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Dapsone reaction -
Dapsone reaction -
These not only kill bacteria but also damage bystander tissues. In addition, dapsone can inhibit the release of prostaglandins and leukotrienes by blocking their inflammatory effects [ 1 , 3 — 5 ]. A list of adverse effects of dapsone some predictable, some idiosyncratic or allergic is provided in Table 1. A rare syndrome, DHS which was first described by Allday, Lowe , and Barnes [ 4 , 5 ] as a hypersensitivity vasculitis syndrome [ 1 , 3 — 8 ].
The incidence of DHS ranges from 0. This variability of the latency time was explained by several factors. Some of those were related not only to the variability of the acetylators but also to the dose and the modality of treatment [ 1 , 4 , 6 , 8 ]. This wide variability of the latency period suggests a multi-organ hypersensitivity reaction, but the exact mechanisms are unclear and reviewed later [ 4 — 7 ].
The classic triad of DHS consists of fever, eruption, and internal organ involvement Table 3. Fever, hepatitis, exfoliative dermatitis, adenopathy and hemolytic anemia might be seen in varying combinations and sequences [ 9 ].
While traditionally a hepatitis or transaminitis is seen, cholangitis has also been described as a component of the DHS [ 9 ]. Studies have shown that this syndrome may begin as early as 7—10 days after administration of the drug or as late as 6 months into therapy with dapsone. Cutaneous lesions can range from erythematous papules as in our patient, to plaques, pustules, and eczematous lesions [ 1 , 3 — 8 ]. The severity of the cutaneous changes does not correlate with the severity or extent of internal organ involvement which may remain asymptomatic of even life-threatening [ 10 ].
Cutaneous lesions usually begin to resolve 2 weeks after stopping therapy. Some patients may also develop severe dermatitis and complications, such as the Steven Johnson Syndrome or toxic epidermal necrolysis Table 1. These patients may experience prolonged morbidity and even mortality with the complications.
Especially in severe cases, malnutrition, protein loss and secondary infection may complicate the illness, and these patients need to be monitored for complications more aggressively. In traditional DHS , antibiotics have little or no role unless obvious infection, cellulitis or sepsis is present. Infiltrative lung disease is the most common pattern of drug-induced injury [ 10 ]. This pattern can cause interstitial lung damage, alveolar damage or vasculitic involvement e.
As listed in Table 3 , DHS can also involve the lung, with 10 cases reported in the literature. In the patient described by us, pulmonary infiltrates and pleural effusions with severe hypoxemia were present suggesting interference with alveolocapillary oxygen transfer.
Other manifestations have also been described in the literature. Table 4 summarizes the different pulmonary manifestations of dapsone. Pulmonary manifestations of the DHS are sometimes dominant features, as occurred in our patient. Manifestations have included the development of eosinophilic pneumonia [ 11 — 15 ], hypersensitivity pneumonia [ 16 ], pleural effusion [ 17 ]. Many reported cases of eosinophilic pneumonia have an associated systemic blood eosinophilia, which however, was not present in our case.
The rapid clinical deterioration seen with DHS can lead to respiratory failure as seen in our patient and sometimes death, if untreated or unrecognized. Other manifestations of this syndrome include hepato-biliary dysfunction such as jaundice[ 1 ], hepatomegaly [ 1 ]and cholangitis [ 9 ], splenomegaly[ 1 ], eosinophilia[ 1 , 13 ], photosensitivity[ 1 ], elevated sedimentation rate [ 1 ], and a mononucleosis picture that can mimic EBV and CMV infection [ 1 , 7 ].
In addition, DHS can include peripheral neuropathy [ 18 ], psychosis [ 19 ], renal involvement such as nephrotic syndrome [ 1 ] and renal papillary necrosis [ 20 ] and pancreatitis [ 17 ] as found in our patient. As listed in Table 3 , a maculopapular eruption, bullous disease, photosensitivity and oral erosions can occur. The differential diagnosis of multisystem illness presenting in a patient on dapsone is shown in Table 5. These include diseases such as: DRESS syndrome and its variants, vasculitis Churg Strauss syndrome , Hypereosinophilic syndrome, TENS Toxic epidermal necrolysis syndrome , Steven Johnson Syndrome, Still's disease, Hematological disorders leukemia, lymphoma , paraneoplastic disorders and certain connective tissue disorders.
We will discuss a few of these important conditions in this section. In the case of the latter, drug rash, eosinophilia and systemic symptoms are often present.
