|Year : 2019 | Volume
| Issue : 1 | Page : 12-24
Leprosy in children
Tarun Narang1, Bhushan Kumar2
1 Department of Dermatology, Venereology and Leprology, PGIMER, Chandigarh, Punjab, India
2 Department of Dermatology, Shalby Multispeciality Hospital, Mohali, Punjab, India
|Date of Web Publication||14-Dec-2018|
Dr. Bhushan Kumar
Shalby Multispeciality Hospital, Mohali, Punjab
Source of Support: None, Conflict of Interest: None
Children are believed to be the most vulnerable group to infection with Mycobacterium leprae due to their immature or nascent immunity and exposure to intrafamilial contacts. The child proportion among newly detected cases of leprosy is a strong indicator of continued transmission of the disease and one of the main targets of the current World Health Organization strategy is “to reduce transmission of the disease and reduction of grade-2 disability among new child cases.” Despite an effective treatment and global achievement of leprosy elimination, the childhood leprosy proportion has not improved significantly. Leprosy in children does not just affect a child's health like other diseases; they can be stigmatized, bullied, and shunned for their lives. Hence, effective planning to bring down the incidence of leprosy and its complications in children should become a top priority. Regular school surveys and annual contact surveys for early detection of cases is therefore an important tool in achieving the goal of elimination of leprosy. In addition to continuing to administer multidrug therapy to patients, new preventive approaches need to be considered to break the chain of transmission and reach zero disease status.
Keywords: Chemoprophylaxis, childhood, disability, immunoprophylaxis, leprosy
|How to cite this article:|
Narang T, Kumar B. Leprosy in children. Indian J Paediatr Dermatol 2019;20:12-24
| Introduction|| |
Leprosy is a chronic mildly infectious disease caused by Mycobacterium leprae. It predominantly effects the skin, mucosa, and nerves. It has been a major public health problem in many developing countries despite the availability of an effective treatment. Leprosy was universally “eliminated as a public health problem” 18 years ago, yet new cases continue to be seen in endemic areas and 9 out of every 100 new cases diagnosed today are children. The current scenario was aptly described by Dr Erwin Cooreman, Team Leader of the World Health Organizations (WHO's) Global Leprosy Programme. “The world has the tools, the right medicines and the political will – yet we are falling short of detecting the disease in time, particularly among children.” Children are believed to be the most vulnerable group to infection with M. leprae due to their immature or nascent immunity and exposure to intrafamilial contacts. Leprosy is a great masquerador and may present as an ill-defined hypopigmented asymptomatic patch on face or arms to diffuse infiltration of the entire skin and neuromuscular symptoms such as sensory loss or muscle weakness. Hence, in areas where leprosy is still prevalent, it should figure in differential diagnoses, not only among the dermatologists but also physicians/neurologists/pediatricians who are involved in medical care of children and adolescents. In the absence of an effective vaccine, early diagnosis and treatment is essential in the prevention of disabilities and deformities, and reduce the physical, psychosocial, and economic burden of the disease.
| Epidemiology|| |
The introduction of the WHO multidrug therapy (MDT) has played a pivotal role in achieving the epidemiological target of “elimination of leprosy as a public health problem.” Elimination was attained at a global level in 2000, whereas India achieved the same in December 2005. Although the WHO MDT has been our main weapon in our fight against leprosy, with more than 16 million treated leprosy cases and a current world prevalence of only 0.25; the annual new case detection rate and the child rate have not decreased significantly suggesting unabated active transmission of the disease. Reports from 150 countries of WHO's six regions show that of the total of 210,671 newly diagnosed cases of leprosy during 2017, 16,979 were children, representing almost 7.5% of all new cases reported annually.
The child proportion among newly detected cases of leprosy is a strong indicator of continued transmission of the disease and a significant pool of undiagnosed cases in the community. Globally, this proportion among total cases has shown a considerable variation within different regions, for example, in Africa, the childhood proportion has ranged from as high as 38.25% in Comoros to as low as 1.12% in Burundi.
According to a recent report by the National Leprosy Elimination Programme, from a total of approximately 135,485 new cases of leprosy in India, 8.7% were among children.
The proportion of child cases was more than 10% of new cases detected in 10 States/UTs, namely Tamil Nadu (17.64%), Maharashtra (10.18%), Bihar (13.70%), Dadar and Nagar Haveli (19.79%), Arunachal Pradesh (10.71%), Punjab (17.25%), Nagaland (11.75%), Daman and Diu (14.29%), and Lakshadweep (11.11%).
