Cutaneous adverse drug reactions from a teaching hospital in Bengaluru: An observational study to determine the spectrum and outcome.
Adverse drug reaction (ADR) has been defined by the World Health Organization (WHO) as "any response to a drug which is noxious and unintended, and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of disease, or for the modification of physiological function."  It has been estimated to be fourth or sixth leading cause of death among hospitalized patients.  It also leads to increased financial burden as the ADR-related costs, such as hospitalization, surgery and lost productivity, often exceed the cost of the medications.  Cutaneous ADR (CADR) is any undesirable change in the structure or function of the skin, its appendages or mucous membrane and encompasses all adverse events related to drug eruption, regardless of the etiology. 
CADR is the most frequent of all manifestations of drug sensitivity.  It is recognized to be a major health problem worldwide having an incidence of 1-3% in developed countries and 2-5% in developing countries. [5,6] There is a wide spectrum of CADR ranging from a transient maculopapular rash to fatal toxic epidermal necrolysis (TEN). 
Drugs, no matter how safe and efficacious, are always associated with risk of adverse reactions.  Development of a skin eruption frequently leads to discontinuation of the treatment, impairment of quality of life and increasing costs of patient care.  Commonly used drugs implicated in CADRs are penicillins, sulfonamides, anticonvulsants, nonsteroidal anti-inflammatory drugs (NSAIDs), etc.  Early recognition and withdrawal of the offending drug improves outcome in the management of CADR. Knowledge of drugs that can cause CADR can help physicians in choosing safer drugs. 
Pharmacovigilance is "the science and activities relating to the detection, assessment, understanding, and prevention of adverse effects or any other drug-related problems." In 1968, the WHO established the International Drug Monitoring Programme to collect data on ADRs and to issue public warnings when warranted. The monitoring and reporting of an ADR is an integral part of drug therapy but is still at infant stage in India.  As new drugs are being introduced every year, every health-care professional must have knowledge about the importance of pharmacovigilance. 
As the pattern of CADRs is changing every year with the introduction of new medications and evolving prescription practices, understanding its precise nature may help narrow down the search for the offending drug. [4,10] Bangalore Medical College and Research Institute (BMC and RI) is one of the ADR Monitoring Centre under Pharmacovigilance Programme of India (PvPI). This study has been undertaken to assess the clinical spectrum, causality, severity, and preventability of various CADRs reported from BMC and RI to the PvPI.
Aims of the Study
1. To determine the clinical spectrum of CADRs and the drugs associated with it
2. To assess the causality, severity, and preventability of CADRs.
MATERIALS AND METHODS
An observational study was conducted from January 2012 to May 2016 to analyze the CADRs reported spontaneously from Dermatology Department of BMC and RI to ADR Monitoring Centre, under PvPI. Patient's demographics, clinical and drug data, details of ADR, onset time, causal drug details, outcome, and severity were collected as per CDSCO form. Causality was assessed using WHO-ADR probability scale; severity was assessed using modified Hartwig and Siegel severity scale and preventability were assessed using modified Schumock and Thornton scale. The data were analyzed using descriptive statistics to study the characteristics of the ADRs. The results were expressed as percentages, odds ratio, etc.,
A total of 809 ADRs were reported, of which 230 (28.4%) were CADRs. Male patients constituted 56% of the total cases. The age group of 21-40 years (57%) was most affected followed by 41-60 years (22.6%) (Table 1). The age range was 4-79 years.
Antimicrobial agents accounted for the highest number of CADRs (37.8%), followed by NSAIDs (17.4%) and antiepileptic drugs (13.5%) (Table 2). Ceftriaxone (12.6%) was the most common offending drug. Other commonly implicated drugs were phenytoin (10.9%), nevirapine (10.9%), and diclofenac (10.4%) (Table 3).
Among the various known patterns of CADRs, the most common was maculopapular rash (26%), followed by fixed drug eruptions (FDEs) (21.7%), and erythematous rash (21.3%) (Figure 1). The offending drugs commonly associated with maculopapular rash were nevirapine (35%), phenytoin (17%), ceftriaxone (15%), and diclofenac (5%). FDEs were mainly caused by NSAIDs (30%) and fluoroquinolones (10%).
