Comparative genomics indicates that leprosy originated in Eastern Africa or the Near East, and was spread by human migration to rest of the world. Leprosy was well-recognized in ancient India and China since 4000 BC with the first known written reference to the disease 600 BC. Leprosy is believed to have arrived in Ireland through trade and commerce with the Far East and travelled to Scandinavia through the Vikings; however, some believe that the crusaders brought the disease to Europe from where it spread to the Americas [1]. Others believe that Alexander the Great’s Greek soldiers introduced it to Europe [2]. By the 12th century leprosy had become a widespread disease in Denmark giving rise to numerous leprosy hospitals/centres, demanding a large number of victims and inflicting a great deal of socioeconomic damage [3]. In Norway the disease raged well into the 19th century giving rise to the world’s first national patient registry. In 1873, driven by epidemiological studies, the causative agent of leprosy was discovered by the Norwegian physician Gerard Armauer Hansen [4], but not until a century later, in 1982, an efficient multidrug therapy (MDT) was recommended by the World Health Organisation (WHO) [5]. The global prevalence rate has declined markedly following implementation of MDT. The WHO ‘elimination of leprosy’ goal is less than 1 per 10,000 persons in a given population receiving MDT. Elimination of leprosy at global level was achieved by the year 2000. At present, leprosy is endemic in countries such as India, Indonesia and Brazil, and these countries account for the bulk of newly detected cases. Thus, in 2013, a total of 180,618 cases were registered, and the prevalence rate was 0.32 in 10,000 worldwide [6]. However, no decline was recorded and a rising incidence in some countries indicate continuous transmission. Some attribute this to the intensified leprosy control and new case finding strategies in endemic regions and not an increasing incidence per se [7, 8].
The vast majority of infected individuals never develop clinically detectable symptoms and signs. Age and sex are important risk factors for developing leprosy: adolescents aged 10–19 and persons aged 30 or above are the most susceptible. Adult men are twice as likely to develop the infection as adult women [9]. Although, household contacts of multibacillary (MB) cases have an increased risk of developing leprosy compared to the general population, infection acquired outside the household and subclinical infection is being recognized as an potential route of transmission, sustaining the high new detection rate of leprosy [10–13]; 90–95 % of spouses to infective leprosy patients did not acquire the infection in the pre-antibiotic era. Children of leprosy patients have an increased risk of acquiring the infection compared to the spouse, indicating that genetic similarity to the infected parent makes one more susceptible to the infection [14]. Even though some studies have shown an association between susceptibility to leprosy and certain genes/chromosomal regions, more studies are needed to fully understand the genetics of susceptibility to leprosy [15–17].
Today, in Scandinavia, as in most of Europe, leprosy remains non- autochthonous, brought to the region by immigrants from endemic areas, thus explaining its rarity: In Denmark less than one case per year has been reported during the last 30 years, and the leprosy situation in Denmark was last reviewed more than 20-years-ago [18].
The aim of our study was to give a brief overview of the history and of the current general knowledge on leprosy and conduct a retrospective review of leprosy cases from 1980 to 2010 in Denmark with emphasis on clinical characteristics and therapeutic challenges.
The causative agent
Leprosy is a chronic granulomatous infection caused by the intracellular acid fast bacilli Mycobacterium leprae (M. leprae) and is most likely transmitted through droplets from the upper respiratory tract of bacilliferous patients. Although transmission through skin under controlled laboratory conditions has been reported, infection through intact skin is not considered possible. The mycobacterium is difficult to study and has not successfully been cultured in vitro but only in armadillos and footpads of nude mice.
The infection has low virulence and a mean incubation period of 4–5 years, but the incubation period may be much longer [19]. Incubation time for paucibacillary (PB) infections is assumed to be shorter than MB.
The bacilli exhibit tropism for histiocytes and Schwann cells, causing anaesthetic skin lesions, and sensorimotor function loss [20], and also for cooler parts of the body, such as eyebrows, earlobes and the nose.
Even though M. leprae has been isolated from several environmental and animal reservoirs including armadillos (10), most authors agree on humans being the main reservoir of infection [21].
