|Year : 2021 | Volume
| Issue : 2 | Page : 173-177
A study of cutaneous adverse drug reactions in a tertiary care center in south India
Lakshmi Rajendran1, Anoop Thyvalappil1, Rajiv Sridharan1, S Ajayakumar1, EM Sparshadeep2, Binoo Divakaran3
1 Department of Dermatology, Government Medical College, Kannur, Kerala, India
2 Department of Pharmacology, Government Medical College, Kannur, Kerala, India
3 Department of Community Medicine, Government Medical College, Kannur, Kerala, India
|Date of Submission||21-Jul-2020|
|Date of Decision||23-Nov-2020|
|Date of Acceptance||07-Sep-2020|
|Date of Web Publication||26-Aug-2021|
Department of Dermatology, Government Medical College, Kannur - 670 503, Kerala
Source of Support: None, Conflict of Interest: None
Background: Cutaneous adverse drug reactions (CADRs) are common among adverse drug reactions (ADRs). Early identification of ADRs can reduce the morbidity and mortality rates. Objectives: To know the pattern of various types of CADRs and to find out the causative drugs involved. Materials and Methods: Retrospective analysis was performed from ADR register, kept in Dermatology department in a tertiary care center. Naranjo's algorithm was used to determine the causality assessment. Details regarding drug intake, morphology of eruption, offending drugs, history regarding hospitalization, drug rechallenge or drug dose modifications, and treatment given to the patients were assessed. The data were subjected to descriptive analysis. Results: A total of 216 patients were recruited into the study, of which 118 were male and 98 were female. Antimicrobials (30.1%) were noted to be the most common offending drugs, followed by antiepileptics (18.1%), analgesics and antipyretics (11.1%), and anticancer drugs (11.1%). The most common presentation of CADR was maculopapular drug eruption (31.5%), followed by fixed drug eruption (13.4%). Conclusion: Among the antimicrobials, penicillins (13.9%) were the most common cause of CADR, followed by cephalosporins (8.8%) and fluoroquinolones (6.9%). A total of 28 patients (13%) were found to have severe cutaneous adverse reactions to drugs. It is important to closely monitor the patient, when a new drug is introduced, which will aid in detecting and preventing of CADRs.
Keywords: Antimicrobials, cutaneous adverse drug reactions, maculopapular drug eruption
|How to cite this article:|
Rajendran L, Thyvalappil A, Sridharan R, Ajayakumar S, Sparshadeep E M, Divakaran B. A study of cutaneous adverse drug reactions in a tertiary care center in south India. Clin Dermatol Rev 2021;5:173-7
|How to cite this URL:|
Rajendran L, Thyvalappil A, Sridharan R, Ajayakumar S, Sparshadeep E M, Divakaran B. A study of cutaneous adverse drug reactions in a tertiary care center in south India. Clin Dermatol Rev [serial online] 2021 [cited 2021 Dec 1];5:173-7. Available from: https://www.cdriadvlkn.org/text.asp?2021/5/2/173/324557
| Introduction|| |
Cutaneous adverse drug reactions (CADRs), often referred to as drug eruptions, are common among adverse drug reactions (ADRs). Approximately 10%–30% of ADRs have cutaneous manifestations of which 2%–3% are seen in hospitalized patients.,, Milder forms of CADRs include maculopapular rash, fixed drug eruption (FDE), morbilliform rash, urticaria, purpura, vasculitis, and a number of other manifestations. Sometimes, it is difficult to find out whether a specific reaction was caused by drugs or not. A detailed patient history for drug use is crucial. Life-threatening CADRs are called severe cutaneous adverse reactions (SCAR). They include Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), acute generalized exanthematous pustulosis (AGEP), and hypersensitivity syndrome or drug reaction with eosinophilia and systemic symptoms (DRESS). Early identification of ADRs can reduce the morbidity and mortality rates. This study was conducted to know the pattern of various types of CADRs and to find out the causative drugs involved.
| Materials and Methods|| |
This retrospective study was conducted at a tertiary care hospital in South India after obtaining approval of the institutional ethical committee. The department of dermatology keeps a registry of all patients with CADRSs. Data involving 216 subjects, both inpatients and outpatient patients of either sex, and of all age groups with a clinical diagnosis of ADR, who were seen at the department were collected, dating from January 2014 to December 2019. The records had details regarding the morphology of eruption, associated mucosal or systemic involvement, previous allergic history drug intake, temporal correlation to drug intake and the onset of symptoms, duration of reaction, and also history regarding hospitalization, rechallenges or drug dose modifications and treatment given to the patients. ADRs caused from the usage of traditional or nonallopathic standardized medications and patients against whom the specific offending drug was not mentioned were excluded from the study.