The demographic characteristics of the children affected by leprosy have been evaluated in many studies in India either by school surveys or hospital-based studies with contact assessment. A substantial variation in the prevalence rates of childhood leprosy from 4% to 34% has been observed in these studies conducted in different parts of the Indian subcontinent.,,,,, However, this statistical disparity in prevalence could be due to variation in the cutoff upper age limit for childhood case definition (ranging from <14 to <19 years) in different studies [Table 1].
|Table 1: Clinico-epidemiological studies on pediatric leprosy from India|
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The priorities and targets of leprosy control programs are constantly changing with the changing epidemiology of leprosy. One of the main targets of the current WHO strategy is “to reduce transmission of the disease and reduction of grade-2 disability (G2D) among new child cases.” The current G2D rate in children is high, and it might be higher than what the statistics reveal as a number of cases are not reported.
Age and sex distribution
Leprosy is known to occur at all ages ranging from early infancy to old age. Among children, the disease tends to occur with the highest frequency in 5–14 years of age group and up to 6% cases are below 5 years of age. Higher frequency in older children may be due to the long incubation period of leprosy (5–7 years), delay in diagnosis of early lesions and difficulty in assessing the sensory loss in younger children., The youngest patient diagnosed to have leprosy was only 3 weeks old, from Martinique, a small island near West Indies. Brubaker et al. reported 91 infants under 1 year of age diagnosed with leprosy thereby disapproving a mistaken belief that leprosy is exceedingly rare or nonexistent in the very young.
Among children, boys are more commonly affected than girls;, however, this may not represent the true statistics as detection in girls may possibly be lower than boys due to neglect of the female child and greater mobility and increased opportunities for contact in the male child.
Transmission and possible sources of infection in children
One of the most important sources of infection in childhood cases is familial contact with leprosy. The risk of developing leprosy in a person is four times when there is a neighborhood contact. However, this risk increases to nine times when the contact is intrafamilial. Further, the risk gets higher (up to 14 times) if the contact has MB form especially lepromatous disease and when the index case is mother or where the number of patients was more than one. Detection of a case of childhood leprosy may provide an opportunity to detect the index case, usually within the family and sometimes even community. The prevalence of familial contact in childhood leprosy has ranged from 10% to 36% as observed in different studies [Table 1].,,,,,,,,,
The exact mode of transmission of leprosy is still not conclusively proven although infection by nasal droplets and direct contact with skin are believed to be the main routes. Other factors that may influence transmission include genetic susceptibility, extent of exposure, and the environmental conditions. Epidemiological evidence of transplacental transmission of leprosy is also present. The report of a child developing leprosy at the age of 3 weeks is an example where the infection could have been intrauterine. Although M. leprae are known to be present in the breast milk of mothers suffering from lepromatous leprosy (LL), the risk of acquiring leprosy infection in the breastfed infant through the gastrointestinal tract remains uncertain.
Transmission by skin to skin contact between baby and the mother is more likely as compared to ingestion through breast milk. Inoculation leprosy occurs by transmission of M. leprae through the broken skin after trauma is also a distinct possibility in children.
There is evidence indicating possible nonhuman sources such as soil and water, insect vectors and the free-living amoebae (Acanthamoeba spp.) may be the reason for unabated transmission of leprosy.,, Early studies had shown that a large number of bacilli are discharged through washing of mouth, nose-blows, and from skin by lepromatous patients,, and these bacilli are known to remain viable in the environment for 9 days or even longer. The location of lesions on the exposed sites in children suggests the role of contact with surfaces contaminated with M. leprae. However, most of these studies are polymerase chain reaction (PCR)-based studies and although M. leprae may remain viable in the environment for a variable period it may not replicate and infect the people exposed to it hence virulence of these organisms has to be proved by animal studies.
Leprosy is a chronic granulomatous disorder caused by M leprae. Leprosy is mildly infectious which is evident by the fact that the majority of the people (about 90%) do not develop clinical manifestations of leprosy due to their innate immune response or defense mechanism against M leprae. The immunologic response to M. leprae consists of two components: innate and acquired immunity. Innate immunity is determined by genetic factors, including alleles of the PARK2/PACRG gene as well as other genes. In a genome-wide association study of patients in China, variants of genes in the nucleotide-binding oligomerization domain-2-mediated signaling pathway (which regulates the innate immune response) were found to be associated with susceptibility to leprosy. The cells of monocyte/dendritic cell origin are important mediators in immune-pathogenesis of leprosy. Individuals with sufficient exposure and susceptibility to M. leprae may develop a broad range of clinical manifestations, depending on the host's ability to mount an acquired immune response to infection. This cellular immune response appears to be controlled by a number of nonhuman leukocyte antigen genes such as tumor necrosis factor-alpha, interleukin (IL)-10, vitamin D receptor, and PARK2. Although it is difficult to quantify the relative contribution, the genetic factors are important risk factors which control not only the susceptibility to leprosy; they also play an important role in the development of different phenotype of leprosy, reactions, and prognosis.