The most common severe CADR reported was Stevens-Johnson syndrome (SJS) (Figure 2), phenytoin (45.5%) and diclofenac (18.2%) being the most common causative agents (Table 4). The odds of developing SJS were 2.75 times more with phenytoin compared to diclofenac. Other severe CADRs
CADR: Cutaneous adverse drug reactions, NSAIDs: Nonsteroidal anti-inflammatory drugs encountered were erythema multiforme, TEN, angioedema, etc. Some rare CADRs, such as ambroxol-induced exfoliative dermatitis and dapsone hypersensitivity syndrome (DHS), were also noted.
Figure 1: Mild-to-moderate cutaneous adverse drug reactions Type of mild to moderate cutaneous adverse drug reactions Maculopapular rash 26.1% FDE 21.7% Erythematous rash 21.3% Acne 11% Urticaria 3.04% Others 3.32% Note: Table made from bar graph. Figure 2: Severe cutaneous adverse drug reactions Type of severe cutaneous adverse drug reactions SJS 4.0% TEN 3.04% Drug hypersensitivity 2.2% Erythema multiforme 1.3% Angioedema 0.9% Exfoliative dermatitis 0.9% Note: Table made from bar graph. Figure 3: Routes of administration Oral 67% Parenteral 25% Topical 8% Note: Table made from bar graph.
The oral administration of drugs was associated with a maximum number of CADRs (67%) followed by parenteral route (25%) (Figure 3). Interval between drug intake and first appearance of cutaneous lesions (reaction time) varied from 10 min to 108 days. Most of the CADRs occurred between 1 and 10 days of drug administration (55%).
The causative drug was withdrawn in 90% of cases. 86% of cases were managed with additional treatment, and no mortality was noted. According to WHO-UMC probability scale, 80.4% had probable causality and 19.6% had possible (Figure 4). The majority of the CADRs (81%) was of moderate severity (Figure 5). Severe CADRs were 6% such as clobazam-induced erythema multiforme and DHS. Preventability scale indicates 86.5% to be "not preventable" and 11% to be "definitely preventable (Figure 6)."
CADRs are distressing to both the patients and physicians. It may lead to poor quality of life due to hospitalization, prolonged hospital stay, increased morbidity, and even mortality in cases of severe reactions.  Not warning a patient about potential adverse effects, prescribing a medicine to a previously sensitized patient, and prescribing a related medication with cross-reactivity are common medicolegal pitfalls.  In this study, a total of 230 CADRs were reported from January 2012 to April 2016. The majority of the patients belonged to the age group of 21-40 years which is similar to the previous studies. Kongkaew et al. reported that higher number of CADRs in elderly could probably be due to polypharmacy and altered pharmacokinetics in them. [5,11] In our study, elderly constituted only 6.5% of the total CADRs. The youngest patient was 4-year-old, whereas the oldest patient was of 79 years. This shows that no age is exempted from CADRs. Our study showed that males (56%) were affected more than the females, which is similar to the study conducted by Sharma et al. in Jammu where male to female ratio was found to be 1.7:1.2.  Moulya et al. also observed a male preponderance (54.5%),  whereas Pudukadan and Thappa in South India showed men and women to be equally vulnerable (0.87:1).  As all these studies were institution based, the difference in demographic profile may be due to the regional variations in health-care seeking behavior of the patients.
Figure 4: Causality assessment of cutaneous adverse drug reactions Probable 45, 20% Possible 185, 80% Note: Table made from pie chart. Figure 5: Severity assessment Mild 27, 12% Moderate 187, 81% Severe 16, 7% Note: Table made from pie chart. Figure 6: Preventability assessment Definitely preventable 25, 11% Probably Preventable 7, 3% Not preventable 199, 86% Note: Table made from pie chart.