The clinico-pathological spectrum
The wide spectrum of clinical presentations reflects the complexity of the immune response towards the causative agent and is graded according to the widely used Ridley–Jopling scheme, which is primarily based on the immunological characteristics. Clinical and histo-pathological characteristics are also considered, and delineated as two stable polar forms ranging from polar tuberculoid (TT) to polar lepromatous leprosy (LL), and in between the unstable borderline forms: borderline tuberculoid (BT), borderline leprosy (BB) and borderline lepromatous leprosy (BL). Thus, tuberculoid leprosy (T) refers to TT and BT while lepromatous leprosy forms (L) to BB, BL and LL. Borderline types are more likely to down- or upgrade through immunological reactions; type 1 reactions [22]. Indeterminate leprosy, the earliest clinically detectable form of the disease is immunologically unstable. Most cases can be cured spontaneously, but some cases may go on to develop one of the determinate forms later. Leprosy may even present with nerve affection as the only symptom: pure neural leprosy.
The clinico-pathological features in leprosy are the result of a varying immune response. Thus, T by mounting a strong cell mediated immune response restricts the infection to a single or few well demarcated, dry (anhydrosis) and scaly anaesthetic skin lesions (macules, plaques) with an elevated margin and central healing. The skin changes are often hypopigmented in dark skin and red/coppery coloured in lighter skin. Although early and significant nerve enlargement is common in T, and the most commonly affected nerves (most common one or few asymmetric nerve affections) are posterior tibial, ulnar, median, lateral popliteal, facial, and radial nerves (may also be affected in L), thickening of the cutaneous nerves close to the skin lesion is an important diagnostic clue.
T lesions are dominated by CD4+ cells, histologically characterized by well-defined granulomas consisting of lymphocytes, epitheloid and giant cells and virtually no bacilli [23], i.e. paucibacillary. The cellular infiltration may extend up to the epidermal layer of the skin. The strong immune reaction in T is probably a result of switching towards a Th1 response. The Th1 type response in patients at the tuberculoid pole (TT and BT) results in abundance of interferon -γ (INF-γ), Tumor Necrosis Factor (TNF-α), interleukins (IL)-2 and IL-15 and a positive skin test (Lepromin test). At the opposite pole (L), the clinical picture reflects a weak cell mediated immune response leading to disseminated infection with multiple skin lesions often distributed symmetrically on the body. In contrast to T, L patients have multiple erythematous or slightly hypopigmented skin lesions (macules, papules and nodules), with poorly defined borders and smooth shiny surfaces which are not necessarily anaesthetic in early stages of the disease. Nerve enlargement and palsy also develop later as compared to T: most common as multiple symmetric nerve affection. Progressive L cases can develop a disseminated infiltration of the skin causing a waxy appearance and thickening of the skin, most prominent in the face, facies leonidae. L cases may display systemic symptoms affecting the eyes, testes, bones and liver.
L lesions are characterized by few T lymphocytes with a predominance of CD8+ cells, no granulomas, diffuse infiltration of undifferentiated ‘foamy’ macrophages and loads of bacilli, i.e. multibacillary. The epidermis stays intact until late stages of the disease. In contrast to the immune response seen in T, L lesions formed during the Th2 type response contain transcripts for IL-4, IL-5 and IL-10, are non-reactive to the Lepromin test and show high anti-M. leprae antibody titres which do not seem to convey any protection [24–26].
The unresponsiveness to M. leprae extracts in the Lepromin test in L may be explained by immune deviation (the above described Th1 and Th2 immune responses), deletion (varying Th0 cell responsiveness to M. leprae) and/or inhibition of T cell responses by regulatory T cells (Tregs) [27]. Some lepromatous patients are capable of mounting a Th1 response upon stimulation with cytokines such as IL-12 secreted by activated dendritic cells and stimulate naïve T cells which are present in T but not L lesions. This observation has led some to conclude that the Th2 immune status in L is reversible [28]. Findings from some studies though do not support the notion of immune deviation in leprosy [29] wherefore increasing interest in clarifying the role of Tregs in leprosy has evolved. However, studies of Tregs in leprosy have found conflicting results as both increased and decreased frequency of Tregs in L patients have been found [30–32]. Thus, more investigations into the role of Tregs in leprosy are needed [33].