The clinical manifestations of leprosy depend on the interplay between innate and acquired immune responses involving interactions of the bacterial proteins with immune components of the host. These interactions may either prevent the invasion and infection or promote their growth and development of leprosy. The immune system has evolved primarily to combat infection, but in leprosy, the immune response is responsible for the broad clinical spectrum of the disease and similar to an autoimmune disease, seems to trigger further complications such as nerve damage.
Nutrition and leprosy
Leprosy has long been known as a disease of poverty as most of the countries where leprosy is still endemic are underdeveloped or developing and leprosy itself along with its disabilities and stigma further pushes them toward poverty. Poverty is considered an important risk factor for leprosy susceptibility, although nutritional deficiencies may be the major contributing factor yet the mechanisms underlying this association and other factors still need to be identified. Some studies have shown a positive association between food shortage or food insecurity and leprosy, and it was suggested that impaired host immune response is a result of malnutrition. Improving dietary diversity or nutrition of people living in high-prevalence communities can be tried as one of the measures to control the transmission of leprosy.
Possible outcomes of leprosy infection in children
The course of childhood leprosy is unpredictable. Progression or regression of lesions is common. There may be three possible outcomes when a child is infected with M. leprae; (a) the child does not develop leprosy; (b) early lesions like indeterminate leprosy may appear, which may remain stationary or disappear due to self-healing; and (c) the indeterminate lesion/s may progress to a determinate type. In the absence of a specific marker for susceptibility and immunological status, it is difficult at present to predict the outcomes in contacts.
The phenomenon of self-healing has been reported in earlier studies; however, the observation period was not long enough to establish its permanence, but Lara and Nolasco observed a cohort of sanitarium-born children who showed self-healing lesions for almost 25 years. In about 75% of these children, the healing was sustained even throughout stressful events in their adult life, implying that self-healing leprosy in children is frequent and sustained.
| Classification|| |
A five group clinico-histological classification based on immunological status described by Ridley and Jopling is still the most widely accepted. The revised Indian classification by IAL in 1981 divided leprosy into five broad groups, namely indeterminate, borderline, tuberculoid, lepromatous, and polyneuritic. A simplified classification based on the number of lesions was given by WHO in 1998; up to 5 lesions (paucibacillary [PB]) and 6 or more lesions/with anyone nerve thickened (MB).
Leprosy in children presents predominantly as PB disease. The spectrum of leprosy in children is reported mostly to be tuberculoid (TT), borderline tuberculoid (BT), mid-borderline (BB), and indeterminate forms. Single skin lesion and indeterminate leprosy were seen to be a common early presentation in most of the studies. BT leprosy is the most common clinical type with the prevalence ranging from 42% to 78% of all childhood cases in different studies [Table 1].,,,,,,, LL can be seen in advanced cases but seems to be rare during the first few years of life. Histoid leprosy and pure neuritic leprosy are rare in children.
Clinical presentation and disease spectrum in childhood leprosy
The data on clinical presentation and disease spectrum in childhood leprosy are mostly derived from hospital-based studies [Table 1]. The most common presentation in these studies is a single hypopigmented patch predominantly on the exposed body parts with normal or impaired sensations.,,,,,,,, However, few studies have also reported low rate of single skin lesions.,, The clinical presentation in the form of bilateral and symmetrical ill-defined macular hypoesthetic lesions, diffuse infiltration of the face and earlobes, are less commonly observed because of the rarity of BB, BL, and LL disease in children. Neuromuscular symptoms like trophic ulcers due to sensory loss or muscle weakness are occasionally the first to be observed. Higher rates of thickened nerves (60%–80%) have also been observed in some of the studies.,,, Rarely children with LL may present with a history of chronic nasal discharge instead of epistaxis due to chronic rhinitis and nasal congestion. [Table 2] gives a list of common differential diagnosis in childhood cases of leprosy.