The final decision of casualty was done according to Naranjo ADR probability scale. The Naranjo's algorithm uses ten questions based on the information for previous conclusive reports of drug-ADR pair, temporal relationship, de-challenge, re-challenge, alternative explanation, plasma concentration of drug, dose, and intensity of ADR relationship, past reactions with similar drugs and of confirmation of reaction with objective evidence. It scores every ADR from −4 to +13. Depending on the score, ADR is considered as “definite” (>9), “probable” (5–8), “possible” (1–4), or “doubtful” (<1). For this study, only those patients entered under the first three categories were selected. The data were subjected to descriptive analysis. Since it was an observational study, no statistical test was conducted.
| Results|| |
A total of 216 patients were recruited into the study, of which 118 were male and 98 females [Table 1]. Age-wise distribution of the subjects is provided in [Table 2]. Majority of the patients developed symptoms in a span of 1 week. Fifteen patients developed the symptoms in <24 h, whereas 17 patients presented only after a month, which included antiepileptic, antituberculous, and anti-cancer drugs.
The time periods of development of symptoms after drug intake (lag period) of different types of reaction were noted. The mean lag period of angioedema was lowest, i.e., 8 h followed fixed drug reaction by 17 h. The mean lag period for urticaria was 37 h, SJS and TEN were 4 days and 3.6 days, respectively, AGEP developed in a mean period of 3 days. Maculopapular rash and erythema multiforme took 6 and 5.3 days. Exfoliative dermatitis and baboon syndrome both developed in 8 days. DRESS in 9.6 days, Acneiform eruption in 12 days and lichenoid drug reaction in 14 days.
Only about one-tenth of the patients were able to give a definitive history of previous adverse reaction to intake of a drug or drug of the same pharmacological group [Table 3]. One hundred and ninety-one patients (88.4%) denied taking the same drug or drug of the same group previously. In some patients, more than one drug was given and was difficult to narrow down to one drug alone. Only 5% of patients had a history of atopic features. Ninety percent of patients had no prodromal symptoms. The itching was the most common presenting complaint.
The progression of symptoms after the onset of cutaneous drug reaction was seen in 75%, while associated symptoms such as itching or burning were seen in 72% of the patients. Itching was the predominant symptom in 88% of the study patients, followed by burning in 20% of the patients. Multiple symptoms, i.e., fever, pain, itching, and burning were present in 18% of the study patients. History of similar episodes of cutaneous drug reaction to a similar drug was present in 10% of the study patients.
Antimicrobials (30.1%) were noted to be the most common offending drugs, followed by antiepileptics (18.1%), analgesics cum antipyretics (11.1%), and anticancer drugs (11.1%). Among the antimicrobials, penicillin group were the most common (13.9%), followed by cephalosporins (8.8%) and fluoroquinolones (6.9%).
Among the penicillin group, amoxicillin was the most commonly consumed and among antiepileptics was phenytoin (11.1%) was the most common culprit. In the analgesics cum antipyretics group, paracetamol (3.2%) was the most common causative drug. Fluoroquinolones were responsible for CADRs in 15 patients (6.9%). Of the 15 cases, 12 were caused by first-generation fluoroquinolones (ciprofloxacin, norfloxacin, and ofloxacin) and the remaining three by newer-generation fluoroquinolones.
The most common presentation of ACDR was maculopapular drug eruption as seen in 68 patients (31.5%), followed by FDE in 29 patients (13.4%) and erythema multiforme in 14 patients (6.5%). Antimicrobials were responsible for most cases of maculopapular drug eruption and erythema multiforme (40% and 57% respectively), followed by anticonvulsants (22% and 15%, respectively). Antimicrobial was again most responsible for FDEs (48%), which was followed by analgesics (31%). Lesions mainly included over the face, upper limb, and lower limbs. Mucosal involvement was seen in 31% of total patients.