This study showed maculopapular rash as the most common reaction (26.1%) followed by FDEs and erythematous rash. These findings are comparable to the study by Saha et al. in which maculopapular rash, FDE, and severe bullous eruptions were the most common.  Sushma et al. also reported maculopapular rash as the most common CADR followed by SJS and FDE.  In our study, nevirapine was the most common drug associated with maculopapular rash, followed by phenytoin. Nevirapine is most commonly used non-nucleoside reverse transcriptase inhibitor as part of first-line antiretroviral therapy (ART) as it is well tolerated and effective. With revision of ART initiation guidelines, the incidence of nevirapine-induced CADRs has also increased.  Nevirapine-induced rash is related to the 12-hydroxylation of nevirapine and is presumed to be due to the conversion of 12-hydroxy metabolite to a reactive quinone methide in skin.  FDE was the second most common CADR reported in our study, the main offending agents being diclofenac and of loxacin. Acneiform eruptions contributed to 4.8% of the total cases, and topical steroids were common causative agents. In this study, severe CADRs constituted 6% of the total number, the most common being SJS (4.7%). SJS is an acute life-threatening mucocutaneous reaction characterized by extensive necrosis and detachment of the epidermis from skin. Its incidence is estimated to be 0.4-1.2/million person-years and has a mortality rate of nearly 1-5%.  It is a delayed type hypersensitivity reaction involving CD8+ cytotoxic T cells leading to keratinocyte apoptosis.  Cytolytic molecules FasL and granulysin also play a role in the pathogenesis of SJS/TEN.  This study showed phenytoin, diclofenac, and carbamazepine to be frequently associated with SJS. This finding was similar to the study conducted by Sasidharanpillai et al. in Kerala, who also found antiepileptic drugs to be the most common class of drugs associated with SJS.  Epilepsy is one of the most common neurological diseases, affecting about 50 million people worldwide, and antiepileptic drugs are the mainstay of treatment.  Antiepileptic drugs are metabolized to toxic substances that are subsequently detoxified in most individuals, but due to a genetic defect in some individuals, the metabolites may bind to the proteins and trigger an immune response leading to SJS.  Studies have also shown an association between HLA-B*1502 and SJS induced by carbamazepine and phenytoin. Thus, identification of genetic polymorphisms offers the possibility of avoiding these high-risk drugs in genetically susceptible individuals. [20,21] Five cases of drug hypersensitivity reactions were reported in this study that included a case of DHS. Dapsone is used for treatment or prophylaxis of several infections and dermatological conditions such as bullous dermatoses, cutaneous vasculitis, and dermatitis herpetiformis. It is one of the commonly implicated drugs in drug-induced systemic hypersensitivity syndrome, apart from anticonvulsants, sulfonamides, etc. DHS is a rare dose-independent adverse effect that can develop several weeks to months after treatment initiation and the incidence reported ranges from 0.5% to 3%.  The proposed mechanism of DHS-metabolites of dapsone form haptens with the production of anti-dapsone antibodies. Differences in dapsone metabolism affect the production and detoxification of its reactive metabolites, and this might be responsible for differential susceptibility of people to the adverse effects of dapsone. Mortality of 12-23% has been reported in severe cases and thus early diagnosis, along with prompt treatment is essential to prevent fatalities. 
The most common class of drugs implicated in causing CADRs was antimicrobial agents. Beta-lactam antibiotics and fluoroquinolones were the major offending antimicrobials, with ceftriaxone being the most common beta-lactam, whereas ofloxacin was the most common fluoroquinolone. A possible mechanism for the development of drug-related exanthematic reaction is proposed to be an interaction between infection and drug exposure.  According to the study by Pudukadan and Thapa, sulfonamides were the most common offending antimicrobials, whereas Sharma et al. in Jammu showed Tinidazole to be most frequently associated with CADRs. This disparity may be due to the difference in pattern of drug use in different hospitals. In our study, NSAIDs accounted for a high number of the total CADRs and were next only to antimicrobials. Diclofenac, followed by ibuprofen, were the major offending NSAIDs. Diclofenac was frequently associated with moderate CADRs, most common being FDEs. The previous studies have shown that diclofenac-induced severe cutaneous reactions are very rare. In a study of 373 cases of TEN/SJS conducted by Mockenhaupt et al., the oxicam NSAIDs (piroxicam and tenoxicam) were shown to have the highest risk while the relative risk with diclofenac was low. [24,25] Inconsistent with the previous literature; the incidence of diclofenac-induced SJS was high in this study. This could be attributed to the increasing use of diclofenac as an over the counter drug for pain relief and inadequate recording of history of drug allergy in our set up.
