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Dapsone hypersensitivity syndrome among leprosy patients in China.

Introduction

Dapsone--diamino-diphenyl sulfone, is an antibiotic and anti-inflammatory drug which is used worldwide for treating many diseases, such as leprosy, dermatitis herpetiformis, linear IgA bullous dermatosis and chronic bullous dermatosis of childhood, bullous eruption of systemic lupus erythematosus, erythema elevatum diutinum, leukocytoclastic and other kinds of vasculitis, malaria, pneumocystis carinii pneumonia, etc (2-8, 8, 17, 27), Since it is widely used, the adverse effects of this drug attract the attention of doctors from different specialties. The side effects can be categorised into two kinds, pharmacological and idiosyncratic ones. The former is related to the dosage of the drug, which includes methemoglobinemia, hemolytic anemia, etc. The latter is not related to the dosage but to cell-mediated hypersensitivity (dapsone hypersensitivity syndrome, DHS), ranging from mild cutaneous manifestations to severe life-threatening complications, such as exfoliated dermatitis, liver function failure, agranulocytosis, toxic epidermal necrolysis, nephritis and renal failure, Stevens-Johnson syndrome, etc. (1,4)

Dapsone hypersensitivity syndrome (DHS) is an idiosyncratic adverse effect caused by dapsone. It is a kind of drug-induced hypersensitivity syndrome (DIHS) and is a triad of eruptions, fever, organ involvement (including liver, kidney, hematological system, etc.) Nowadays dapsone is not commercially available at the market in China, it is only available in MDT blister packs for treating leprosy patients. The dosage of dapsone for adult MB and PB patients is 100mg/d, which rarely causes any toxic effects. In order to understand the clinical-epidemiological profiles, outcome and prognosis of DHS among newly treated leprosy patients, we carried out a retrospective survey in the whole China.

Materials and Methods

Because China has a well organised leprosy control programme, all new leprosy patients were diagnosed and classified by local professional health worker (leprosy doctors) at county level. The patients can get free MDT provided by WHO from local health workers. If there was a leprosy patient who developed DHS, local health workers would withdraw dapsone and give an alternative regimen for the treatment of leprosy. There were very few defaulters who took the short-term of MDT and returned for re-treatment. There also was no patient who took less than 3 months of MDT and relapsed for re-treatment. The study was a retrospective survey. A special questionnaire was designed for collecting various data. It was sent with the formal document from the National Center for Leprosy Control to all county units responsible for leprosy control through provincial and district units in China. The questionnaire included four parts: basic information about the patient, clinical leprosy condition, clinical characteristics of DHS and information of treatment of DHS. During the survey, patients with DHS registered from 2006 to 2009 were requested to report to leprosy doctors from different units for leprosy control. The local health workers working at county level were asked to fill in a questionnaire according to the previous medical documents with the clinical data of those patients then sent these questionnaires to provincial centres for checking. We collected the questionnaires from provinces, and again checked them all, removing those who were inconsistent with diagnostic criteria, and analysed the remaining qualified data with software of SPSS11-5, mainly by Chi-Square and ANOVA.

The following criteria proposed by Richardus and Smith (2) were used with a little modifications in our study for the diagnosis of DHS: (1) showing at least two of the following symptoms: 1. fever, 2. eruptions, 3. lymphopathy, 4. hepatic function abnormalities (hepatomegaly, jaundice and/or hepatic dysfunction); (2) symptoms and signs appearing linked with the administration of dapsone, and clinical improvement along with the withdrawal of the drug; (3) symptoms not attributed to other drugs, or leprosy reactions; (4) excluding other diseases causing similar manifestations. The patients meeting all four indicators mentioned above could be confirmed to have DHS and were included in the study. Although there were some patients who might be at a very early stage of DHS, we had no sensitive method to diagnose whether they were real DHS or not. During this study, we only confirmed patients with DHS based on the clinical symptoms and signs. We had checked up some patients in the field, who were reported to have DHS. The results of field checks showed that patients without typical symptoms and signs of DHS could not be diagnosed as DHS. These patients reported to have 'DHS' might be some side-effects of drugs or leprosy reaction other than DHS.