Indeterminate leprosy (IL) is an early and transitory stage of leprosy characterized by one or more hypopigmented macules. Indeterminate leprosy may evolve over a period of 2–5 years and may spontaneously resolve or establish into one of the subtypes in the spectrum of leprosy. Towards the end of indeterminate stage, there may be signs of subtle neurological deficits such as decreased sweating and/or a loss of thermosensitivity, whereas pain sensitivity is still intact. It usually presents with macular lesions with fairly well-defined edges and slight or no sensory loss, usually over the covered areas of the body [Figure 1]. This clinical ambiguity in the diagnosis of IL [Table 2] is further compounded by negative slit skin smears (SSS) for acid-fast bacillus (AFB) and the nonspecific histology which reveals chronic inflammation with the predominance of lymphohistiocytic infiltrate in the perineural, intraneural, and periadnexal areas. Molecular diagnostic tests like multiplex PCR can help in the diagnosis of IL with limited clinical manifestations. However, one has to be very careful while giving a diagnostic label of leprosy in a child for obvious psychological trauma and social stigma.
|Figure 1: Indeterminate leprosy. Solitary hypopigmented, ill-defined lesion on the face of a child|
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Nodular leprosy of childhood
Nodular leprosy (NL) of childhood is a benign clinical variant of tuberculoid leprosy. The lesions are usually localized on cheeks, limbs, and buttocks [Figure 2] and may result from the intimate skin contact with parents or relatives who have LL. On histopathology, NL lesions are characterized by dense granulomas with a greater number of confluent tubercles in comparison to the classical tuberculoid lesions. Strong stimulation of cell-mediated immunity against M. leprae evoked by the inoculation of bacilli into the skin has been thought to be responsible for the stability and auto-resolution of NL of childhood.
|Figure 2: Nodular leprosy of childhood. Nodular lesion on the cheeks of a girl|
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Tuberculoid (TT), borderline, and lepromatous leprosy
TT disease and LL disease represent the two ends of the leprosy spectrum which is associated with good and poor immunity against M. leprae, respectively. Between these two ends lies the unstable group designated as borderline leprosy.
Good immunity: Tuberculoid or paucibacillary leprosy (TT)
Polar tuberculoid form of leprosy is characterized by solitary papules and plaques which may coalesce into sharply demarcated erythematous or skin colored plaques with raised borders and an annular appearance in an asymmetrical distribution. Neurological examination reveals anesthesia or decrease in thermal, touch, and pain sensitivity as well as anhidrosis usually in the center of the lesion. The lesions of TT can undergo spontaneous resolution.
Poor immunity: Lepromatous leprosy
The LL form initially appears as hypochromic, diffuse, and symmetric lesions which eventually involve the entire skin and the skin appears erythematous or reddish brown, shiny and later on infiltrated with papules or nodules [Figure 3]. The characteristic features of LL are diffuse infiltration of the face, loss of the lateral third of the eyebrow (madarosis); and infiltration of the earlobes [Figure 4]. The sensory loss or NFI is symmetrical and observed late in MB spectrum as compared to the PB spectrum; the temperature, pain and touch sensitivity is lost in that order. It is a systemic disease involving internal organs, such as the eyes, larynx, pharynx, liver, spleen, suprarenal glands, kidneys, bone marrow, and lymph nodes due to the lack of cellular immune response or specific anergy to M. leprae. SSS is strongly positive with live, regular staining AFBs [Figure 5], and the histopathology reveals diffuse macrophage infiltration in the dermis; cytoplasm of many of these macrophages is loaded with bacilli or globi with large quantities of lipids, which on staining give the appearance of foam cells (Virchow cells). The infiltrate is separated from the epidermis by collagenous fiber bands (Unna band) giving the appearance of subepidermal clear zone.
|Figure 5: Slit skin smear showing multiple uniformly staining, slender bacilli in a case of lepromatous leprosy|
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Intermediate stage: Borderline leprosy or dimorphic leprosy
Borderline leprosy is an immunologically unstable form, as it presents clinical, bacteriological, and histopathological characteristics, which can shift either toward the TT pole (borderline tuberculoid; BT), or the LL spectrum (borderline-borderline, BB or borderline-lepromatous, BL).