DRESS syndrome can be seen with a variety of medications, including anticonvulsants, sulfonamides, allopurinol, calcium channel blockers, NSAIDS Non-steroidal anti-inflammatory drugs and dapsone [ 21 ]. Fever, skin eruption, adenopathy, eosinophilia and internal organ involvement might also be seen [ 21 ].
It is important to note, that both disorders may overlap. A prodromal phase, similar to a flu-like illness, lasting up to14 days, may precede the skin eruption. The acute phase of TENS consists of persistent fevers, generalized epidermal sloughing and mucous membrane involvement [ 22 ]. Cutaneous vasculitis which can be part of a systemic disease needs also to be excluded. The evaluation of such patients needs a complete work-up for the presence of systemic disease. Skin biopsy and immunofluorescence studies may also helpful in the diagnosis of cutaneous vasculitis in which immunoglobulin and complement deposition are found [ 23 ].
If dermatitis and pulmonary disease is the dominant feature, necrotizing vasculitides and Churg Strauss syndrome needs to be excluded. If dermatological manifestations dominate the presentation, with or without mucosal involvement, Steven Johnson Syndrome and TENS need to be excluded. In some patients with a dominant eosinophilia and pulmonary infiltration, PIE syndrome [ 10 ] needs to be excluded.
Laboratory tests can include a complete blood count and differential, comprehensive chemistry profile, sedimentation rate, urine analysis, arterial blood gases and a chest roentgenogram. Skin biopsy may not be specific but will assist in excluding vasculitis or hematological malignancies. It might be important to obtain a thyroid stimulating hormone level in patients 3—4 months after the diagnosis of DHS as detailed below. The exact immune mechanism behind DHS is unclear. A few mechanisms have been proposed.
Alternately, DHS could be a modified graft versus host disease mediated by activated T-lymphocytes [ 5 ]. It is worth noting that DHS is not a dose-related effect [ 3 — 6 , 8 ], whereas dapsone hepatotoxicity is a dose-dependent effect [ 3 ]. According to Prussick and Shear , there is some evidence suggesting that the metabolic differences in the production and detoxification of reactive metabolites are an important factor in sulfonamide hypersensitivity reactions [ 24 ].
After absorption from the gastrointestinal tract, dapsone is transported through the portal circulation to the liver where it is metabolized primarily via two pathways: N-acetylation and N-hydroxylation [ 1 , 24 ]. N-acetylation which has a bimodal pattern of activity slow and fast acetylation , has been shown not to determine total clearance of dapsone [ 24 ]. However, the N-hydroxylation pathway which is mediated primarily by human liver microsomal enzymes PA4, 2C6, and 2C11 [ 1 , 24 ], is shown to be the initial step in the formation of toxic intermediate metabolites, such as nitrosamines and possibly other compounds, which can induce hemolytic anemia and methemoglobinemia [ 24 ].
It is presumed that these molecules are also important in the pathogenesis of DHS. While N-hydroxylation yields a potentially toxic metabolite known as the hydroxylamine, produced by cytochrome P, acetylation by N-acetyltransferase yields the nontoxic metabolites monoacetyl dapsone and diacetyl dapsone [ 1 ]. Moreover, it has been shown that a reduction in either quantity or activity of N-hydroxylation enzyme systems resulted in decreased total clearance of dapsone.
Furthermore, this information is supported by studies showing an extensive population and individual variation in this ability involving both genetic increased or decreased P activity, decreased reduced glutathione [GSH] and environmental drugs or chemicals such as smoking inducing P, cirrhosis and drugs inhibiting P, decreased GSH such as in AIDS, deficiency of antioxidants such as Vitamin E, C, selenium [ 24 ].
Fortunately, other factors such as increased age and preexisting liver disease e. However, with the lack of clinical studies, those aforementioned protective factors remain speculations. These have not been routinely studied. The rapid response to glucocorticoids [ 27 ] also suggests that activation and nuclear translocation of nuclear factor kappaB NF-kappa B may occur, resulting in a massive inflammatory response [ 25 , 26 , 28 ].
Glucocorticoids have also been shown to have both genomic and nongenomic mechanisms that influence inflammatory diseases [ 27 ]. How such events may relate to the ultimate pathogenesis and evolution of this syndrome are unclear but need further examination.
Treatment options for DHS are listed in Table 6. The main treatment for DHS is immediate discontinuation of the drug with initiation of oral or parenteral glucocorticoids, depending on severity [ 1 , 5 ].