Diagnosing leprosy
According to WHO diagnostic criteria, a person with one of the two cardinal signs: (1) positive skin smear or (2) characteristic anaesthetic leprosy skin lesions with or without nerve thickening/enlargement with sensory or motor loss, is regarded as having leprosy. WHO recommends a simpler classification scheme based on number of skin lesions and bacillary load in skin smears. This is often used to classify leprosy based on number of skin lesions alone, where Paucibacillary (PB) leprosy corresponds with 1-5 skin lesions (indeterminate leprosy, TT and BT) and MB leprosy with >6 skin lesions (BB, BL and LL) [34].
However, a considerable amount of patients will be misclassified with risk of both over- and undertreatment. Therefore, if not used in the field for operational purposes, experts recommend classifying patients according to the Ridley–Jopling scheme. Thus, whenever possible, a patient suspected of leprosy should undergo examination for the three cardinal signs of leprosy: (1) thorough inspection of the skin for leprosy lesions (morphology described above) and anaesthesia (light touch, pin prick and temperature) of such, (2) enlargement with or without sensory or motor loss of most commonly affected peripheral nerves (predilection sites mentioned above), and (3) positive skin smear. A total of 3–6 skin smears should be performed from skin lesions and in L cases from cooler sites with a high probability of finding AFB (earlobes, the forehead, extensor surfaces of the forearms and knees). Skin smears are used to assess the bacillary load: the bacteriological index (BI) and the viability of the mycobacteria; the morphological index (MI). The BI indicating the bacterial load is expressed on a logarithmic scale from 1 + (at least 1 bacillus in every 100 fields) to 6 + (at least 1000 bacilli in every field). Leprosy patients with a BI < 2 are designated as PB while a BI > 2 as MB. Before WHO recommended the current operational method of counting skin lesions to classify a patient as PB or MB, a positive skin slit smear from any site designated the patient as MB. Skin slit smears show poor sensitivity (particularly in PB cases), but their high specificity is very useful for identifying MB, which is the most infectious.
Skin biopsies are usually performed when there is doubt about the diagnosis and remain the golden standard. Biopsies should be taken from an ‘active’ site i.e. red, enlarged and infiltrated. A modified Ziehl-Neelsen stain, such as the Wade Fite stain is preferable for the histological diagnosis. The histopathological characteristics of T and L are described above. According to WHO, only leprosy bacilli which appear as solid acid fast rods are viable while dead leprosy bacilli stain irregularly; this can aid in assessing the treatment effect.
The Lepromin test is analogous to the tuberculin test used in tuberculosis. It relies on the host’s ability to mount a delayed hypersensitivity reaction after an intradermal injection of M. leprae antigens. The Lepromin test has low sensitivity and specificity, and a long waiting period of 3 weeks before a reaction can be observed after injection; therefore the test is rarely used. It has no diagnostic value, and was previously used to classify leprosy patients in tuberculoid when positive, and in lepromatous when negative.
Serological tests are under development but are not used routinely due to their low sensitivity in patients at the tuberculoid pole, and have shown false positive reactions in non-leprosy patients [35]. Some studies indicate that antibodies specific M. leprae antigens may be useful for detection of early disease in house hold contacts and for monitoring treatment efficacy [36, 37].
PCR for M. leprae is sensitive and specific but not widely applied due to cost. Its use until now has been for epidemiological research purposes. In endemic areas it has a promising role for detection of early leprosy, PB cases with a low bacillary load and relapse [38–40].
Treatment
The WHO MDT for leprosy has proven to be highly effective and should be the first choice for all patients. Patients with up to five skin lesions and/or no bacilli (PB) are treated for 6 months with daily dapsone and monthly rifampicin, while multibacillary (MB) cases with more than six skin lesions and abundant bacilli should undergo a 12 months course of daily dapsone and clofazimine supplemented by monthly rifampicin and clofazimine [41]. Skin lesions in MB patients with a high BI may clear more slowly and have a high BI at the end of treatment compared to MB patients with a lower BI; if such patients do not show improvement after completion of 12 months of MDT, WHO recommends an additional 12 months of MDT.
Severe haemolysis can follow dapsone treatment in patients with Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency. Dapsone should therefore be avoided in these patients. An adverse effect of clofazimine which doctors should be aware of, since it can lead to poor compliance, is reddish discoloration of the skin, conjunctivae and body excretions such as sputum and urine.
