**2. Epidemiology**

According to data from the World Health Organization (WHO), there are 5.35 million leprosy patients in 1985, and this figure has declined to 210,758 in 2015 [1, 2]. The most probable cause of this decline in prevalence is the increasing public awareness, trainings made regarding diagnosis and treatment after the worldwide determination of leprosy as a public health problem [3]. When the prevalence of leprosy is determined, the data of registered patients receiving MDT every year are used. While the state of the disease on the world is determined, aside from prevalence, new patient detection rates and grade-2 disabilities (G2D) definitions and new cases with visible deformities are also used by WHO [2].

skin contamination [10–13]. In addition, leprosy cases seen in the infant period also suggest a possible infection from mother via blood or with breast milk [7, 14, 15]. Numerous cases of leprosy following direct or indirect contact, especially with nine-band armadillo, have been reported [16, 17]. In addition, a leprosy case developed after blood transfusion has been reported [18].

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Bacillus *M. leprae* is showed by methods, e.g., skin biopsy, direct skin smear and electron microscopy; in different ratios in saliva, oral mucosa, hair follicle, hair shaft, sweat gland and canal, in the sebaceous gland orifice, in the mother's milk, and very little in the placenta [13, 15, 19–24]. It should be kept in mind that leprosy, which still continues to be a public health problem, may

Although *M. leprae* is thought to be a largely human-depended parasite for a very long time, there is so much evidence supporting a reservoir other than human [25]. According to recent data, there is no significant decrease in new case detection rates between 2010 and 2015, suggesting that there may be reservoirs other than human [2]. The development of leprosy cases after direct or indirect contact with the nine-banded armodillo in the United States of America (USA) supports this idea [16, 17, 26]. In female chimpanzees brought from Africa to Japan for clinical trial purposes, development of leprosy after 30 years is important for the evidence regarding that leprosy may have both an incubation period and a non-human reservoir [27]. Findings also show that *M. leprae* is also present in environments such as insects, amoebae, soil, and water [25, 28–31]. Considering that bacillus can survive for 46 days in moist environment and 60 days in water; even backwater may become the medium in which they can survive for a long time [32].

Since there is no serological or biological method that may detect *M. leprae* in the latent phase, which is subclinic, it is not yet possible to identify exactly the duration of the incubation; but observational estimates can be made. The estimated average incubation period for multibacillary leprosy (MB) is 5–10 years and sometimes more; for paucibacillary leprosy (PB), the aver-

In a case control study, when compared to the control group, those who had social contact and when compared to living in the same aquifer, those who are core households have a

According to many specialist age is a risk factor and children below 14 years old who is in contact with MB patients as a householder are found to be at greater risk than adults [35–37].

have different modes of transmission.

age incubation period is 2–5 years [5].

**2.2. Reservoir**

**2.3. Incubation**

**2.4. Risk factors**

higher risk [33, 34].

*2.4.1. Contact*

*2.4.2. Age*

In reducing of the prevalence of leprosy over a period of several years, in particular, reducing the treatment with dapsone for many years (4–10) to up to 1 year with MDT was effective [4, 5]. In contrast with the decline in prevalence, the new patient detection rate continued to increase until 2001. After 2001, the number of new diagnoses in parallel with the decrease in prevalence due to the early diagnosis and the success of MDT has decreased [5]. The healthcare infrastructure, which plays a very important role in detecting and controlling the disease, and the accessibility of health services directly affect these rates [6].

At the end of 2015, the prevalence was calculated to be 0.29 (174,608 cases) per 100,000 population, and the rate of new cases was calculated to be 3.2 (210,758 cases) per 100,000 population, according to the number of patients receiving MDT in collected data by WHO from 138 countries [2]. Although the programs against leprosy are being prepared worldwide, currently, 14 countries, each reporting more than 1000 new patients per year, are generating 95% of newly diagnosed patients worldwide. In 2015, India alone accounts for 60% (127,326) of newly diagnosed patients, 13% of Brazil (26,395) and 8% of Indonesia. The Democratic Republic of the Congo, Ethiopia, Madagascar, Mozambique, Nigeria, the United Republic of Tanzania, Bangladesh, Nepal, Sri Lanka, Myanmar and Philippines totally have a new patient detection rate of 14%. Although the rates vary in different countries, on average, 38.8% of the patients reported worldwide are woman and 8.9% of them are children. It is rare to have leprosy in infancy due to long incubation period [7].

The rate of G2D, which indicates identification of early signs and symptoms of leprosy and the response to treatment, is around 6.7% worldwide (1409 cases), indicating a delay in the detection of cases where this rate is still high [2]. The aim of the Global leprosy 2016–2020 is to reduce G2D ratio to less than 1 per 1 billion worldwide; and to withdraw the G2D ratio to zero in children [8].

