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ORIGINAL ARTICLE
Year : 2022  |  Volume : 13  |  Issue : 2  |  Page : 98-102

A cross-sectional study of adverse cutaneous drug reactions with special reference to reaction time


1 Consultant Dermatologist, Taluk Hospital, Thrissur, Kerala, India
2 Department of Dermatology, Government Medical College, Manjeri, Kerala, India
3 Department of Dermatology, Government Medical College, Thiruvananthapuram, Kerala, India
4 Department of Dermatology, Government Medical College, Thrissur, Kerala, India

Date of Submission24-Aug-2022
Date of Acceptance27-Oct-2022
Date of Web Publication10-Jan-2023

Correspondence Address:
Dr. Sandhya George
Department of Dermatology, Government Medical College, Manjeri, Kerala
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mjmsr.mjmsr_49_22

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  Abstract 


Background: Adverse cutaneous drug reactions (ACDRs) present with different morphologies and times of onset. Knowledge about the common drugs causing them, their reaction time (time interval between drug intake and the onset of symptoms), and the clinical presentations are helpful in identifying an offending drug, especially in the setting of multiple drug therapies, thereby reducing the morbidity and mortality associated with them. Aims: This study aims to identify causative drugs and clinical patterns of ACDRs in a tertiary care center and to estimate their reaction time. Methods: Sixty-two patients diagnosed to have ACDRs who attended the department of dermatology of a tertiary care teaching hospital during an 18-month period were selected for the study. They were classified into certain, probable, or possible categories as per the World Health Organization-Uppsala Monitoring Centre (WHO-UMC) classification. The frequency of each type of drug reaction, common causative agents, and reaction time of different drug reactions was analyzed. Results: Of the 62 patients, 40 (64.5%) were probable, 18 (29%) possible, and 4 (6.4%) were certain. The most common types of reactions encountered were fixed drug eruption (FDE) (13, 21%), drug hypersensitivity syndrome (12, 19.4%), and maculopapular rash (9, 14.5%). As a single group of drugs, antimicrobials were the most common causative agents (23, 37%) followed by anticonvulsants (16, 25.8%). As an individual drug, phenytoin was the most common causative agent (10, 16.1%), followed by paracetamol (7, 11.3%) and isoniazid (5, 8.1%). Reaction time varied from less than an hour for FDE and urticaria to 3–4 months for exfoliative dermatitis, lichenoid eruption, and folliculitis. Limitations: Small sample size was the major limitation. Conclusion: Reaction time varied from less than 24 h in FDE, urticaria, and angioedema to 3–4 months in exfoliative dermatitis, lichenoid eruption, and folliculitis.

Keywords: Adverse cutaneous drug reactions, latent period, reaction time


How to cite this article:
Deepthi P, George S, Sanker A, Asokan N. A cross-sectional study of adverse cutaneous drug reactions with special reference to reaction time. Muller J Med Sci Res 2022;13:98-102

How to cite this URL:
Deepthi P, George S, Sanker A, Asokan N. A cross-sectional study of adverse cutaneous drug reactions with special reference to reaction time. Muller J Med Sci Res [serial online] 2022 [cited 2023 Jan 27];13:98-102. Available from: https://www.mjmsr.net/text.asp?2022/13/2/98/367409




  Introduction Top


Adverse cutaneous drug reactions (ACDRs) present with different morphological types, each with a different time of onset. As new drugs are being developed day by day, the patterns of ACDRs are also changing. Knowledge about the common drugs causing drug reactions, identification of different morphological types, and their reaction time will help in prompt diagnosis of ACDRs and in identifying an offending drug, especially in the setting of multiple drug therapies, thus decreasing the morbidity and mortality arising from them.

The objectives of this study were to identify causative drugs and clinical patterns of ACDRs in a tertiary care center and to estimate their reaction time.