Results

From 2006 to 2009 China has registered 6243 new leprosy patients. Among these patients, we received 126 questionnaires reported to have DHS by local doctors in 17 provinces in high leprosy endemic areas. Fourteen other provinces did not report any patient with DHS. So it was considered that the data of DHS from 17 provinces could represent the incidents of DHS in all China. After carefully checking up, 61 patients not having at least two indicators such as fever, lymphopathy skin eruption, or liver disfunction were excluded from DHS. There were two patients who had incomplete data, and they were also excluded from the study. So only 63 patients diagnosed as having DHS and were analysed. Among them, 13 were the complete type of DHS. The incidence of DHS in China each year can be seen in Table 1.

Among the 63 cases, 43 were male and 20 were female. The male to female ratio was 2.15. The average age of the patients was 38 years old, ranging from 11 to 76 years old, and most of them were 20-40 (26/63, 41.3%). Most patients (63/87.5) were MB patients, and the average BI of these patients was 2.1, consistent with the leprosy epidemiological characteristic in China (Table 2).

Moreover, most patients had no disabilities (42/63, 66.7%) or reactions

(51/63, 81%), or other systemic diseases at the time of diagnosis which meant that most patients' general condition was good.

All 63 patients developed one or more symptoms between 14 days and 2 months after MDT, 27 (42.9%) of whom had an incubation period of about 1 month (mean 32.8 days). The manifestations varied among patients. The main clinical manifestations were focused on two organs--the skin and the liver. The former caused different kinds of eruptions such as maculopapule, excoriation, blisters, edema, ulcer, and the latter caused jaundice, hepatosplenomegaly or abnormal hepatic function. And the eruptions mainly appeared on the trunks of the patients (45/63, 71.4%). The main complaint was fever (56/63, 88.9%) besides eruptions, lymphadenopathy (22/63, 34-9%) and other systemic involvements included hematological system (12/63, 19.0%), kidney (2/63, 3.2%) and others (6/63, 9.5%) such as gastrointestinal symptoms (2/63), neurological discomfort (2/63), toxic myocarditis (1/63), and electrolyte disturbances (1/63) (Table 3).

Most patients had various combinations of these symptoms. Most (41/63, 65.1%) patients went to see their doctor quickly--within 7 days after the DHS symptoms appeared, and the average interval between onset of DHS to being diagnosed was 12.6 days. The management of DHS included discontinuation of dapsone, systemic glucocorticosteroid, hepatic protection, vitamins, topical glucocorticosteroid cream, and so on. The treatment of DHS is individualised according to the severity of DHS. For severe patients with DHS, the systemic glucocorticosteroid regimen used dexamethasone at an initial dosage of 15-20 mg daily in intravenous instillation for 7-10 days, then tapered dexamethasone dosage based on the patient's body temperature; once returned to normal the dose was changed to oral prednisone at 20-30 mg for at least 1 month. Hepatic protection measures were given to patients: glucose, albumin, vitamin C, and avoiding giving them drugs mainly metabolised in the liver. The duration of the course of DHS varied among patients, from 1 week to more than 4 weeks. The average duration time for full recovery was 38.1 days among our patients. Seven (11.1%) patients died of DHS. There was a significant difference between the patients who recovered and those who died in the delay time from DHS onset to receiving treatment (10.89d vs 21.86d, P = 0.01). However, the two groups had no statistical difference among variables, such as ages, clinical types, BI, latency and duration of treatment (P = 0.523, 0.47, 0.611, 0.873, 0.364).