#### **2.1. Contamination**

Despite the fact that leprosy is a very old disease, we still have a limited knowledge of contamination routes and reservoirs. Contamination usually occurs after prolonged contact with the nasal and oral secretions of lepromatous leprosy (LL) patients infected and untreated with *M. leprae* [9]. However, many cases have been reported supporting the possibility of transmission by different ways, and discussions on different ways of transmission are continuing. There are reports that leprosy cases reported to develop by tattooing and accidental needle penetration support that they can be transmitted through damaged skin, there are also reports supporting undamaged skin contamination [10–13]. In addition, leprosy cases seen in the infant period also suggest a possible infection from mother via blood or with breast milk [7, 14, 15]. Numerous cases of leprosy following direct or indirect contact, especially with nine-band armadillo, have been reported [16, 17]. In addition, a leprosy case developed after blood transfusion has been reported [18].

Bacillus *M. leprae* is showed by methods, e.g., skin biopsy, direct skin smear and electron microscopy; in different ratios in saliva, oral mucosa, hair follicle, hair shaft, sweat gland and canal, in the sebaceous gland orifice, in the mother's milk, and very little in the placenta [13, 15, 19–24]. It should be kept in mind that leprosy, which still continues to be a public health problem, may have different modes of transmission.

### **2.2. Reservoir**

**2. Epidemiology**

38 Hansen's Disease - The Forgotten and Neglected Disease

**2.1. Contamination**

According to data from the World Health Organization (WHO), there are 5.35 million leprosy patients in 1985, and this figure has declined to 210,758 in 2015 [1, 2]. The most probable cause of this decline in prevalence is the increasing public awareness, trainings made regarding diagnosis and treatment after the worldwide determination of leprosy as a public health problem [3]. When the prevalence of leprosy is determined, the data of registered patients receiving MDT every year are used. While the state of the disease on the world is determined, aside from prevalence, new patient detection rates and grade-2 disabilities (G2D) definitions

In reducing of the prevalence of leprosy over a period of several years, in particular, reducing the treatment with dapsone for many years (4–10) to up to 1 year with MDT was effective [4, 5]. In contrast with the decline in prevalence, the new patient detection rate continued to increase until 2001. After 2001, the number of new diagnoses in parallel with the decrease in prevalence due to the early diagnosis and the success of MDT has decreased [5]. The healthcare infrastructure, which plays a very important role in detecting and controlling the disease,

At the end of 2015, the prevalence was calculated to be 0.29 (174,608 cases) per 100,000 population, and the rate of new cases was calculated to be 3.2 (210,758 cases) per 100,000 population, according to the number of patients receiving MDT in collected data by WHO from 138 countries [2]. Although the programs against leprosy are being prepared worldwide, currently, 14 countries, each reporting more than 1000 new patients per year, are generating 95% of newly diagnosed patients worldwide. In 2015, India alone accounts for 60% (127,326) of newly diagnosed patients, 13% of Brazil (26,395) and 8% of Indonesia. The Democratic Republic of the Congo, Ethiopia, Madagascar, Mozambique, Nigeria, the United Republic of Tanzania, Bangladesh, Nepal, Sri Lanka, Myanmar and Philippines totally have a new patient detection rate of 14%. Although the rates vary in different countries, on average, 38.8% of the patients reported worldwide are woman and 8.9% of them are children. It is rare to have leprosy in infancy due to long incubation period [7].

The rate of G2D, which indicates identification of early signs and symptoms of leprosy and the response to treatment, is around 6.7% worldwide (1409 cases), indicating a delay in the detection of cases where this rate is still high [2]. The aim of the Global leprosy 2016–2020 is to reduce G2D ratio to less than 1 per 1 billion worldwide; and to withdraw the G2D ratio to zero in children [8].

Despite the fact that leprosy is a very old disease, we still have a limited knowledge of contamination routes and reservoirs. Contamination usually occurs after prolonged contact with the nasal and oral secretions of lepromatous leprosy (LL) patients infected and untreated with *M. leprae* [9]. However, many cases have been reported supporting the possibility of transmission by different ways, and discussions on different ways of transmission are continuing. There are reports that leprosy cases reported to develop by tattooing and accidental needle penetration support that they can be transmitted through damaged skin, there are also reports supporting undamaged

and new cases with visible deformities are also used by WHO [2].

and the accessibility of health services directly affect these rates [6].

Although *M. leprae* is thought to be a largely human-depended parasite for a very long time, there is so much evidence supporting a reservoir other than human [25]. According to recent data, there is no significant decrease in new case detection rates between 2010 and 2015, suggesting that there may be reservoirs other than human [2]. The development of leprosy cases after direct or indirect contact with the nine-banded armodillo in the United States of America (USA) supports this idea [16, 17, 26]. In female chimpanzees brought from Africa to Japan for clinical trial purposes, development of leprosy after 30 years is important for the evidence regarding that leprosy may have both an incubation period and a non-human reservoir [27]. Findings also show that *M. leprae* is also present in environments such as insects, amoebae, soil, and water [25, 28–31]. Considering that bacillus can survive for 46 days in moist environment and 60 days in water; even backwater may become the medium in which they can survive for a long time [32].