SCARs accounted for 13% of the total CADRs. These cases were SJS, TEN, DRESS, AGEP, exfoliative dermatitis. None of them had family history of SCAR. A total of 28 patients (13%) were found to have SCAR, with SJS-TEN and overlap of the two being the most common SCAR. This accounted for about half of SCAR patients (6.5%). In SCAR patients, anti-epileptic phenytoin contributed to a large number cases (16 of 28). Eosinophilia was present in five patients (14.67%) with SCARs, six patients (22.8%) had deranged liver enzymes, and four patients (13.33%) had deranged renal profile. Death occurred in 1 case of SCAR.
The mean body surface area (BSA) for monotherapy was 15.5 and the mean BSA for FDE in monotherapy was 3.69% as compared to polytherapy, which was 7.4% and was statistically not significant. Similarly, we calculated the mean BSA for maculopapular rash, erythema multiforme, urticaria, SJS/TEN in monotherapy and compared with polytherapy, but the findings were not statistically significant.
Causality assessment was made with the help of Naranjo's scale. Most of the study patients were in probable causality assessment of the Naranjo's scale, i.e., 75%, followed by definite in 12% and possible in 13% of the patients. Scale was most useful in establishing causality in cases of fixed drug reaction, which demonstrated definite association in 31.6% of cases of FDE. However, most of the CADRs (75%) were in probable causality assessment of the Naranjo's scale.
Drug withdrawal was made in 188 patients (87%). The drugs were replaced by the chemically unrelated drug in 93 patients (43.1%) and in 17 patients, a dose reduction was done rechallenge was done only in one patient with antituberculous drugs. Once identified, the drug responsible for CADR, patients were given a drug card mentioning the name of the offending drug and also a list of cross-reacting drugs.
| Discussion|| |
Cutaneous reactions are one of the common manifestations of ADRs. CADRs are distressing to both the patient and physician. CADRs may vary from mild benign reaction to those that are life-threatening. The development of a skin eruption is a common cause for treatment noncompliance. ADRs are a common reason for litigation too. Failing to warn a patient about possible side effects, prescribing a drug to a previously sensitized patient, and prescribing a related medication with cross-reactivity are common medicolegal issues and therefore should be addressed seriously.
The treating doctor should have a thorough knowledge of the clinical spectra of CADRs, as well as knowledge of the drugs which are frequently involved in such adverse reactions. This will definitely help to minimize the extent of iatrogenic morbidity and mortality. There are no specific tests for the diagnosis of CADRs. Taking a proper history, including duration of drug intake, reaction time, the response of drug dechallenging and rechallenging of the suspected drug, and any past history of similar reactions may aid in diagnosing CADRs. Biochemical methods that measure the blood level of drugs such as high-performance liquid chromatography, liquid chromatography-mass spectrometry, liquid-liquid extraction, solid-phase extraction, and protein precipitation tests, are not easily available in India. Histopathology is helpful in the diagnosis of CADR, such as FDE, SJS/TEN, lichenoid drug reaction, and AGEP. Severe reactions are unlikely to be detected in premarketing clinical trials because of the low frequency of such severe reactions. Such reactions to new drugs can be noticed only if clinicians recognize and report severe reactions to regulatory authorities and manufacturers.
In our study, a slight male predominance (male:female = 1.2:1) was noted, which is in conformity with the study done by Jha et al. and Patel and Marfatia., In contrast, another study done by Pudukadan and Thappa showed a female preponderance. In this study, the frequency of CADRs was maximum in patients with an age group of 40–60 years (38.4%). This may be explained by increased use of medicines as age advances, thus leading to more drug interactions. The decline after 60 years could be due to the decreased immunity associated with old age.
The frequency of atopy was found to be on the lower side in our study (5.1%). The frequency of atopy was 12.40% in the study by Jha et al., which was comparable to the findings of Inbaraj et al. where 6.8% of patients were found to have bronchial asthma., In contrast, a study done by Al-Raaie and Banodkar found 21.0% of patients to have personal or family history of atopy.