Discussion

DHS, or dapsone hypersensitivity syndrome, is a kind of idiosyncratic adverse effect of dapsone, causing fever, hepatitis, exfoliative dermatitis, generalised lymphadenopathy, hemolytic anemia and so on. It was first reported by Lowe and Smith in 1949 who called it adenoid fever, which they noted in 305 Nigerian leprosy patients. (3) Then in 1951 Aldday Barnes gave a new name DADPS, which was then simplified as DHS. (4) Since dapsone can be used in different dermatological diseases as mentioned above, the DHS can be seen in leprosy and non-leprosy patients. The exact incidence of DHS is unclear due to the lack of a worldwide monitoring system for DHS. But according to the studies on different areas, the incidence is about 0.2-5% in all patients (5-7,8,10) and 1-4% in WHO/MDT patients. (3,6,9-11,12) There has been an increased incidence of DHS in the past three decades worldwide, which may be due to several points. First, the introduction of free MDT to leprosy patients from WHO. Second, increased awareness of DHS among physicians and the rate of reporting is increasing yearly. Our study showed that the total incidence of DHS among leprosy patients was a little lower than other reports with only 0.85 ~ 1.23%. Because there was no sensitive diagnostic tool to confirm DHS, especially in its very early stages, some patients stopped the MDT treatment once they experienced any discomfort after taking it. We consider that the incidence of DHS in China was under-estimated. However the numbers of DHS patients in China remained constant from 2006 to 2009, suggesting a need for more attention from local health workers working on leprosy control. A higher rate of male patients was observed in this study. This observation was also in accord with other studies. (6,11,13) Most patients were less than 40 years of age, and the number of patients with DHS declined with increasing age. The mechanism of DHS may be related to the mechanistic enzyme activity, which is closely related with the adverse effects of the drug, decreasing with ageing. These findings were consistent with previous reports. (6)

DHS is a delayed hypersensitivity reaction of dapsone, one of the distinguishing features between it and other common drug allergies is its longer latent period. It usually develops within 2-8 weeks after the taking of dapsone, (2,6,8,14-16) which supports the another name 'fifth-week dapsone dermatitis.' However, cases of early onset types of DHS were increasing. (13) These patients developed DHS within 2 weeks, (10) especially 2-6 hours for some pre-sensitised ones. (14,17) Also, there were some case reports showing that intervals were longer than 8 weeks, if corticosteroids or other immunosuppressive drugs were simultaneously used. (17) Sener et al. found a case taking dapsone for prophylaxis of malaria with an interval of 12 weeks before the onset of DHS. (15) In our study, we had not collect information about prednisone therapy before DHS, but most patients (51, 81%) had no leprosy reaction and were in good health except for leprosy, therefore most probably they did not take prednisone before DHS. We found that the average incubation time from oral taking dapsone to DHS onset was 32.5 days, very close to the period of "fifth-week dermatitis."

DHS is a multi-organ involvement syndrome. In addition to the usual manifestations of drug allergy such as fever and eruptions, it also involves many other systems and organs, such as hematological system, (8,16) circulatory system, (18) neurological system, (6,19) gastro-intestinal system, (20) liver, (21,22) lung, (23) kidney, (24) and so on. All of these manifestations could be seen in our study. But not all the patients presented all of these symptoms and signs of DHS. Of 63 patients, only 13 developed the complete type, presenting with full symptoms and signs of DHS such as fever, eruptions, lymphadenopathy and hepatic damage (hepatomegaly, jaundice or hepatic dysfunction). Most patients were the 'incomplete' type of DHS, which was similar to other studies showing an increasing incidence of incomplete DHS. (13,25) Some patients showed a manifestation of cholangitis as the symptom of DHS, without the three hepatic symptoms mentioned above. (21) Dermal eruptions were the main manifestation, including maculopapules, excoriations, and unusual vesicles and ulcers, etc. The eruptions can be diffused on the body. (15,22,26,27) Among our patients, the rashes showed the viability in modality and mainly appeared on the trunk, and about half (25/63) of patients presented their eruptions on more than one part of the body.