Glucocorticoids such as prednisone, prednisolone or methylprednisolone have profound anti-inflammatory actions, as summarized earlier. Weighted mean of latency between dapsone initiation and occurrence of first hypersensitivity symptoms was Fever and skin symptoms were the most prevalent HR Hepatitis and lymphadenopathy were reported in All 4 symptoms were presented by Concomitant symptoms, such as nausea and vomiting, were reported in patients.
Eosinophilia was seen in Systemic glucocorticosteroid treatment was administered in With 33 deceased hypersensitivity patients lethality was 9. Patients deceased 5—60 days mean In 3 patients the cause of death was not specified two of them discharged themselves and died at home Table I summarizes patient characteristics stratified by outcome of HR recovery vs.
Age, years, median P 25; P NR: not reported; HR: hypersensitivity reactions. In bivariate analyses mucosal involvement OR Delayed drug cessation showed a non-significant tendency to increase risk for fatal outcome OR 1. However, as all deceased patients had skin symptoms, regression could not be applied. Results of the multivariate analysis are summarized in Table II.
The multivariate logistic regression model revealed a significant association between age OR 2. Table II. NR: not reported; NC: not calculable. Interaction analyses did not show any evidence for effect modification by age, sex or affluence. Based on the published epidemiological studies, the prevalence of HR to dapsone is 1. Overall, the case-fatality rate is 9.
Mucosal involvement, rash, hepatitis, higher age, leprosy as indication for dapsone use, and disease occurrence in non-affluent countries were associated with a higher risk of fatal outcome. However, the association between higher age and fatal outcome of HR to dapsone did not reach statistical significance in all analyses. Frequency of HR onset may be influenced by the general and immunological status of leprosy patients It is worth noting that the association with leprosy treatment may largely be accounted for by higher incidence rates of leprosy in non-affluent countries.
Mucosal involvement could be shown to be a potent risk factor for fatal outcome of HR to dapsone. Rash was also associated with a higher risk of fatal outcome in the published reports. However, diagnostic criteria for rash were not declared, although rash may refer to an acute reddening rather than exanthema.
It is possible that more acute clinical courses may account for a higher risk of fatal outcome. Further research is necessary to clarify this important issue. Severity of skin symptoms and severity of internal organ involvement may not correlate Besides the liver, other internal organ involvement, such as renal , cardiac , pulmonary or pancreatic 77 , were present as additional complications. Our systematic review suggests the need to discontinue dapsone treatment immediately in case of suspected dapsone hypersensitivity, as delayed drug cessation appears to double the risk for fatal out-come.
Latency of HR onset ranged from 6 h to 21 weeks 57 , but in general it ranged from 3 to 5 weeks. As multi-drug therapy is used in leprosy, interactions between the different anti-leprosy drugs may influence the likelihood of HR occurrence Rifampicin is known to induce dapsone metabolism In our analyses co-medications and dapsone dosage do not seem to affect the occurrence or outcome of HR to dapsone.
Wear protective clothing and use sunscreen SPF 30 or higher when you are outdoors. Use Dapsone exactly as directed on the label, or as prescribed by your doctor. Do not use in larger or smaller amounts or for longer than recommended. Follow all directions on your prescription label. Your doctor may occasionally change your dose to make sure you get the best results.
Do not take this medicine in larger or smaller amounts or for longer than recommended. Dapsone may be only part of a complete program of treatment that may also include a special diet. Follow the diet plan created for you by your doctor or nutrition counselor. Get familiar with the list of foods you must avoid to help control your condition.
Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose. Overdose symptoms may vomiting, feeling restless or excited, and a pale or blue-colored appearance.
Health Conditions A-Z. Health Tools. See All.
❾-50%}Dapsone reaction -
She denied cough, hemoptysis, or chest pain at this time. Oral mucosa was normal, with no visible lesions. Neck examination was supple, with no palpable lymphadenopathy or evidence of thyroid enlargement. Lung examination revealed bilateral diffuse crackles, decreased breath sounds in both bases and dullness to percussion.
Cardiac examination showed tachycardia without audible murmur while the abdominal examination revealed hypoactive bowel sounds with diffuse mild tenderness on deep palpation, without palpable organomegaly or evidence of rebound tenderness.
The patient demonstrated a diffuse maculopapular eruption with sparing of the hands, feet, and mucosa. There was no blanching on pressure. There was a healing ulcer on her left shin with a dried-up scar site of presumed insect bite , without surrounding erythema or other signs of inflammation or infection. The absence of significant necrosis or surrounding inflammation suggested that the symptoms the patient was experiencing were independent of the insect bite.
