Spatial heterogeneity in projected leprosy trends in India

Leprosy (Hansen’s disease) is a chronic infectious disease caused by infection with Mycobacterium leprae, a mycobacterium closely related to the tuberculosis agent. The clinical condition of leprosy is characterized by lesions on the dermis of the skin or damage to the peripheral nerves [1, 2], and patients are classified as either paucibacillary (PB) when presenting up to five skin lesions, or multibacillary (MB) when exhibiting more than five lesions [3]. Typically, a patient demonstrates symptoms specific to either paucibacillary or multibacillary leprosy from the outset of infection, and maintains that condition throughout the duration of disease (though some borderline cases initially diagnosed as paucibacillary may later resolve into multibacillary form [4]). Patients with paucibacillary leprosy control the disease largely via cell-mediated immune pathways, while humoral immune responses are generally more pronounced among those exhibiting multibacillary characteristics [4]. Both manifestations of leprosy can be readily treated via effective multidrug therapy (MDT): a combination of rifampicin and dapsone for paucibacillary cases, with the addition of clofazimine in multibacillary cases [5]. Because of the disease’s treatability, leprosy has been a longtime target for elimination campaigns; indeed, in 1991, the World Health Assembly set a goal for “elimination of leprosy as a public health problem” by the year 2000 [5].

In spite of these goals, leprosy has proven elusive, perhaps due in part to a slow pathogen lifecycle that necessitates protracted treatment regimens [5], delays in diagnosis due to stigma (e.g. [6]), or even the possibility of asymptomatic carriers (e.g. [7]). In leprosy endemic regions, it has been suggested that most of the population will be exposed to M. leprae within a lifetime, though few will develop actual disease [8, 9]; indeed, approximately 5 % of the population in some endemic areas has been said to carry active M. leprae in nasal passageways, most without demonstrating signs [5, 10, 11]. Despite over a century of research, the mechanism of transmission for leprosy has yet to be fully resolved [2, 12]. Respiratory inhalation of aerosolized M. leprae particles and repeated contact with nasal mucosa and/or skin excretions are thought to play a role [13–15]. The relationship between leprosy and tuberculosis (TB, caused by M. tuberculosis [16]) is also of note. An inverse relationship between global and regional incidence of leprosy (decreasing) and tuberculosis (increasing) has led to the development of theories suggesting mutual exclusion between the two bacteria [17–19]. The tuberculosis vaccine, Bacille Calmette-Guérin, or BCG, infects the inoculated with an attenuated strain of Mycobacterium bovis, operating (with variable success) by these same principles of mycobacterium exclusion and, thus, offers some protection against leprosy [5], as well as TB (in particular, severe childhood TB [20]).

Despite these challenges, the WHO reports that the global prevalence of leprosy fell from over five million cases to fewer than 200,000 since the mid 1980s [21]. The new case detection rate, however, has remained fairly stable over the past five years. In 2012, several leading global pharmaceutical companies joined forces with the World Health Organization (WHO), the World Bank and the Bill and Melinda Gates Foundation to issue the London Declaration on Neglected Tropical Diseases. This declaration addressed several neglected tropical diseases, including two bacterial diseases—trachoma and leprosy—specifically pledging to “sustain, expand and extend programmes that ensure the necessary supply of drugs and other interventions to … help eliminate [leprosy] by 2020” [22]. The WHO currently states, “Vigorous case-finding and treatment would lead to global interruption of [leprosy] transmission by 2020, and reduce grade 2 disabilities in newly detected cases to below 1/million population at global level” [23]. Grade 2 disability is defined as visible deformity or damage present on the hands and feet, severe visual impairment, lagophthalmos, iridocyclitis, or corneal opacities [24, 25].

Most leprosy cases today are concentrated in a few nations, most particularly India, Brazil, Indonesia and the 14 other signatories of the 2013 Bangkok Declaration [26], which reaffirmed these countries’ commitment to anti-leprosy activities. Leprosy has been endemic on the Indian subcontinent since ancient times, at least as early as 2000 B.C. [27], and to this day, the region leads the world in leprosy incidence. In 2014, India accounted for more than half of the approximately 200,000 reported new leprosy cases globally [21]. Thus, India remains central to worldwide leprosy control efforts.

We used publicly available data from the National Leprosy Eradication Programme of India to explore spatial and temporal patterns in leprosy new case detection. Our aims were to: (1) estimate the rate of change in new case detections for leprosy over time and (2) estimate the extent of geographic clustering in leprosy cases to identify any district or state-level high incidence regions which may be driving nationwide trends. Additionally, we sought to investigate spatial associations in leprosy detection with (3) tuberculosis incidence, (4) BCG vaccination coverage and (5) specific clinical manifestations of disease, including the fraction of cases exhibiting grade 2 disability, the fraction occurring in children under age 15, and the fraction presented in multibacillary form.