  Methods Top


The study was a cross-sectional descriptive study, carried out in the department of dermatology of a tertiary care teaching hospital from January 2015 to June 2016 after approval from the institutional ethics committee. Patients who were diagnosed to have ACDRs were included in the study. Criteria for exclusion were those who did not know which drugs were taken, whose skin lesions could be explained by other diseases, those who had cutaneous reactions to topical medications, and those who did not give consent to participate in the study.

After taking informed consent, relevant data were collected using a questionnaire and were recorded in a pro forma. Demographic data and clinical history including that of drug intake, onset and duration of skin lesions, and temporal association with drug intake were noted. Past history of drug rash, if any, was noted. All drugs taken before the onset of reaction for a time period usually associated with each reaction pattern were enlisted. History of atopy and that of other systemic illnesses such as renal disease, liver disease, collagen vascular disease, malignancy, and infections including HIV, intake of concurrent medications, and family history of drug allergy were noted. General examination and dermatological examination were done to characterize the type of skin lesions, distribution, and extent of involvement. A clinical examination of all systems was done.

Patients were investigated with complete blood count, blood sugar, serum electrolytes, and renal and liver function tests. Peripheral smear examination was done in suspected cases of drug hypersensitivity syndrome (DHS). Serum bicarbonate level was estimated in toxic epidermal necrolysis (TEN) cases for assessment of SJS/TEN-specific severity-of-illness score (SCORTEN). Viral markers (immunoglobulin M hepatitis A, surface antigen of Hepatitis B (HBsAg), anti-hepatitis C virus, and HIV) were done if clinically relevant. Biopsy was done in necessary cases.

Causality assessment was done based on the WHO-UMC classification and cases were categorized into certain, probable, or possible as per the definitions provided by the WHO collaborating center.[1] Rechallenge was not done for the purpose of the study. Whenever a rechallenge was done as part of management or when there was a history of rechallenge by the patient himself, resulting observations were recorded. Data were analyzed to find the frequency of each type of drug reaction, common causative agents, and reaction time in different drug reactions. Potential risk factors were noted and the association was analyzed using the Chi-square test.


  Results Top


The frequency of ACDR was 1.04/1000 (62/59,095) patients attending the dermatology department. There were 62 patients (34 males and 28 females) of which 15 patients belonged to 51–60 years age group. The mean age was 43.9 (+18.4) years. It was comparatively uncommon toward the extremes of age. According to the WHO-UMC classification, 40 (64.5%) were probable, 18 (29%) were possible, and 4 (6.5%) were certain cases.

Fixed drug eruption (FDE) was the most common type, accounting for 21% (n = 13), followed by DHS (19.4%, n = 12); maculopapular rash (n = 9); urticaria (n = 4); angioedema, lichenoid eruption, and xerosis (n = 3) each; exfoliative dermatitis, Stevens–Johnson syndrome (SJS), TEN, erythema multiforme (EM), photodermatitis, and Sweet's syndrome (n = 2) each; heparin-induced skin necrosis, acute generalized exanthematous pustulosis (AGEP), and drug-induced folliculitis (n = 1) each. Common drug groups causing each drug reaction are summarized in [Table 1].
Table 1: Common drug groups causing each type of drug reactions

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The most common causative agent were antimicrobials including antibiotics, antivirals, antifungals, and antituberculous drugs (n = 18; 29%) followed by anticonvulsants (n = 16; 25.8%). As an individual drug, phenytoin was the most common causative agent (n = 10; 16.1%), followed by paracetamol (n = 7; 11.3%) and isoniazid (n = 5; 8.1%). Anticonvulsants were the most common causative agents in DHS, SJS, TEN, and EM, whereas antimicrobials were more commonly implicated in a maculopapular rash, FDE, and photodermatitis. Phenytoin was implicated in five DHS, two maculopapular rashes, two SJS, and one TEN cases.