The admitting laboratory data is provided in Table 2. Liver function abnormalities consistent with transaminitis were seen. The peripheral smear review showed a normocytic, normochromic anemia with mild neutrophilia and toxic granulations. The patient also demonstrated mild anisocytosis, poikilocytosis and reticulocytosis. The urine sample tested positive for blood but the patient had negative urine, blood and stool cultures. A chest roentgenogram was done on admission and showed a diffuse bilateral air space disease involving the majority of the lung with sparing of the lung apices with bilateral pleural effusions.
Computed tomography of the abdomen and pelvis with contrast showed gallbladder wall-thickening and mild dilatation, with small amount of abdominal fluid ascites. Computed tomography of the chest showed bilateral infiltrates mainly on the left, along with bilateral pleural effusion Figure 1.
Computed chest tomography of the patient described in this report, showing bilateral interstitial infiltrates yellow arrow and pleural effusions red arrow. Image taken at a mid-thoracic level. Based on the clinical picture of multisystem involvement, lack of a defining microbiological cause and the progression of disease, a diagnosis of DHS was made.
The patient was immediately initiated on intravenous glucocorticoids methylprednisolone with dramatic improvement in her symptoms and clinical disease. This improvement is shown in Table 2 and includes dramatic reversal of anemia, improvement in transaminitis and in inflammatory parameters.
This was also evidenced by stabilization of hypoxemia with less need for oxygen supplement. DHS is characterized by a hypersensitivity response to the drug, dapsone which is a sulfone. Dapsone 4,4'-Diaminodiphenylsulphone is used mainly as an anti-inflammatory and anti-bacterial agent for the treatment of skin diseases, bacteria, and fungi [ 1 ]. The anti-inflammatory effects of dapsone are mainly related to its interference with neutrophil chemotactic migration and adherence [ 1 ].
Other multiple mechanisms are listed in the literature. These describe suppression of neutrophil recruitment, inhibition of local production of toxic respiratory and secretory products, as well as formation of oxidants. These not only kill bacteria but also damage bystander tissues. In addition, dapsone can inhibit the release of prostaglandins and leukotrienes by blocking their inflammatory effects [ 1 , 3 — 5 ].
A list of adverse effects of dapsone some predictable, some idiosyncratic or allergic is provided in Table 1. A rare syndrome, DHS which was first described by Allday, Lowe , and Barnes [ 4 , 5 ] as a hypersensitivity vasculitis syndrome [ 1 , 3 — 8 ]. The incidence of DHS ranges from 0. This variability of the latency time was explained by several factors. Some of those were related not only to the variability of the acetylators but also to the dose and the modality of treatment [ 1 , 4 , 6 , 8 ].
This wide variability of the latency period suggests a multi-organ hypersensitivity reaction, but the exact mechanisms are unclear and reviewed later [ 4 — 7 ]. The classic triad of DHS consists of fever, eruption, and internal organ involvement Table 3. Fever, hepatitis, exfoliative dermatitis, adenopathy and hemolytic anemia might be seen in varying combinations and sequences [ 9 ]. While traditionally a hepatitis or transaminitis is seen, cholangitis has also been described as a component of the DHS [ 9 ].
Studies have shown that this syndrome may begin as early as 7—10 days after administration of the drug or as late as 6 months into therapy with dapsone. Cutaneous lesions can range from erythematous papules as in our patient, to plaques, pustules, and eczematous lesions [ 1 , 3 — 8 ]. The severity of the cutaneous changes does not correlate with the severity or extent of internal organ involvement which may remain asymptomatic of even life-threatening [ 10 ].
Cutaneous lesions usually begin to resolve 2 weeks after stopping therapy. Some patients may also develop severe dermatitis and complications, such as the Steven Johnson Syndrome or toxic epidermal necrolysis Table 1.
These patients may experience prolonged morbidity and even mortality with the complications. Especially in severe cases, malnutrition, protein loss and secondary infection may complicate the illness, and these patients need to be monitored for complications more aggressively. In traditional DHS , antibiotics have little or no role unless obvious infection, cellulitis or sepsis is present.
Infiltrative lung disease is the most common pattern of drug-induced injury [ 10 ]. This pattern can cause interstitial lung damage, alveolar damage or vasculitic involvement e. As listed in Table 3 , DHS can also involve the lung, with 10 cases reported in the literature. In the patient described by us, pulmonary infiltrates and pleural effusions with severe hypoxemia were present suggesting interference with alveolocapillary oxygen transfer.