National, state and district level leprosy trends in India suggest a slowly changing endemic disease in very gentle decline, with the rate of new cases over the 2008–2015 time series diminishing by less than 2 % per year at the district level. These trends echo global patterns of slow leprosy decline over the past decade, following a dramatic decrease in new case reports in the early 2000s [51]. Some have argued that the substantial reduction in global reporting of new leprosy cases witnessed between the 1990s and 2000s may be the result of underdetection or changes in reporting [51]. In 209 Indian districts selected for enhanced case finding initiatives post-2011, significantly more new cases were found in subsequent years following the induction of heightened surveillance efforts. Additionally, our analysis demonstrates substantial spatial clustering and heterogeneity at both the district and state level for India, including identification of some states or districts with notable increases in new leprosy cases.

Whatever the case in past centuries [17–19] before widespread BCG vaccination and chemoprophylaxis, we found no evidence of a strong relationship between tuberculosis and leprosy at the state level in India. Additionally, we found no evidence of an association between new leprosy case detection rates and average BCG coverage. Such lack of correlation is hardly a surprise, given very high BCG coverage rates and the relative rarity of leprosy at this time. There is simply not enough variability in BCG coverage for the efficacy of BCG against leprosy [5] to become manifest. At the district level, the best predictor of future annual case detection rates is the past rate; at the state level, we can distinguish that annual new case detection rates are higher when the percentage of cases in children is higher and when the percentage of paucibacillary cases of multibacillary form is lower. Regression analysis of the rate of multibacillary to paucibacillary case detection by state further suggests that those states with higher total new case detection rates report higher levels of paucibacillary vs. multibacillary, possibly indicative of lowered detection rates for the more subtle paucibacillary clinical condition in regions of less intensive case surveillance.

Enormous strides have been made by India and by other countries in fighting leprosy. Substantially fewer cases are reported today than in years past [21]. However, our analysis indicates both optimism and pessimism in consideration of the challenge of global leprosy reduction. While overall declining trends in new case detection rates for leprosy in India have been substantial, spatial patterns of leprosy persistence suggest that the reality of this public health burden is more nuanced. Clearly, new case detection rates can fall because the burden of disease is truly decreasing in the community. The new case detection rate could also fall because infected individuals are becoming diagnosed later, because less effort is spent on active case finding [6, 51–53], because a given effort expended in active case finding is becoming less effective as prevalence declines [25], or because of changes in reporting criteria (such as not reporting single lesion cases [53]). If active case finding activities in India were curtailed in the years following 2000–2005, as has been suggested in the literature [51–53], then reported new case detection rates may not reflect the true extent of leprosy disease. Many active enhanced case finding surveys conducted by Indian researchers in recent years have reported finding substantial numbers of new cases in specific locations [54–56], thus supporting these views.

A fall in the new case detection rate can, therefore, be favorable or unfavorable. Yet for the other bacterial disease targeted in the London Declaration—trachoma—evaluation is based on objective population surveys of clinical signs [57] and does not depend on health care seeking behavior (with active case finding by the program not typically conducted in any event). The two diseases could hardly differ more: trachoma—a common subclinical infection whose relatively uncommon late sequelae are of concern, and leprosy—a now uncommon disabling and disfiguring infection with insidious onset and a clinical course of years to decades. Yet the trachoma experience may contain a valuable lesson: active surveys (which have been conducted on relatively large scales for leprosy) could be included for a time as a routine components of leprosy evaluation [58] as they are for trachoma, given a suitable survey frequency and a cost-saving design.

Current recommendations include a goal of “interruption of transmission.” It is unlikely that transmission can be completely interrupted or stopped as long as a single undiagnosed active case exists in the world. Disease incidence and prevalence will eventually drop to zero if and only if we attain (and sustain) subcriticality—the condition that one case, on average, causes fewer than one new case, and thus never replaces itself [59, 60]. The reproduction number is defined as the expected number of cases that a given case of disease can directly cause in a fully susceptible population; thus, subcriticality corresponds to a reproduction number less than one. Reduction of the reproduction number for leprosy to well below the replacement value of one, through effective case finding and cure, should be our goal (e.g. [61]). Unfortunately, epidemiological trends suggest that, barring changes, leprosy will persist—and transmission will be maintained—in India for many years, likely beyond the stated 2020 goal of the London Declaration (see also [62, 63]). Far-reaching policy changes may be needed to accelerate the projected time course of leprosy reduction. Perhaps enhanced case holding and case finding [64], enhanced use of contact investigation and chemoprophylaxis [65], or newer technological developments will be the key to achieving a more rapid pace of decline.