Second line agents, ofloxacin and minocycline can be used in a single dose regimen for PB cases; Rifampicin-Ofloxacin-Minocycline, ‘ROM,’ for patients with a single leprosy skin lesion. This regimen was introduced by WHO in 1998 and should only be administered after careful examination of the skin making sure the patient only has one lesion and no nerve involvement. Since ROM has proven to be less effective than MDT for treatment of PB cases with more than one skin lesion, it is currently not recommended for PB cases presenting with 2–5 skin lesions [42].
Leprosy reactions
Around 30 % of borderline cases experience type 1 [43] reactions resulting in an upgrading of the cellular immune response, shifting the patients towards the tuberculoid pole and a Th1 response. Leprosy type 1 reactions are type IV delayed hypersensitivity immune reactions. The reactions are most commonly observed at initiation of therapy or during the puerperium. However, when the immune system fails to contain the infection a downgrading towards the lepromatous pole is taking place. Distinction between up- and downgrading may be difficult, and may require histo-pathological examination, although downgrading is usually observed prior to initiation of leprosy treatment, whereas upgrading, often occurs as a response to treatment. Type 1 up- and downgrading reactions cause acute inflammation of existing skin (oedema and ulceration) and nerve (motor-sensory loss) disease, new lesions and nerve involvement can also appear. Prompt diagnosis and treatment is of utmost importance due to the risk of permanent nerve damage. Patients should undergo thorough examination of nerves most commonly affected (as described earlier) and followed closely. Prednisolone starting at 30–40 mg tapered to 5 mg over 5–6 months under close observation of nerve function is generally recommended for type 1 reactions; there is however, currently no consensus on dosage and treatment duration [43]. Results are awaited from controlled trials looking into different treatment regimens with prednisolone for leprosy patients with nerve impairment, and the effect of prednisolone prophylaxis for subclinical nerve function impairment [44].
Type 2 reactions, erythema nodosum leprosum (ENL) are mainly seen in BL and LL patients of whom 50 % (the 50 % refers to the subpolar LL group which is immunologically unstable compared to the LL polar form) are at risk of experiencing this complication. ENL is a type III immune response brought about by the inflammatory reaction towards immune-complexes. The immune-complexes deposited in various organ systems cause fever, erythematous painful nodules, uveitis, neuritis, arthritis and orchitis [45]. ENL lesions are characterized by heavy neutrophil infiltration and high levels of TNF-α. The immunological mechanisms underlying the leprosy reactions are not fully understood [46].
Severe ENL can be life threatening and require prolonged immunosuppressive treatment. WHO recommend corticosteroids 1 mg/Kg body weight for 12 weeks. In case of severe ENL not responding to corticosteroid, clofazimine a corticosteroid sparing agents can be used; according to WHO guidelines clofazimine should be started at 100 mg, three times a day for maximum 12 weeks, where after it should be tapered to 100 mg twice a day for 12 weeks and then 100 mg once a day for 12–24 weeks. Clofazimine is more effective than thalidomide for prevention of ENL recurrences. Thalidomide in doses of 100–400 mg/day have shown to be effective in controlling the reaction, but more and larger trials are needed to prove its efficacy [47], and due to its teratogenic side effects, WHO does not recommend its use for the treatment of ENL in women of childbearing age [48]. Despite this: thalidomide is by many practitioners considered to be the most effective drug against ENL. Pentoxifylline is less effective than thalidomide, but has shown to be effective in alleviating ENL symptoms, and could be used as an alternative to thalidomide against ENL when thalidomide is contraindicated [49].
The time frame is important when distinguishing between relapse and leprosy reactions: New elements or nerve affection appearing less than 3 years after a successful course of MDT is more likely to be a reaction. However, the final diagnosis will depend on presence or not of bacilli. According to WHO a relapse in a MB case is defined as “multiplication of M. leprae, suspected by the marked increase (at least 2+ over the previous value) in the BI at any single site, usually with evidence of clinical deterioration”. To distinguish between relapse and reversal reactions in PB cases a trial of prednisolone is recommended; improvement within 4 weeks favours the diagnosis of a reversal reaction.
Although co-infection with HIV does not seem to shift the patients towards the L pole, some studies indicate an increased incidence of type 1 reactions in patients receiving anti-retroviral treatment, probably as part of an immune reconstitution syndrome [50, 51].