Other manifestations have also been described in the literature. Table 4 summarizes the different pulmonary manifestations of dapsone. Pulmonary manifestations of the DHS are sometimes dominant features, as occurred in our patient. Manifestations have included the development of eosinophilic pneumonia [ 11 — 15 ], hypersensitivity pneumonia [ 16 ], pleural effusion [ 17 ]. Many reported cases of eosinophilic pneumonia have an associated systemic blood eosinophilia, which however, was not present in our case.
The rapid clinical deterioration seen with DHS can lead to respiratory failure as seen in our patient and sometimes death, if untreated or unrecognized. Other manifestations of this syndrome include hepato-biliary dysfunction such as jaundice[ 1 ], hepatomegaly [ 1 ]and cholangitis [ 9 ], splenomegaly[ 1 ], eosinophilia[ 1 , 13 ], photosensitivity[ 1 ], elevated sedimentation rate [ 1 ], and a mononucleosis picture that can mimic EBV and CMV infection [ 1 , 7 ].
In addition, DHS can include peripheral neuropathy [ 18 ], psychosis [ 19 ], renal involvement such as nephrotic syndrome [ 1 ] and renal papillary necrosis [ 20 ] and pancreatitis [ 17 ] as found in our patient. As listed in Table 3 , a maculopapular eruption, bullous disease, photosensitivity and oral erosions can occur. The differential diagnosis of multisystem illness presenting in a patient on dapsone is shown in Table 5. These include diseases such as: DRESS syndrome and its variants, vasculitis Churg Strauss syndrome , Hypereosinophilic syndrome, TENS Toxic epidermal necrolysis syndrome , Steven Johnson Syndrome, Still's disease, Hematological disorders leukemia, lymphoma , paraneoplastic disorders and certain connective tissue disorders.
We will discuss a few of these important conditions in this section. In the case of the latter, drug rash, eosinophilia and systemic symptoms are often present.
DRESS syndrome can be seen with a variety of medications, including anticonvulsants, sulfonamides, allopurinol, calcium channel blockers, NSAIDS Non-steroidal anti-inflammatory drugs and dapsone [ 21 ]. Fever, skin eruption, adenopathy, eosinophilia and internal organ involvement might also be seen [ 21 ].
It is important to note, that both disorders may overlap. A prodromal phase, similar to a flu-like illness, lasting up to14 days, may precede the skin eruption.
The acute phase of TENS consists of persistent fevers, generalized epidermal sloughing and mucous membrane involvement [ 22 ]. Cutaneous vasculitis which can be part of a systemic disease needs also to be excluded. The evaluation of such patients needs a complete work-up for the presence of systemic disease.
Resulting agreement between the two reviewers was Disagreements between the reviewers were resolved by discussion. For the analyses relating to countries, we defined two strata using the World Bank criteria regarding income.
Information on age of patients and latency between dapsone initiation and HR onset is presented by weighted means weighted by number of patients to consider information from epidemiological studies.
Reported skin symptoms were classified in the following three groups: i exanthema and erythema, ii erythroderma, and iii rash not specified. A multivariate logistic regression model was used to analyse the relationship between sociodemographic factors sex, age, affluence , disease characteristics dapsone indication and administration terms, latency between dapsone initiation and HR onset, clinical manifestations , and characteristics related to the medical system HR therapy and the final outcome of the HR to dapsone recovery vs.
Interaction analyses were also performed on these parameters. Negative and missing information were always differentiated, leading to differing values for missing data in the single analyses. All analyses were carried out at the individual patient level using SPSS version A total of studies, comprising patients with HR to dapsone, met the inclusion criteria and were analysed Fig. A total of 92 articles were published in English, 6 in Spanish 31, 52, 74, 88, , , 5 in French 41, 57, 64, 67, , 4 in Portuguese 63, 81, 84, 97 , 3 in Korean 70, 87, and 2 in each of Japanese 48, 83 and Chinese , A total of Of the reported patients with HR to dapsone, the weighted mean age was In epidemiological studies information on the total dapsone user population regarding gender and age, however, was given only in exceptional cases.
The majority of HR publications 63 of , and thus patients with HR, originated from Asian countries Ninety-three patients Chronic inflammatory dermatoses, e.
Furthermore, non-infectious entities comprised mainly vasculitides and arteritides 3. However, with Malaria prophylaxis, Pneumocystis jiroveci pneumonia in HIV patients, and tuberculosis were present as other infectious conditions 7. As multidrug therapy MDT is the recommended regimen for leprosy treatment the percentage of co-medication in dapsone users was very high MDT consists of dapsone and rifampicin for paucibacillary PB leprosy and additional clofazimine in multibacillary MB leprosy.