The most common cause for FDE was paracetamol (6/13), which showed a male preponderance (11/13, 84.6%) and had onset of skin lesions within 24 h of drug intake. Ciprofloxacin was causative in three cases. DHS was seen in 12 patients of whom 8 were caused by anticonvulsants (phenytoin-5). Reaction time was 3–4 weeks.

A maculopapular rash was found in nine patients. Antimicrobials were the most common causative drugs (five cases) followed by antiepileptics (two cases). The average reaction time was 1–2 weeks but in one patient, it was 40 days. Four patients had urticaria and the causative drugs were antimicrobials, nonsteroidal anti-inflammatory drugs (NSAIDs), paracetamol, and tramadol. All patients had lesions within 1 week of drug intake with three patients having onset within 24 h. Three patients had angioedema developed due to ramipril, amoxicillin, and omeprazole. Two patients had symptoms within 24 h, whereas one had an interval of 2 weeks between drug intake and skin lesions.

Lichenoid eruptions were present in three patients. Antituberculous drugs, chemotherapeutic agents (vincristine, paclitaxel, and carboplatin), and amlodipine were the drugs implicated. The reaction time varied from 3 weeks to 3 months. There were two cases of exfoliative dermatitis both due to isoniazid. Here, skin lesions appeared 2–3 months after drug intake.

There were two cases each of SJS and TEN. Two cases of SJS and one case of TEN were due to phenytoin. One patient had TEN due to carbamazepine. One patient had a past history of SJS and the skin lesions appeared within 1 week of drug intake. Other patients had a reaction time of 2–4 weeks. EM was seen in patients. Both were due to anticonvulsants, lamotrigine, and carbamazapene. Reaction time was 1–4 weeks.

Chemotherapeutic agents caused xerosis (three cases by docetaxel), maculopapular rash (one case), folliculitis (one case by erlotinib), and lichenoid eruption (one case). Reaction time varied from 3 weeks to 3 months. There were two cases of photodermatitis caused by doxycycline and cotrimoxazole. Reaction time was less than a week in both cases.

Heparin-induced skin necrosis developed within 24 h of starting heparin. One patient had AGEP due to fluconazole and the reaction time was 2 days. Two cases of Sweet's syndrome were seen, one due to cotrimoxazole (skin lesions in sun-exposed sites) and the other due to diclofenac (lesions were localized to the lower limbs). Reaction time varied from 1 to 3 weeks.

Reaction time is summarized in [Table 2]. Certain types of drug reactions such as DHS, exfoliative dermatitis, lichenoid eruption, folliculitis, and drug-induced xerosis had a longer reaction time of more than 3 weeks, whereas urticaria, FDE, angioedema, and maculopapular rash had shorter reaction time.
Table 2: Type of drug reactions with reaction time

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Concurrent intake of multiple drugs was present in 53 patients (85.5%). Eighteen patients (29%) had a coexistent systemic illness in the form of diabetes mellitus, hypertension, heart disease, bronchial asthma, liver disease, renal disease, malignancy, and psychiatric disease.

Past history of drug allergy was present in 14 patients (22.6%) and family history of drug allergy in five patients (8.1%). Personal or family history of atopy was obtained in seven patients (11.3%). Four patients had HIV infection in our study. Head injury was present in four patients and history of neurosurgery in two patients. Of the potential risk factors assessed among patients, concurrent intake of multiple drugs (P = 0.028) and past history of drug allergy (P = 0.003) were found to have a significant association with drug reactions.