The most common CADR noted in our study was maculopapular drug eruption (31.5%), which is in conformity with the studies done by Saha et al. (30.18%), Choon and Lai (42.3%), Noel et al. (35%), and Jha et al. (42.64%).,,, Al-Raaie et al. (35%) and Chatterjee et al. (27.19%) found drug-induced urticaria more common in their studies., Pudukadan and Thappa found FDE to be more common. This variation could be due to the variation in the pattern of drug utilization, the reaction rates of the drugs and the pharmacogenetics traits of the population being studied [Table 4].
|Table 4: Comparison of clinical types of cutaneous adverse drug reactions with previous studies|
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Antimicrobials were the most common offenders in our study (30.1%). Similar findings were seen in studies by Jha et al. (64.73%), Chatterjee et al. (34.15), Mahatme and Narasimharao (48%), Choon and Lai (77.1%), and Pudukadan and Thappa (58.88%).,,,, Al-Raaie et al. found NSAIDs to be the most common causative drug, whereas Noel et al. found antiepileptics to be the most common offending drug in their study (44%) [Table 5]. Different patterns of drug usage in different populations studied can explain this variation.
|Table 5: Comparison of offending drug class causing cutaneous adverse drug reactions with previous studies|
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Penicillins group were the most common antimicrobials causing CADRs in our study, responsible for about 13.4% of cases, which was similar to some other studies., Cephalosporins were the most common drugs causing CADR in the study by Jha et al. (16.67%) and sulfonamides (17.00%) in the study by Saha et al., Amoxicillin was the only offending penicillin group noted in our study. Another study noted ampicillin (16.5%) to be more common, followed by amoxicillin (8.4%).
The most common offending drug causing exanthematous drug eruption noted in our study was Amoxicillin, which was similar to the findings by Amrinder et al. According to Saha et al. and Noel et al., antiepileptics to be the most common drug causing exanthematous type of CADR., Mucosal involvement was noted in 31.5% of subjects. While this was similar to the findings of Jha et al., (27.52%) much lower was reported by another study (5.1%).
SCARs accounted for 13% of the total CADRs, which was similar to a study by Sasidharanpillai et al., Saha et al. (32.04%), while Choon and Lai (39.7%) reported a higher incidence of SCAR., Few other studies had lower incidence., The incidence of SCARs differs by time of recognition of drug eruption and withdrawal of the suspected drug, and proper management of patients, halting progression of the drug eruption. None of our patients had family history of SCAR. As some familial cases have been reported in cases of SACR, it is recommended that, first-degree relatives should be warned about their increased risk of reaction to the same drugs.
A total of 28 patients (13%) were found to have SCAR with SJS, TEN and overlap of two being the most common SCAR. This accounted for about half of SCARs patients (6.5%). Other studies have quoted varying numbers from 30.39% by Choon and Lai, 6.84% by Patel et al., and 2.32% by Jha et al.,, Most of the studies have reported antiepileptics to be the most common drugs causing SCARs like in ours.,, Phenytoin was the most common antiepileptic to cause SCAR in our study (16 of 28). A systematic review of SJS/TEN in the Indian population reported fluoroquinolones as the most common causative antimicrobials, as was seen in our study.
The limitation of the study was the exact incidence of cutaneous ADRs could not be ascertained because it was spontaneous method of ADR reporting. The single centered study was another limitation of this study. The antimicrobial prescription pattern differs in government and private health-care set up. Our cases were from a tertiary care teaching government hospital. Drug rechallenge was not attempted deliberately except in one case. Long-term follow-up and monitoring of the patients could not be done.
| Conclusion|| |
A wide clinical spectrum of CADRs ranging from FDE to exanthematous drug eruption to serious SJS was observed. Antimicrobials were noted to be the most common offending drugs, followed by antiepileptics. The most common presentation of CADR was maculopapular drug eruption followed by FDE. It is important to closely monitor the patient when a new drug is introduced, which will aid in early detection and prevention of ADRs. Patients should be advised to avoid self-administration of drugs and re-administration of the offending drug. We recommend more studies to create an awareness of possible ADRs and to help in the early recognition of ADRs to prevent iatrogenic morbidity and mortality.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient (s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initial s will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]