Lesions in BL often begin as multiple, small, nearly symmetrically distributed hypopigmented to coppery-hued macules that have indistinct borders that merge into the intervening normal skin. Sometimes, these lesions coalesce to form bigger patches which tend to be distributed symmetrically. A decrease in appendages and sweating, which are features of the disease in the BT and TT spectrums, are not prominently seen in BL. With time as the disease downgrades toward lepromatous pole, the macules become infiltrated beginning from the center and forming plaques and nodules [Figure 6]. BB is the most immunologically unstable portion of the borderline spectrum. Patients quickly move either toward the lepromatous or the tuberculoid poles. Lesions characteristic of both the tuberculoid and lepromatous types, are seen in this part of the spectrum. Skin lesions, which are in the form of infiltrated papules, plaques, and even nodules at times, tend to be symmetric. The characteristic lesion of BB leprosy is an annular plaque with a well-demarcated “punched-out” inner margin and a sloping outer margin, giving a “swiss cheese” appearance [Figure 7]. Lesions in BT often resemble those in TT, but are more numerous, larger in size, and less well defined. Unlike TT, where the outer margin is well defined, lesions in BT have an outer margin that at places slopes toward the surrounding skin. BT lesions are characterized by “finger-like” extensions, known as pseudopodia [Figure 8]. There may be small satellite lesions surrounding the plaque. The lesions are often dry, scaly, hypoesthetic plaques with loss of appendages, and decreased sweating; but not as marked as seen in lesions of TT. The nerves are asymmetrically and irregularly thickened in BT leprosy. The patient may present with localized anesthesia and motor deficits.
|Figure 6: Multiple erythematous infiltrated plaques on the face in a child with BL disease|
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|Figure 7: Mid borderline leprosy, annular plaque with a well-demarcated “punched-out” inner margin and a sloping outer margin, giving a “swiss cheese” appearance|
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|Figure 8: Well defined plaque of borderline tuberculoid leprosy with pseudopodia and satellite lesion|
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Musculoskeletal manifestations, such as arthralgia, arthritis, and myalgia, are known to occur as a part of reactions, however, chronic polyarthritis, asymmetric polyarthritis with predominantly rheumatoid distribution can occur in the absence of reaction due to direct synovial infiltration by M. leprae. It is erosive, deforming, and responds poorly to anti-leprosy treatment. Neder et al. and Chopra reported musculoskeletal manifestations such as asymmetric polyarthritis of the joints of the hands as a manifestation in 14% of the examined children.,, Aberrant immunological response in leprosy leads to the production of numerous autoantibodies such as RA, ANA, and ANCA and this may create diagnostic dilemma in patient of chronic polyarthritis, raising the possibility of co-occurrence of juvenile rheumatoid arthritis, and lupus erythematosus. However, anti-cyclic citrullinated peptide (anti-CCP) is less likely to be found positive in leprosy arthritis cases.
Leprosy reactions are acute/subacute inflammatory processes, mediated by T lymphocytes or by antibodies, which are present before, during, and after treatment. The triggering or precipitating factors can be MDT, infections, parasite infestations, vaccinations, physical or emotional stress and should always be addressed while managing the reactions. Lepra reactions are subdivided into type 1 reactions, which results from spontaneous enhancement of cellular immunity and delayed-type hypersensitivity to M. leprae antigens, and type 2 reactions or erythema nodosum leprosum, mediated by immune complexes and proinflammatory cytokines. In childhood leprosy, reactional episodes and disabilities are less frequently seen. The frequency of reactions in children is reported to vary from 3.1% to 33.9%,,,,,,, as compared to adults where more than 50% of the patients develop reactions. Older children and children with borderline disease are at higher risk for reactions., Higher incidence of reactional episodes, both type 1 and 2 occurring with or without neuritis in children has also been observed, mostly in hospital-based studies., Severe reactions are accompanied by fever, malaise, anorexia, swelling of the face and extremities, and neuritis. Rarely, the only manifestation of a reaction can be isolated neuritis, which presents as spontaneous pain, nerve tenderness, and NFI. Lepra reactions are the main causes of neural damage and deformities and should be identified and treated urgently as well as adequately to prevent disabilities.
Deformities and disability
Children with irreversible deformity and disability face many difficulties in education, social life, and day-to-day activities, which differ to some extent from their adult counterparts. The prevalence of deformities associated with childhood leprosy in India varies from 0.5% to 40.7% [Table 1]. One of the targets of the Global Leprosy Strategy is Zero new child cases with G2D. According to the WHO weekly epidemiological report 2017, this indicator was reported by 120 countries, of which 88 reported 0 cases, and 27 reported, 1–10 and five countries reported more cases. Majority of these deformities involve upper limbs. Various factors responsible for increased risk of deformities in childhood leprosy have been identified. The presence of neuritis at presentation or later on, older children, MB disease (smear positivity, multiple skin lesions, and multiple nerve involvement) significantly increases the risk of deformities. It was also observed that children with thickened nerve trunks are at 6.1 times higher risk of developing deformities compared to those who did not have nerve enlargement. Other factors contributing to the development of deformities include; delay in accessing health care and lepra reaction at the time of presentation. Children with these risk factors should be followed up more diligently so as to detect the onset of any deformity and initiate management as early as is possible.