As there are so many manifestations mentioned above, DHS should be differentiated from many other diseases, such as leprosy reaction, DRESS syndrome and its variants, vasculitis (Churg Strauss syndrome), Hypereosinophilic syndrome, TEN, Steven Johnson Syndrome, Still's disease, Hematologic disorders (leukemia, lymphoma), interstitial pneumonia, paraneoplastic disorders and certain connective tissue disorders, etc. (14,22,23) However, the cutaneous manifestations of DHS can be more serious than S-J syndrome and TEN. (26) DHS is also presented with new extensive skin lesions with edema mainly not on the previous skin lesions. The simultaneously existed fever and liver dysfunction among patients with DHS can be helped to distinguish from leprosy reaction.

The mechanism of DHS remains uncertain. The views worldwide focused on two possibilities, of metabolism and immune explanations. After entering the body, dapsone can be metabolised through two routes, N-acetylation and N-hydroxylation. N-acetylation has no relation with the adverse effects. However, hydroxylamine, which is known as a toxic intermediate metabolite and formed by N-hydroxylation may resulted in hemolytic anemia, and DHS. The metabolite can combine/modify some immunologically-significant chemicals, such as major histocompatibility complex (MHC), on the surface of the immune cells (antigen-presenting cells), then facilitate the T cells recognizing the antigen. (22) Drugs are haptens, which should be combined with proteins to form a complete antigen. Bhaiya et al. (28) investigated the bioactivation and protein haptenation of sulphonamides, including sulfamethoxazole (SMX) and dapsone, showing the drug's metabolite and cellular protein forms a covalent product which induced the cellular toxicity. Besides, SMX can reversibly combine with antigen-presenting cells and activate the T cells, which need to be investigated in dapsone.

Timely and correct management is also important in DHS. The first and most important one is the discontinuation of dapsone. Most patients improve after prompt withdrawal of dapsone, but some still need supportive treatment and systemic glucocorticoid. (14,15,20,21,27,29) Supportive treatment includes fluid and electrolyte balance, body temperature regulation, nutritional support, antibiotics when necessary, skin care, etc. (14,17,20) Although there were no controlled trials evaluating the effectiveness of glucocorticosteriod, anecdotal experiences show that the systemic use of it can improve the condition of patients with DHS, resulting in worldwide application of corticosteroids, with the recommended dose of 1-2 mg/kg/d. (6,14) Considering the long retention period (35 days) of dapsone in human body, which may be due to the retention of drugs through hepatic storage and enterohepatic circulation, the adequate tapering of the dosage of corticosteriods will be the most important. The experiential duration of treatment is at least 1 month, (6,14,15,20,26,27) which is similar to the result of our study showing the average treatment duration was 39.5 days.

The severity of the disease depends on delayed diagnosis of DHS. The longer the delay in diagnosis of DHS, the more serious the severity of the disease. Our study showed that mortality was 11-1% among DHS patients, and death was closely related with the longer delay time compared with that of recovered patients. A retrospective study in Kathmandu, Nepal (17) showed that 40 (2%) MDT-treated patients were diagnosed with DHS and five (12.5%) died.

So DHS is a serious adverse event resulting from dapsone. It can occur in a small number of leprosy patients newly treated with MDT. Some patients may die of DHS if not taking timely and adequate management. Therefore local doctors should pay close attention to DHS, especially among leprosy patients newly treated with an MDT regimen containing dapsone.

Acknowledgements

We would like to thank all the local heath workers at leprosy units at county, district and province level in 17 provinces across China for collecting and reporting the data.

References

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(2) Richardus JH, Smith TC. Increased incidence in leprosy of hypersensitivity reactions to dapsone after introduction of multidrug therapy. Lepr Rev, 1989; 60: 267-273.

(3) Lowe J, Smith M. The chemotherapy of leprosy in Nigeria. Int J Lepr, 1949; 17: 181-195.

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(20) Bucaretchi F, Vicente DC, Pereira RM et al. Dapsone hypersensitivity syndrome in an adolescent during treatment of leprosy. Rev Inst Med Trop Sao Paulo, 2004; 46: 331-334.

