD: A cross-sectional study based on an analysis of the medical records of the patients who were treated at
the Leprosy Clinics of the Ribeirao Preto Medical School, University of Sao Paulo, was conducted from 2000 to 2010.
Information was recorded regarding the age, sex, clinical status, WHO classification, treatment, presence of
reactions and coinfections. Focal and systemic infections were diagnosed based on the history, physical
examination, and laboratory tests. Multinomial logistic regression was used to evaluate the associations between
the leprosy reactions and the patients gender, age, WHO classification and coinfections.

RESULTS: Two hundred twenty-five patients were studied. Most of these patients were males (155/225 = 68.8%) of
an average age of 49.3115.92 years, and the most prevalent clinical manifestation was the multibacillary (MB)
form (n = 146), followed by the paucibacillary (PB) form (n = 79). Erythema nodosum leprosum (ENL) was more
prevalent (78/122 = 63.9%) than the reversal reaction (RR) (44/122 = 36.1%), especially in the MB patients (OR 5.07; CI
2.86-8.99; p,0.0001) who exhibited coinfections (OR 2.26; CI 1.56-3.27; p,0.0001). Eighty-eight (88/225 = 39.1%)
patients exhibited coinfections. Oral coinfections were the most prevalent (40/88 = 45.5%), followed by urinary tract
infections (17/88 = 19.3%), sinusopathy (6/88 = 6.8%), hepatitis C (6/88 = 6.8%), and hepatitis B (6/88 = 6.8%).

CONCLUSIONS: Coinfections may be involved in the development and maintenance of leprosy reactions.

KEYWORDS: Leprosy Reaction; Mycobacterium leprae; Oral Infection; Coinfection.

Motta AC, Pereira KJ, Tarqunio DC, Vieira MB, Miyake K, Foss NT. Leprosy reactions: coinfections as a possible risk factor. Clinics. 2012;67(10):1145-1148.
Received for publication on March 28, 2012; First review completed on April 16, 2012; Accepted for publication on May 24, 2012
E-mail: anacfm@usp.br
Tel.: 55 16 3633-0236

INTRODUCTION Because both types of reactions are accompanied by an

increased release of inflammatory markers (5,6), it is
Leprosy reactional episodes (REs) are serious complica- possible that these episodes might be associated with
tions of leprosy because these reactions are most likely the infectious processes, such as systemic viral infections,
predominant cause of permanent nerve damage, leading to urinary tract infections or oral infections. These coinfections
disability and deformities (1). There is an urgent need to can over-stimulate the host immune system through the
understand the pathogenesis of these alterations to deter- release of numerous inflammatory markers, including
mine which patients may be considered to be at risk. These cytokines, acute-phase proteins and chemokines (7-9).
episodes represent an exacerbation of the inflammatory The follow-up of leprosy patients is often interrupted by
process that can occur before, during and after treatment for recurrent leprosy REs that interfere with the course of the
leprosy (2,3). There are two well-recognized types of disease; therefore, it is important to evaluate the role of
reactions: the reversal reaction (RR) and erythema nodosum coexistent factors in each patient that could be related to the
leprosum (ENL). RRs may be caused by an increase in the exacerbation of the M. leprae infection. To this end, the
cell-mediated Th1 response to Mycobacterium leprae. ENL is a present study aimed to determine the clinicopathological
systemic inflammatory process with the clinical manifesta- profiles of leprosy patients based on the occurrence of
tions of an acute inflammatory reaction; this reaction is leprosy REs and to evaluate whether the presence of these
characterized by intralesional neutrophilic infiltrations and reactions could be associated with coinfections.
a Th2 response (3,4).
METHODS
Copyright ! 2012 CLINICS This is an Open Access article distributed under Subjects
the terms of the Creative Commons Attribution Non-Commercial License (http://
creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-
The present investigation was a cross-sectional study
commercial use, distribution, and reproduction in any medium, provided the of leprosy patients medical records, conducted at the
original work is properly cited. University Hospital of the Ribeirao Preto Medical School
No potential conflict of interest was reported. from 2000 to 2010. All of the patients who were treated at

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Motta AC et al.