Further co-medications were mostly antibiotics, glucocorticosteroids and pyrimethamine. Almost all cohort studies From the information on total numbers of dapsone users given in epidemiological studies HR prevalences were determined, leading to a total prevalence rate of 1. Weighted mean of latency between dapsone initiation and occurrence of first hypersensitivity symptoms was Fever and skin symptoms were the most prevalent HR Hepatitis and lymphadenopathy were reported in All 4 symptoms were presented by Concomitant symptoms, such as nausea and vomiting, were reported in patients.
Eosinophilia was seen in Systemic glucocorticosteroid treatment was administered in With 33 deceased hypersensitivity patients lethality was 9. Patients deceased 5—60 days mean In 3 patients the cause of death was not specified two of them discharged themselves and died at home Table I summarizes patient characteristics stratified by outcome of HR recovery vs.
Age, years, median P 25; P NR: not reported; HR: hypersensitivity reactions. In bivariate analyses mucosal involvement OR Do not take this medicine in larger or smaller amounts or for longer than recommended.
Dapsone may be only part of a complete program of treatment that may also include a special diet. Follow the diet plan created for you by your doctor or nutrition counselor. Get familiar with the list of foods you must avoid to help control your condition. Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose.
Do not take extra medicine to make up the missed dose. Overdose symptoms may vomiting, feeling restless or excited, and a pale or blue-colored appearance. Health Conditions A-Z. Health Tools.
See All. DailyOM Courses. Brand Names:. Reviewed: June 23, You should not use dapsone if you are allergic to it. To make sure dapsone is safe for you, tell your doctor if you have: a genetic enzyme deficiency called glucosephosphate dehydrogenase G6PD deficiency; methemoglobin reductase deficiency hemoglobin M ; liver disease; heart disease; or lung disease.
Dapsone is widely used in the treatment of leprosy and several chronic inflammatory dermatological conditions. Hypersensitivity reactions to dapsone are potentially fatal adverse drug reactions with unknown prevalence and risk factors.
We performed a systematic review covering all reported cases of hypersensitivity reactions, in order to systematically summarize the published evidence on prevalence, clinical course and fatality rate. Articles were identified through standardized search strategies. Included studies were reviewed for hypersensitivity characteristics and odds ratios were calculated in univariate and multivariate regression models to assess the risk factors for fatal outcome.
A total of articles 17 epidemiological studies, 97 case reports totalling patients with hypersensitivity reactions were included for analysis. From the epidemiological studies a total hypersensitivity reaction prevalence rate of 1.
Mucosal involvement, hepatitis, higher age and disease occurrence in non-affluent countries were associated with higher risk of fatal outcome.
Overall, the fatality rate was 9. Key words: dapsone; adverse drug reaction drug safety ; drug hypersensitivity; systematic review; death rate; epidemiological studies. E-mail: Jochen. Schmitt uniklinikum-dresden. The sulphone dapsone 4,4-diaminodiphenylsulphone 1 has been used as an oral drug since 2.
Initially, it was approved for leprosy, for which it is still frequently used. In addition to its antimicrobial effects dapsone is a potent anti-inflammatory agent with high effectiveness in dermatitis herpetiformis and a wide variety of other inflammatory dermatological conditions 3, 4.
Although dapsone is generally well tolerated and suitable for long-term treatment, adverse drug reactions ADR may occur 5. Obligatory dose-dependent ADRs include haemolytic anaemia and methaemoglobinaemia 6.
Important, less well-known, potentially fatal ADRs with unknown pathomechanisms are hypersensitivity reactions HR to dapsone, such as the so-called dapsone syndrome synonymous with sulphone syndrome The complete syndrome consists of all four of these symptoms To date, systematic research concerning the most important clinical, epidemiological, and prognostic features of HR to dapsone, is missing.
We performed a systematic review covering all reported cases of HR in order to summarize the evidence on the frequency of HR occurrence as well as the clinical presentation, risk factors and fatality rate. A total of potentially relevant articles were found. In addition, Scopus and Google, as well as the reference lists of all identified articles were searched manually by the first author MLidentifying 19 and 29 additional relevant papers, respectively.
No publication language restrictions were imposed. A total of articles was screened for eligibility, of which were included in this systematic review Fig. Identification of relevant studies for inclusion in the systematic review. Data extraction comprised information about study design, patient characteristics, clinical and paraclinical characteristics of HR, as well as therapy and outcome full recovery vs.