(21) Itha S, Kumar A, Dhingra S et al. Dapsone induced cholangitis as a part of dapsone syndrome: a case report. BMC Gastroenterology, 2003; 3: 21.

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WEIWEI TIAN, JIANPING SHEN, MIN ZHOU, LIANGBIN YAN & GUOCHENG ZHANG

Department for Leprosy Control, Institute of Dermatology, Chinese Academy of Medical Sciences, Jiangsu, P.R. China

Correspondence to: Jianping Shen, Department for Leprosy Control, Institute of Dermatology, Chinese Academy of Medical Sciences, Jiangsu, P.R. China (e-mail: jianping_shen2@yahoo.com.cn)

Accepted for publication 15 October 2012
Table 1. The incidence of DHS from 2006 to 2009

                      2006   2007   2008   2009   Total

Number of new cases   1506   1526   1614   1597   6243
Number of DHS cases    15     13     17     18     63
Incidence (%)         1.0    0.85   1.05   1.13    1.0

Table 2. Basic information of DHS patients with leprosy in
China (2006-2009)

Selected                           Number (%) of patients
characteristics

                                 2006        2007        2008

Gender            Male         12(19.0)    11(17.5)     9(14.3)
                  Female       3(4.8)       2(3.2)      8(12.7)
                  M/F ratio    4.0          5.5         1.13

Age (years)       0 ~ 20       3(4.8)       3(4.8)      4(6.3)
                  20 ~ 40      6(9.5)       7(11.1)     7(11.1)
                  40 ~ 60      3(4.8)       2(3.2)      5(7.9)
                  > 60         3(4.8)       1(1.6)      1(1.6)

Type of           TT           1(1.6)       2(3.2)      3(4.8)
  leprosy *       BT           3(4.8)       1(1.6)      4(6.3)
                  BB           2(3.2)       1(1.6)      0
                  BL           4(6.3)       5(7.9)      2(3.2)
                  LL           5(7.9)       4(6.3)      6(9.5)
                  I            0            0           1(1.6)

Total                         15(23.8)     13(20.6)    17(27.0)

Selected                       Number (%) of patients
characteristics

                                 2009        Total

Gender            Male         11(17.5)     43(68.3)
                  Female       7(11.1)      20(31.7)
                  M/F ratio    1.57         2.15

Age (years)       0 ~ 20       2(3.2)       12(19.0)
                  20 ~ 40      6(9.5)       26(41.3)
                  40 ~ 60      6(9.5)       16(25.4)
                  > 60         4(6.3)       9(14.3)

Type of           TT           1(1.6)       7(11.1)
  leprosy *       BT           2(3.2)       10(15.9)
                  BB           3(4.8)       6(9.5)
                  BL           5(7.9)       16(25.4)
                  LL           7(11.1)      22(34.9)
                  I            0            1(1.6)

Total                         18(28.6)     63

* The clinical type of one patient was not clear in 2008.

Table 3. Different clinical manifestations of DHS patients

                         Number (and %)     Total
                          of patients

Skin
  Papule                   47 (74.6)      60 (95.2)
  Erythema                 39 (61.9)
  Excoriation              23 (36.5)
  Blister                  16 (25.4)
Fever                      56 (88.9)      56 (88.9)
Lymphadenopathy            22 (34.9)      22 (34.9)
  Liver and spleen
    Jaundice               25 (39.7)      40 (63.5)
    Hepatosplenomegaly     18 (28.6)
    Liver dysfunction      32 (50.8)
Hematological system       12 (16.7)      12 (16.7)
Kidney                      2 (3.2)        2 (3.2)
Other                       6 (9.5)        6 (9.5)
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Author:Tian, Weiwei; Shen, Jianping; Zhou, Min; Yan, Liangbin; Zhang, Guocheng
Publication:Leprosy Review
Article Type:Report
Geographic Code:9CHIN
Date:Dec 1, 2012
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