#### **2.3. Incubation**

Since there is no serological or biological method that may detect *M. leprae* in the latent phase, which is subclinic, it is not yet possible to identify exactly the duration of the incubation; but observational estimates can be made. The estimated average incubation period for multibacillary leprosy (MB) is 5–10 years and sometimes more; for paucibacillary leprosy (PB), the average incubation period is 2–5 years [5].

#### **2.4. Risk factors**

#### *2.4.1. Contact*

In a case control study, when compared to the control group, those who had social contact and when compared to living in the same aquifer, those who are core households have a higher risk [33, 34].

#### *2.4.2. Age*

According to many specialist age is a risk factor and children below 14 years old who is in contact with MB patients as a householder are found to be at greater risk than adults [35–37]. In addition, a study showing that bimodal distribution of risk for age has been shown that the risk increase ages 5–15 years and over 30 years.

Reproduction of *M. leprae* in vitro conditions has not been fully successful until now and the reason for this is still unclear. Amako et al. reached results showing that *M. leprae* Thai-53 strain grew in vitro in different media by digital droplet PCR method [50]. Most of the studies on the *M. leprae* have been carried out on armadillos. Low body temperatures (33–35**°**) of armadillos (*Dasypus novemcinctus*), long life cycles, and adequate body sizes have made them

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41

In 2001, by dissolving the genome sequence of *M. leprae*, new information about the disease has begun to be obtained [51]. *M. leprae* has the smallest genome among the mycobacteria species. *M. leprae* bacillus has undergone severe genomic disruption and diminution with reductive evolution [52]. Reductive evolution, especially in catabolism, has removed metabolic pathways along with control pathways [53]. More than half of the genome consists of pseudogenes, inactive reading frames or regulating sequences. In addition, dominance of the bacillus genome has led to advances in topics such as molecular epidemiology, drugsusceptibility testing, and understanding of the spread of the bacterium over the world [52].

Leprosy exhibits a broad spectrum of clinical and histopathological findings based on the cellular immune response of the host. In 1966, Ridley and Jopling classified leprosy according to clinical and histopathologic features [54, 55]. According to this classification system there is a tuberculous form (TT) consisting of a strong immune response and a small number of microorganisms at one end and a weak immunologic response and a lepromatous form (LL) overloading of microorganisms at the other end and three types of borderline leprosy; borderline tuberculoid leprosy (BT), mid-borderline (BB), borderline lepromatous leprosy (BL) between these two end. Conceptually, tuberculoid leprosy (TT) and lepromatous leprosy (LL) are clinically stable, while

In 1997, the WHO created a classification to provide leprosy treatment based on the number of lesions present, regardless of the size, localization, and histopathological features of the lesions, without laboratory support in endemic areas [56]. According to these, leprosy is divided to 3 subgroup: single lesion leprosy, PB, 2–5 lesions and MB, more than 5 lesions. According to the WHO classification, BT may be considered in the PB, BB and BL may be considered in the MB spectrum.

Clinical findings of leprosy are primarily due to skin and nervous system involvement. There

**1.** Enlargement of peripheral nerves: Peripheral nerves are more frequently affected by superficial placement. Unique findings such as anesthesia or hypoesthesia may develop as well as sensitivity and enlargement [55, 57]. Ulnar nerve in the elbow, median and superficial

borderline forms may shift to stronger or weaker immunity.

are five common types of peripheral nerve changes:

suitable hosts in experimental areas [26].

**4. Classification**

**5. Clinics**

#### *2.4.3. Gender*

Although there are a number of studies showing no significant difference between men and women, there is also a study reported that men are at greater risk [34–36].

#### *2.4.4. Leprosy type and physical distance to the patient*

Compared to the general population, sharing the same house with a leprosy patient increases the risk. Contact with MB leprosy patients is more risky when compared to contact with patients with PB single lesion leprosy, while the risk of contact with MB patients is similar to contact with PB leprosy patients with 2–5 lesions [34, 36, 38]. If there are two or more patients in the same house, the risk of contamination doubles [11].

#### *2.4.5. BCG vaccine*

For individuals in contact with the general population and leprosy patients, BCG vaccination administration at repeated doses provides protection against the leprosy [39–41]. Those who live in the same household and do not vaccinated with BCG vaccine are at greater risk [42].

#### *2.4.6. Genetic distance*

Studies have been carried out for years to clarify whether there is a relationship between leprosy and genetics. Although not fully adequate, there are conclusions that support this idea. Moet et al. reported that genetic association is a risk factor predisposing to leprosy, regardless of physical distance [34]. Mire et al. found that the chromosome 6q25 locus was associated with leprosy susceptibility; Siddiqui et al. showed that the 10p13 locus was associated with PB leprosy [43]. There are also studies showing that HLA DR2 and non-HLA (SLC11A1, formerly NRAMP1 and TNF alpha) genes are also associated with leprosy [44, 45]. Genomic studies are important in combating leprosy in terms of having potential for improvement in treatment and vaccination. On the other hand, the presence of IL-17F (7488 t > C) single nucleotide polymorphism and the presence of IL-4 gene 4-590 T/C polymorphism are associated with decreased predisposition to leprosy [46, 47].