Monitoring for new nerve function impairment
The assessment of NFI like sensory loss or motor weaknesses and nerve thickening should be done at the first visit to stratify the subsequent risk of developing new NFI and based on the risk category the frequency of monitoring can be determined in patients [Table 3] to ensure that any new primary impairment will be detected early. With early detection, there is a greater chance of reversal with treatment, before the onset of secondary impairments as MDT is not likely to reverse the NFI. Monitoring might include home testing, by the parent or the child, and formal nerve function assessment with SW filaments, thermal testing, and motor function assessment by the treating physician. Since there is little evidence on the outcomes of new NFI in children, deciding whether to prescribe steroids in a particular situation entails balancing individual risks and benefits.
|Table 3: Clinical prediction rule for probability of new nerve function impairment: Risk of new nerve function impairment during the first 2 years after diagnosis|
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Accurate diagnosis is important in children but it can be very difficult at times. For instance, single hypopigmented patch on the face in children has high risk of misdiagnosis, since there are numerous common causes of hypopigmented patches [Table 2] in this age group. Elicitation of sensory impairment in younger children may be quite difficult on the facial lesions as well as otherwise. Moreover, the fact that indeterminate leprosy may progress to more definitive forms of leprosy, emphasizes the need for greater caution and diligence in early diagnosis and early initiation of treatment among children. Since the demonstration of classical histological features of leprosy or AFB in cutaneous lesions of IL is difficult; hence, a reasonable period of observation is recommended if the diagnosis cannot be confirmed at the time of presentation.
Slit-skin Smear examination
Slit-skin smears, from the suspected lesions of leprosy, should be stained for acid-fast bacilli (AFB) to estimate the number of M. leprae when present, (bacillary index, BI) and the proportion of viable bacilli (Morphological Index, MI). Smears are positive in LL, BL, and sometimes BT cases. However, a large proportion of early cases of childhood leprosy is AFB negative because most of them are TT, BT, or indeterminate. Positive skin smears have been reported in <10% cases in many previous studies. Some of the recent studies have reported higher smear positivity rates ranging from 17.4% to 30% [Table 1]. The skin smear positivity has been shown to increase with age.
Histopathological examination of skin biopsy is considered better than SSS and some experts believe that histopathology with Fite staining if done properly can be more useful than SSS. Granuloma formation may not be observed in children due to immature immune system. The clinicopathological correlation in childhood leprosy has ranged from 37% to 93% in various studies.,
Newer methods (serology and molecular diagnostic methods)
None of the currently available tests like SSS, skin biopsy is sensitive enough so the current diagnostic challenge is to identify or develop a point-of-care test that can contribute to or facilitate early diagnosis and classification of leprosy. Serological tests for antibodies against M. leprae antigens such as phenolic glycolipid-I (PGL-I), or conjugated antigens leprosy anti–natural octyl disaccharides- Leprosy Infectious Disease Research Institute diagnostic-1 or NDO-LID can assist in the diagnosis and classification of leprosy. Furthermore, the assessment of these antibodies may also help to monitor the effectiveness of treatment, and help in prognosis and even prediction of reactions. A major challenge for leprosy control and elimination is to identify individuals who will develop leprosy after exposure and to take steps to prevent illness especially among the contacts of leprosy patients. People with positive anti-PGL-1 antibody have 2.7 times higher odds of developing overt disease and it has shown promise in predicting the development of leprosy among contacts and school children; however, it might not be useful in the detection of PB cases., PGL-1 has been widely studied, but its diagnostic potential as a single marker in India may be limited due to cross-reactivity with Leishmania donovani. Serological markers cannot be used as confirmatory tests for diagnosis of leprosy, however, they can be used as a supplementary test in endemic settings while planning for chemo or immunoprophylaxis to the contacts or general population.,
M. leprae specific genetic markers such as the 16s rRNA, or 16S rDNA, RLEP, and TTC repetitive sequences have the potential to diagnose early leprosy in childhood, with sensitivities of approximately 80% and 30% in MB and PB cases, respectively.,
MDT is the mainstay of leprosy treatment. The WHO recommended fixed duration multidrug treatment for 6 months in PB leprosy and 12 months in cases of MB leprosy. Parental education is essential before starting MDT for the child. Parents and young patients need to understand the following [Box 1].