  Discussion Top


The overall incidence of drug reactions was 1.04/1000 which was less when compared to an Indian systematic review, where it was 9.22/1000.[2] More males were involved and the mean age group was 43.6 which is comparable to an Indian study.[3] The most common pattern of ACDR was FDE, as in several other studies.[3],[4],[5] Some studies have found maculopapular rash and urticaria to be the most common type of ACDR.[2],[6],[7] In agreement with many studies, we found that antimicrobials including antibiotics, antivirals, antifungals, and antituberculous drugs were the most common causative agents followed by anticonvulsants.[2],[3],[6],[7],[8],[9],[10]

The most common cause of ACDR was phenytoin followed by paracetamol and that of FDE was paracetamol which is reported by other studies.[4],[5] Brahimi et al.[11] observed female preponderance in FDE which was not seen in our study. DHS was most commonly caused by anticonvulsants, especially phenytoin. DHS is commonly associated with the aromatic antiepileptic drugs phenytoin, carbamazepine, phenobarbital, and lamotrigine and usually occurs within 60 days of starting the therapy.[12] A relatively high number of DHS maybe because ours is a tertiary care center.

There were two cases each of SJS and TEN, due to phenytoin and carbamazepine which are the most frequent causes of these reactions in Indian studies.[13]

Common causative drugs described as causing lichenoid eruption are antimalarials, NSAIDS, penicillamine, and thiazide diuretics.[14] However, in our study, it was Isoniazid (INH), chemotherapeutic drugs, and amlodipine. Photodermatitis was induced by doxycycline and ciprofloxacin, which are common causes of the same.[15]

Two cases of exfoliative dermatitis were there and both were due to isoniazid. A similar case was reported by Garg et al.[16] Exfoliative dermatitis due to isoniazid is underreported.

Antineoplastic drugs can cause several adverse reactions in the skin. Xerosis has been reported with the use of docetaxel, paclitaxel, hormonal therapy, and epidermal growth factor receptor inhibitors.[17] Folliculitis was caused by erlotinib in our study which is a well-documented adverse effect.[18]

Similar findings as in our case of heparin-induced skin necrosis and photodistributed Sweet's syndrome due to cotrimoxazole have been previously reported.[19],[20]

Only a few studies have reported the reaction time. Noel et al. reported that the reaction time for different types of drug reactions were 2–7 days for maculopapular rash, 1–3 weeks in EM, 2–3 weeks for TEN, 1–3 weeks for SJS, 1–3 days for urticaria, 1–4 weeks for DHS, 3–4 weeks for photodermatitis, 6 weeks for exfoliative dermatitis, and 1 day for FDE.[6] AGEP usually develops within 24 h[15] and lichenoid eruption occurs many months after initiation of the drug.[14]

Although most types of ACDRs in our series had reaction time similar to what is described by Noel et al.,[6] we observed that one case of maculopapular rash developed 40 days after drug intake which is usually described to occur in 2–7 days. This case was maybe incomplete DHS. Some cases of exfoliative dermatitis were reported after 3 months of starting the drug intake which is longer than the usually described reaction time.

Of the potential risk factors assessed among our patients, concurrent intake of multiple drugs (P = 0.028) and past history of drug allergy (P = 0.003) were found to have a significant association with drug reactions. This potentially contributed to an increased risk of drug reaction in view of increased drug interactions. In a study by Pudukadan and Thappa, past history of drug allergy with similar cutaneous reaction was present in 14.4%.[3] Associations found in other studies including HIV infection,[21] presence of atopy in urticarial and morbilliform reactions,[10] and acute neurotrauma for anticonvulsant hypersensitivity syndrome[22] were not found significant in our study.

Limitations

The small sample size was the major limitation of this study.


  Conclusion Top


The most common type of drug reaction observed was FDE. The most common group of drugs producing ACDR was antimicrobials and the most common drug was phenytoin. Of the potential risk factors assessed among our patients, concurrent intake of multiple drugs and past history of drug allergy were found to have a significant association with drug reactions. Reaction time varied from less than an hour in FDE and urticaria to 3 months in exfoliative dermatitis, lichenoid eruption, and folliculitis.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Pudukadan D, Thappa DM. Adverse cutaneous drug reactions: Clinical pattern and causative agents in a tertiary care center in South India. Indian J Dermatol Venereol Leprol 2004;70:20-4.  Back to cited text no. 3
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