the Leprosy Clinics and whose diagnoses were based on the Table 1 - The number (n) and row percentages (%) of the
Ridley and Jopling classification criteria (1966) (10) were demographic and clinical data from the leprosy patients
included in the study. The following clinical data were managed at the Leprosy Clinics of the Ribeirao Preto
considered: age at diagnosis, gender, clinical form of Clinical Hospital at the Medical School of Sao Paulo
leprosy, World Health Organization (WHO) classification, University, calendar period 2000-2010.
REs, multidrug therapy (MDT) and coinfections confirmed
by clinical and laboratory examinations. Subjects were Variables Patients
excluded if they had not concluded treatment or if they n %
were pregnant or breastfeeding. The study was approved by
the Ethics Committee of the University Hospital, Ribeirao Gender
Preto Medical School, University of Sao Paulo, Brazil. Male 155 68.9
Female 70 31.1
Age (years)
Study design #30 27 12.0
The clinical forms of leprosy were characterized as 31-45 62 27.5
indeterminate (I), tuberculoid (TT), borderline tuberculoid 46-60 79 35.1
.60 57 25.3
(BT), borderline (BB), borderline lepromatous (BL), and
WHO classification
lepromatous leprosy (LL); the leprosy reactions were PB 79 35.1
characterized as RRs or ENL. The frequencies of the clinical MB 146 64.9
forms and REs were correlated with the frequency of Leprosy evolution
coinfections. The diagnosis of leprosy REs was based on the ,6 months 71 31.5
presence of erythema and/or the infiltration of the previous 612 months 65 28.8
.12 months 89 39.5
lesions; new erythematous or hypochromic lesions; nerve Leprosy treatment - MDT
thickening; edema of the hands, feet or face and/or diffuse 6 months 35 15.5
cutaneous hyperesthesia (for RRs); and the presence of 12 months 115 51.1
erythematous nodules, with or without systemic symptoms .12 months 65 28.8
such as fever, asthenia, nerve thickening and pain, myalgia Reactional episodes
Erythema nodosum 78 34.6
and lymphadenitis (for ENL).
Reverse reaction 44 19.6
No reaction 103 45.7
Statistical analysis Reactional episodes evolution*
The odds ratio obtained by multinomial logistic regres- Before MDT 49 40.1
During MDT 63 51.6
sion was used to evaluate the associations between the
After MDT 49 40.1
leprosy reactions and the gender, age, WHO classifica- Coinfections
tion and coinfections. The statistical significance of these Yes 88 39.1
associations was evaluated by the chi-square (x2) test. The No 137 60.9
level of significance was set at 5% in all of the analyses,
MDT: multidrug therapy; *Thirty-nine patients presented more than one
which were performed using the Statistical Analysis System reactional episode: 1 before and after MDT, 1 before and during MDT, 35
- SASH 9.0 software (San Diego, Cary, NC, USA). during and after MDT, and 2 before, during and after MDT.

RESULTS 122 = 51.6%) presented these reactions during their MDTs

(Table 1).
Subjects
The results of the 225 leprosy cases, which were screened Coinfections
for leprosy reactions and coinfections, are presented in
Eighty-eight patients (88/225 = 39.1%) exhibited coinfec-
Tables 1 and 2. Of the 225 patients, 155 (68.8%) were male,
tions, whereas 137 (137/225 = 60.9%) were free of coinfections
and 70 (31.1%) were female. The mean age of the patients
(Table 2). The most prevalent coinfections were chronic oral
was 49.3115.92 years (range: 4-89). Regarding the clinical infections (40/88 = 45.5%), followed by urinary tract infec-
forms, 5.7% (13/225) of the patients exhibited I leprosy, tions (UTIs) (17/88 = 19.3%), sinusopathy (6/88 = 6.8%),
9.3% (21/225) exhibited TT, 20% (45/225) exhibited BT, hepatitis C (6/88 = 6.8%), hepatitis B (6/88 = 6.8%), and
10.6% (24/225) exhibited BB, 20.4% (46/225) exhibited BL, intestinal parasitosis (5/88 = 5.7%). The other infections (8/
and 33.7% (76/225) exhibited LL. Regarding the operational 88 = 9.1%) included pneumonia, oropharyngeal infections,
forms, 35.1% (79/225) were PB patients, and 64.9% (146/ syphilis, leishmaniasis, tuberculosis, and staphylococcus
225) were MB patients (Table 1). infections.

Reactional episodes
DISCUSSION
One-hundred twenty-two (122/225 = 54.2%) patients
exhibited REs, 78 (78/122 = 63.9%) presented with ENL, The determination of which patients may be considered
and 44 (44/122 = 36.1%) exhibited RRs. One-hundred three to be at risk of developing leprosy REs has important
(103/225 = 45.8%) patients did not exhibit any REs (Table 2). implications for reducing the morbidity of these inflamma-
ENL was more prevalent in the MB patients (74/78 = 94.9%) tory reactions (11-15). The analysis of our results revealed
(OR 5.07; CI 2.86-8.99; p,0.0001) and in those patients who that 122 (54.2%) patients presented with REs (Table 1), and
exhibited coinfections (47/88 = 53.4%) (OR 2.26; CI 1.56-3.27; most of the cases (98/122 = 80.3%) were associated with MB
p,0.0001). The analysis of the RE evolution based on the patients rather than PB patients (24/122 = 19.7%). Although
MDT revealed that most of the patients with REs (69/ these data are consistent with those from other studies

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Motta AC et al.