The dosage regimen, of both PB and MB MDT for children, according to the different age groups, has been shown in [Table 4] and [Table 5]. In children <10 years of age the doses should be preferentially calculated according to the weight of the child: dapsone 2 mg/kg/day, rifampicin 10 mg/kg, and clofazimine 1 mg/kg/day daily and 6 mg/kg monthly. Fortunately, tolerance to standard antileprosy drugs is good in children. Available MDT blister packs though convenient are not child-friendly. Treatment dropout rates in children range from 10% to 20% in some programs,, main cause being the child's refusal to cooperate in swallowing tablets. Child-friendly treatment options such as flavored syrups are a need of the hour for improvement in dosing and compliance.
|Table 4: Dosage of multidrug therapy for children with paucibacillary leprosy|
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|Table 5: Dosage of multidrug therapy for children with multibacillary leprosy|
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Children with dapsone hypersensitivity syndrome are usually offered a modified WHO MDT regimen consisting of rifampin monthly and clofazimine daily at the usual doses and same duration. In children with “single skin lesion leprosy” (smear negative) without any nerve involvement, the single dose rifampin, ofloxacin, and minocycline combination (ROM) has been used. However, ROM is no longer supplied through the WHO, and most national programs do not endorse it. Minocycline is generally contraindicated in early childhood. Quinolones, such as ofloxacin have been shown to cause arthropathy (degenerative changes in weight-bearing joints) in young animals, so have to be used with caution in children and adolescents. However, field trial using single-dose regimen of minocycline and ofloxacin in children for the treatment of single lesion PB leprosy did not show significant adverse effects. Any child with rifampicin resistance requires an individually tailored regimen, based on the recommendations from the WHO expert committee, with due regard to the risks that all second-line drugs carry for children. There is not enough data regarding the safety of newer antileprosy drugs in children.
Response and follow-up
The erythema and induration of skin lesions may diminish within a few months of initiating therapy. It may take a few years for cutaneous lesions to resolve fully, depending on the initial number of lesions and severity of infection. Most lesions heal without scarring. Once killed, dead bacilli are removed from the tissues very slowly; some may persist in the tissues for several years hence mere smear positivity should not mean nonresponsiveness or drug resistance, it is important to establish viable bacilli by mouse footpad or RNA probes. The NFI does not improve significantly with treatment and patients should be taught to evaluate these areas on hands and feet regularly for evidence of injury so as to obtain treatment promptly. Special protective shoes with soft insoles made of microcellular rubber may be needed to avoid injury or ulceration. Motor loss resulting in deformities may require corrective surgery.
Treatment of neuritis and reactions
Children with reactions (both type 1 and 2) require the prompt use of steroids for the prevention of nerve damage and deformity. Clofazimine can also be used for management of both type 1 and 2 reactions, it is generally recommended at 1.5–2 mg/kg three times daily for 1 month, then reducing by one dose per day each month. The maximum dose of 300 mg daily can be administered. Other drugs which can be used for reactions are hydroxychloroquine, methotrexate, azathioprine, cyclosporine, and nonsteroidal anti-inflammatory drugs like paracetamol, etc. Thalidomide is not recommended for children below 12 years old, due to the lack of safety information, but it might be used – if legally available – in adolescent boys. Rehabilitative measures such as physiotherapy and corrective surgeries should also be offered to selected patients.
Preventive measures for leprosy include early diagnosis and management of active cases as well as contact management. Household contacts should be evaluated annually for evidence of disease for at least 5 years and should be educated to seek immediate attention if suspicious skin or neurologic changes develop. Hence, community education about leprosy along with mandatory household contact and school surveys if implemented nationally would result in the reduction of disease burden.
Vaccines in leprosy
The ideal leprosy vaccine should induce strong, long-lasting T-cell responses directed against M. leprae, thereby preventing disease, limiting infection, and furthermore, reducing bacterial transmission. Several vaccine strategies have used whole mycobacteria in the immunoprophylaxis; however, to date, none besides Bacille Calmette–Guérin (BCG) and Mycobacterium indicus pranii (MIP) vaccines have advanced into common use. There is an emerging need in leprosy research to further evaluate the available vaccines such as BCG or MIP for leprosy prevention and immunomodulation and develop new subunit or recombinant vaccines. Newer vaccines like a LepVax (a tetravalent vaccine) has been tested in mice, wherein it was found to reduce bacillary load and delay motor NFI and may prove useful in humans.