Resulting agreement between the two reviewers was Disagreements between the reviewers were resolved by discussion. For the analyses relating to countries, we defined two strata using the World Bank criteria regarding income. Information on age of patients and latency between dapsone initiation and HR onset is presented by weighted means weighted by number of patients to consider information from epidemiological studies.
Reported skin symptoms were classified in the following three groups: i exanthema and erythema, ii erythroderma, and iii rash not specified.
A multivariate logistic regression model was used to analyse the relationship between sociodemographic factors sex, age, affluencedisease characteristics dapsone indication and administration terms, latency between dapsone initiation and HR onset, clinical manifestationsand characteristics related to the medical system HR therapy and the final outcome of the HR to dapsone recovery vs.
Interaction analyses were also performed on these parameters. Negative and missing information were always differentiated, leading to differing values for missing data in the single analyses.
All analyses were carried out at the individual patient level using SPSS version A total of studies, comprising patients with HR to dapsone, met the inclusion criteria and were analysed Fig. A total of 92 articles were published in English, 6 in Spanish 31, 52, 74, 88, 5 in French 41, 57, 64, 67,4 in Portuguese 63, 81, 84, 973 in Korean 70, 87, and 2 in each of Japanese 48, 83 and Chinese A total of Of the reported patients with HR to dapsone, the weighted mean age was In epidemiological studies information on the total dapsone user population regarding gender and age, however, was given only in exceptional cases.
The majority of HR publications 63 ofand thus patients with HR, originated from Asian countries Ninety-three patients Chronic inflammatory dermatoses, e.
Furthermore, non-infectious entities comprised mainly vasculitides and arteritides 3. However, with Malaria prophylaxis, Pneumocystis jiroveci pneumonia in HIV patients, and tuberculosis were present as other infectious conditions 7. As multidrug therapy MDT is the recommended regimen for leprosy treatment the percentage of co-medication in dapsone users was very high MDT consists of dapsone and rifampicin for paucibacillary PB leprosy and additional clofazimine in multibacillary MB leprosy.
Further co-medications were mostly antibiotics, glucocorticosteroids and pyrimethamine. Almost all cohort studies From the information on total numbers of dapsone users given in epidemiological studies HR prevalences were determined, leading to a total prevalence rate of 1. Weighted mean of latency between dapsone initiation and occurrence of first hypersensitivity symptoms was Fever and skin symptoms were the most prevalent HR Hepatitis and lymphadenopathy were reported in All 4 symptoms were presented by Concomitant symptoms, such as nausea and vomiting, were reported in patients.
Eosinophilia was seen in Systemic glucocorticosteroid treatment was administered in With 33 deceased hypersensitivity patients lethality was 9. Patients deceased 5—60 days mean In 3 patients the cause of death was not specified two of them discharged themselves and died at home Table I summarizes patient characteristics stratified by outcome of HR recovery vs.
Age, years, median P 25; P NR: not reported; HR: hypersensitivity reactions. In bivariate analyses mucosal involvement OR Delayed drug cessation showed a non-significant tendency to increase risk for fatal outcome OR 1. However, as all deceased patients had skin symptoms, regression could not be applied. Results of the multivariate analysis are summarized in Table II. The multivariate logistic regression model revealed a significant association between age OR 2.
Table II. NR: not reported; NC: not calculable. Interaction analyses did not show any evidence for effect modification by age, sex or affluence. Based on the published epidemiological studies, the prevalence of HR to dapsone is 1. Overall, the case-fatality rate is 9. Mucosal involvement, rash, hepatitis, higher age, leprosy as indication for dapsone use, and disease occurrence in non-affluent countries were associated with a higher risk of fatal outcome. However, the association between higher age and fatal outcome of HR to dapsone did not reach statistical significance in all analyses.
Frequency of HR onset may be influenced by the general and immunological status of leprosy patients It is worth noting that the association with leprosy treatment may largely be accounted for by higher incidence rates of leprosy in non-affluent countries. Mucosal involvement could be shown to be a potent risk factor for fatal outcome of HR to dapsone. Rash was also associated with a higher risk of fatal outcome in the published reports. However, diagnostic criteria for rash were not declared, although rash may refer to an acute reddening rather than exanthema.
It is possible that more acute clinical courses may account for a higher risk of fatal outcome. Further research is necessary to clarify this important issue. Severity of skin symptoms and severity of internal organ involvement may not correlate Besides the liver, other internal organ involvement, such as renalcardiacpulmonary or pancreatic 77were present as additional complications. Our systematic review suggests the need to discontinue dapsone treatment immediately in case of suspected dapsone hypersensitivity, as delayed drug cessation appears to double the risk for fatal out-come.