Table 2 - A comparison of the number (n) and percentages (%) of reactional episodes (RE) by gender, age and the
presence of infections among the leprosy patients managed at the Leprosy Clinics of the Ribeirao Preto Clinical Hospital
in the Medical School of Sao Paulo University, calendar period 2000-2010.
Reversal reaction Erythema nodosum None reaction
Variables (n = 44) (n = 78) (n = 103) p-value*

Gender
Male 28 (63.6) 56 (71.8) 71 (68.9) 0.64
Female 16 (36.4) 22 (28.2) 32 (31.1)
Age (years)
#30 7 (15.9) 7 (9) 13 (12.6) 0.20
31-45 9 (20.4) 28 (36) 25 (24.2)
46-60 12 (27.3) 26 (33.3) 41 (39.8)
.60 16 (36.4) 17 (21.7) 24 (23.4)
WHO classification
PB 20 (45.4) 4 (5.2) 55 (53.4) ,0.0001
MB 24 (54.5) 74 (94.8) 48 (46.6)
Coinfections
Yes 15 (34.1) 47 (60.3) 26 (25.2) ,0.0001
No 29 (65.9) 31 (39.7) 77 (74.8)
*
chi-square test.

(12-14), the results are not typical of a non-endemic region, or immunosuppressive drugs and corticosteroids, and those
such as the area of this present investigation. However, patients who presented with multiple recurrent episodes
these findings can be explained by the fact that the present were excluded from the study.
study was conducted at a referral center that treats patients The analysis of the RE evolution with respect to MDT
with more severe complications, such as leprosy reactions. revealed that most of the patients with REs (69/122 = 51.6%)
Of the two main types of leprosy reactions, ENL is the exhibited these reactions during their MDTs (Table 1). The
most common, with a prevalence of approximately 50% MDT consists of dapsone, rifampicin and clofazimine; based
among leprosy patients (12,14). Most people with ENL have on the bacteriostatic effect of dapsone on M. leprae, this
acute multiple episodes of ENL or chronic ENL over several therapy would be expected to promote moderate bacillary
years. ENL is recurrent, especially in MB patients. These destruction and, consequently, a decreased inflammatory
episodes involve a type 2 immune-mediated reaction that is reaction. However, MDT drugs have different mechanisms
characterized by a peripheral inflammatory reaction (6), and of action, and the bactericidal drug rifampicin (600 mg/
the disease may manifest as fever, arthralgias, myalgias, an month) promotes massive bacillary destruction and the
orexia, and sparse, tender, and erythematous nodules on the release of many antigenic fractions that cause an inflamma-
extensor surfaces of the extremities. Conjunctivitis, neuritis, tory reaction. This reaction, in most cases, is not controlled
synovitis, nephritis, hepatosplenomegaly, orchitis, and by clofazimine (300 mg/month) or by a daily dose of
lymphadenopathy may also occur (16). Our results demon- dapsone (100 mg) and clofazimine (50 mg). These facts
strated that 63.9% (78/122) of the patients with RE had ENL could explain the high proportion of reactions during MDT
(Tables 2 and 3). In addition, a high prevalence of ENL was in the present study.
associated with the MB patients; ENL occurred in 74 (74/ The results of the multinomial analysis, after adjusting
78 = 94.9%) MB patients as opposed to 4 (4/78 = 5.1%) PB for the gender and age group, revealed that the opera-
patients. Subjects exhibiting REs were treated with steroids tional classification and the presence of coinfections were

Table 3 - Multinomial logistic regression model of the risk factors for reactional episodes (reference = no reaction) by the
gender, age, WHO classification, and presence of coinfections in the leprosy patients managed at the Leprosy Clinics of
the Ribeirao Preto Clinical Hospital in the Medical School of Sao Paulo University, calendar period 2000-2010. Odds ratio
(OR), 95% confidence interval (95% CI) and p-value.

Variables Reversal reaction vs. None Erythema nodosum vs. None

OR 95% CI p-value OR 95% CI p-value

Gender
Male vs. Female 0.81 0.55-1.20 0.29 0.80 0.53-1.20 0.29
Age (years)
#30{ 1.0 - - - - -
31-45 0.80 0.41-1.55 0.51 1.61 0.87-2.97 0.13
46-60 0.66 0.36-1.19 0.16 0.89 0.50-1.59 0.70
.60 1.47 0.81-2.66 0.20 0.85 0.45-1.61 0.62
WHO classification
MB vs. PB 1.21 0.83-1.76 0.32 5.07 2.86-8.99 ,0.0001
Coinfections
Yes vs. No 1.26 0.85-1.86 0.25 2.26 1.56-3.27 ,0.0001
{
relationship used as reference for comparison between the other variables.

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Motta AC et al.

significantly associated with ENL (OR 2.26; CI 1.56-3.27; ACKNOWLEDGMENTS

p,0.0001) (Table 3). Bacterial loads, clinical forms, MDTs,
The study was funded by the Foundation of Support to Teaching,
and coinfections have been indicated as inducers or
Research and Assistance of the HCFMRP-USP (FAEPA).
maintainers of the pathogenesis of these disorders (9,14-
17). Based on the particular underlying immunological
pattern of leprosy, the development and/or maintenance of AUTHOR CONTRIBUTIONS
these episodes might be associated with an infectious Motta AC and Foss NT conceived and designed the study, analyzed the
process. Therefore, leprosy patients would possess immu- data, and wrote the paper. Motta AC, Pereira KJ, Tarqunio DC, Vieira
nological characteristics that would impair the clearance of MB, and Miyake K conducted the study.
certain viruses, such as the hepatitis B virus (HBV) and
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