BCG remains the only vaccine widely administered for the prevention of leprosy and has played an important role in leprosy control. Systematic meta-analyses indicate that BCG has a protective efficacy of around 50%, and that protection appears to be better against the MB than PB forms. The protection rates with BCG revaccination have varied between 26% and 61%. The level of protection varies greatly with an overall protection of 41% in trial studies and 60% for cohort studies. Moreover, the efficacy was significantly more for household contacts (66%) when compared to the general population. Although the effect diminished with age, no variation was observed in the BCG action in relation to the age on application of the first dose of the vaccine, the revaccination increased its response. Merle et al. found no additional protective effect when applying revaccination with BCG, but they did report that a longer follow-up time may well reveal the benefits of the second dose. However, the WHO guidelines do not support BCG revaccination, and there is a concern that it may also accelerate the onset of PB leprosy patients. BCG has also been used in combination with killed M. leprae and M. vaccae, but this did not significantly increase the protective efficacy.
In an attempt to make BCG more immunogenic and to extend its protective lifespan, several investigators have genetically refined the bacteria. Recombinant BCG strains that over-express antigens that are homologous with M. leprae like Ag85 complex, or rBCG that secretes M. leprae major membrane protein-II (also known as bacterioferritin; ML2038) have shown better efficacy in inhibiting the multiplication of bacilli in mouse foot pad as compared to BCG. However, these are BCG vaccines might not work in populations that have been successfully primed with current BCG strains.
In the south Indian vaccine trial comparing BCG, BCG + killed M. leprae, Mycobacterium w (M. w)(now called MIP) and ICRC vaccines, ICRC provided the best protection, at 65.5%. However, the widespread use of ICRC for the prevention of leprosy has not been reported.
MIP, previously M. w, has also been investigated as an immunoprophylactic measure against M. leprae. In the south Indian vaccine trial, MIP provided only 25.7% protection. The protective efficacy was better in the Uttar Pradesh M. w trial where protective efficacies of 69%, 59%, and 39% were reported after 3, 6, and 9 years, respectively, when only the contacts were vaccinated, and the efficacy was 68%, 60%, and 28% when both patients and contacts were vaccinated and the vaccine efficacy was highest in children. The waning of immunity after 9 years suggests the utility of booster dose. MIP has also been found to be effective as a immunotherapeutic modality in few studies from India. It was seen that the MIP vaccine led to a faster reduction in bacillary load along with decrease in the frequency and severity of type 2 reactions without exacerbating type 1 reactions and neuritis. It can be used as an adjunct to MDT in leprosy patients with a high bacillary load.
Chemoprophylaxis in high-risk contacts
Leprosy contacts are at highest risk of acquiring leprosy hence some researchers have suggested chemoprophylaxis in high-risk contacts, that is, contacts with MB disease and seropositive to anti-PGL-I cases, using single-dose rifampicin (SDR), 600 mg for adults above 35 kg of body weight, 450 mg for children above 9 years of age, and adults 20–35 kg, and 300 mg for children weighing <20 kg. The protection rate for chemoprophylaxis varies from 30% to 70% and even a minimal reduction in incidence among the contacts can significantly affect the incidence in countries like India, recommending its use in public health policies. SDR treatment is being practiced by the Indian National Leprosy Programme since November 2017.
Experts believe that SDR may be a cheap and easier intervention, but it does not prevent MB leprosy hence it is unlikely to have an effect on transmission. It may also not help contacts of MB patients or contacts with high anti-PGL-I levels as their bacillary load may be too high to be eliminated by a single dose. It may also not help individuals who acquire infection after the dose as drugs do not provide immunological memory as opposed to vaccines. Moreover, it may lead to the development of rifampicin-resistant M. leprae, and that will be a big blow to the leprosy control program in endemic countries like India.
| Conclusion|| |
Leprosy in children is a strong indicator of recent transmission of the disease and failure of leprosy control programs. Leprosy elimination as a public health problem has been misunderstood as “zero leprosy.” The skill for diagnosing and managing leprosy is diminishing leading to missed and misdiagnosis of leprosy in infants and young children. This delay in diagnosis transforms into deformities and disabilities which have a significant bearing on the physical, psychosocial, and financial aspects on children and their families. Fear of social ostracism may dissuade children or their families from seeking medical care at an early stage. Children have a low frequency of voluntary reporting for leprosy care, unless there are serious consequences. Hence, effective planning to bring down the incidence of leprosy and its complications in children should become a top priority. Regular school surveys and annual contact surveys for early detection of cases is, therefore, an important tool in achieving the goal of elimination of leprosy. In addition to continuing to administer MDT to patients, new preventive approaches need to be considered to break the chain of transmission and reach zero disease status.
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The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
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Conflicts of interest
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]