Latency of HR onset ranged from 6 h to 21 weeks 57but in general it ranged from 3 to 5 weeks. As multi-drug therapy is used in leprosy, interactions between the different anti-leprosy drugs may influence the likelihood of HR occurrence Rifampicin is known to induce dapsone metabolism In our analyses co-medications and dapsone dosage do not seem to affect the occurrence or outcome of HR to dapsone.
Regarding the metabolism of dapsone, two main pathways are known: acetylation and hydroxylation, with dapsone hydroxylamine being thought to be responsible for side-effects The exact underlying pathomechanisms, however, are unclear 11, Although no double-blind studies on efficacy of oral glucocorticosteroids exist, anecdotal positive experience led to common use of oral glucocorticosteroids in the treatment of HR to dapsone Systemic glucocorticosteroids were administered in However, glucocorticosteroids are recommended only in patients with internal organ involvement Our review suggests that systemic steroids should also be considered in cases of HR with mucosal involvement in the absence of organ involvement, but still more clinical evidence is needed to strengthen this suggestion.
If used, glucocorticosteroids should be tapered gradually over one month, as dapsone persists up to 35 days in organs due to protein binding This study meets the standards for systematic reviews and is based on the highest available number of patients showing HR due to dapsone.
Dapsone syndrome is an uncommon hypersensitivity reaction to diamino diphenyl sulfone. This syndrome is characterised by high fever. Dapsone is widely used in the treatment of leprosy and several chronic inflammatory dermatological conditions. Hypersensitivity reactions to dapsone are. Dapsone syndrome is an uncommon hypersensitivity reaction to diamino diphenyl sulfone. This syndrome is characterised by high fever. blurred vision, ringing in. However, the use of dapsone may be associated with a plethora of adverse effects, some of which may Table 1 Adverse reactions to Dapsone. How such events may relate to the ultimate pathogenesis and evolution of this syndrome are unclear but need further examination.Dapsone is an anti-infective medicine that fights bacteria. Dapsone is used to treat dermatitis herpetiformis a skin condition and leprosy. Dapsone may also be used for purposes not listed in this medication guide. FDA pregnancy category C. It is not known whether dapsone will harm an unborn baby.
Tell your doctor if you are pregnant or plan to become pregnant while using this medication. Dapsone can pass into breast milk and may harm a nursing baby. You should not breast-feed while using this medicine. Get emergency medical help if you have any of these signs of an allergic reaction : hives; difficult breathing; swelling of your face, lips, tongue, or throat.
This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. Avoid exposure to sunlight or tanning beds. Dapsone can make you sunburn more easily. Wear protective clothing and use sunscreen SPF 30 or higher when you are outdoors. Use Dapsone exactly as directed on the label, or as prescribed by your doctor. Do not use in larger or smaller amounts or for longer than recommended. Follow all directions on your prescription label.
Your doctor may occasionally change your dose to make sure you get the best results. Do not take this medicine in larger or smaller amounts or for longer than recommended. Dapsone may be only part of a complete program of treatment that may also include a special diet.
Follow the diet plan created for you by your doctor or nutrition counselor. Get familiar with the list of foods you must avoid to help control your condition. Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.
Overdose symptoms may vomiting, feeling restless or excited, and a pale or blue-colored appearance. Health Conditions A-Z. Health Tools. See All. DailyOM Courses. Brand Names:.
Reviewed: June 23, You should not use dapsone if you are allergic to it. To make sure dapsone is safe for you, tell your doctor if you have: a genetic enzyme deficiency called glucosephosphate dehydrogenase G6PD deficiency; methemoglobin reductase deficiency hemoglobin M ; liver disease; heart disease; or lung disease.
Side Effects. Side Effects What are the side effects of Dapsone? Common side effects may include: stomach pain, nausea, vomiting; headache; dizziness or spinning sensation; blurred vision, ringing in your ears; or sleep problems insomnia.
Based on FDA pregnancy categories. Interactions What drugs and food should I avoid while taking Dapsone? Your doctor will need to check your progress while you are using dapsone. Store at room temperature away from moisture, heat, and light.
What should I do if I missed a dose of Dapsone? Overdose Signs What happens if I overdose on Dapsone? If you think you or someone else may have overdosed on: Dapsone , call your doctor or the Poison Control center. If someone collapses or isn't breathing after taking Dapsone , call No image available. See More. Medical Disclaimer Drugs A-Z provides drug information from Everyday Health and our partners, as well as ratings from our members, all in one place.
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