The time interval between drug administration and the first appearance of cutaneous lesion varied with the type of CADR and the drug. In this study, it ranged from 10 min to 108 days. Most of the drug reactions occurred between 1 and 10 days of drug administration. Considering the different drugs and their respective reaction times, it appears that some of the drugs such as antimicrobial agents and analgesics have short reaction time, whereas antiepileptic drugs and antiretroviral drugs tend to take more time to develop the reaction.  This implies that physicians need to be vigilant about recent as well as remote drug history, which may be helpful in identifying the offending drug, and will prevent unnecessary withdrawal of innocuous medication.  According to the WHO-UMC causality assessment, the majority of the CADRs in our study had a probable causal relationship with the implicated drug. The causality could not be established as "Certain" because rechallenge was not done due to ethical considerations. Some of the CADRs had a possible causality, mostly owing to the concurrent use of other medications. 11% of the CADRs were definitely preventable, common reasons being the improper recording of the previous drug reaction history, and wrong choice of self-medications by the patients. Inappropriate use of topical steroids was a common cause of rashes and acneiform eruptions. The majority of the CADRs were not preventable according to Modified Schumock and Thornton scale. Modified Hartwig and Siegel severity scale showed most of the CADRs to be of moderate severity. Mild CADRs were less (11%) which could be a result of underreporting of mild and self-limiting cases. Severe CADRs (6%) such as SJS-TEN and exfoliative dermatitis required prolonged hospitalization and intensive care monitoring but no mortality was reported. The study highlights the importance of timely diagnosis and prompt withdrawal of the offending drug as it can be lifesaving. This study had some limitations. It was a retrospective study based on the analysis ofthe reported ADRs, so the patients follow-up was not possible. Furthermore, it did not provide a reliable estimate of reaction rate. Most of the patients attending the outpatient department of this hospital belong to low socioeconomic status, so the pattern of drug use among them is mainly restricted to the drugs supplied from the hospital pharmacy. Therefore, the generalizability of drug data generated from this study was not possible. Despite the above limitations, the study had strengths too. As it was a 5 years retrospective analysis of 809 spontaneously reported ADRs, it revealed some important aspects of CADRs. Some rare reactions such as DHS and ambroxol-induced exfoliative dermatitis were noted. It is evident that there is a need to create awareness among physicians as well as patients regarding CADRs so as to reduce the morbidity and mortality. A robust ADR monitoring system is the need of the hour and regional centers could play a role in the education of health-care providers in pharmacovigilance.
A wide clinical spectrum of CADRs was observed. Definitely preventable CADRs were found to be due to the absence of recording previous history of drug allergy and wrong choice of self-medication by the patients. Inconsistent with the previous literature, incidence of diclofenac-induced SJS was high in this study. Although the mortality reported for DHS is high, it was prevented by early diagnosis and management in our center. Diligent and timely reporting of drug reactions are required as the most common offending drugs vary with the general prescription practices in a region and an early recognition of various morphological patterns can lead to timely intervention with better outcomes.
The authors would like to thank the faculty and Postgraduate students from the Department of Pharmacology and Department of Dermatology, BMC and RI, Bengaluru, for their support in conducting the project work.
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How to cite this article: Jayanthi CR, Bedwal A, Rajarathna K. Cutaneous adverse drug reactions from a teaching hospital in Bengaluru: An observational study to determine the spectrum and outcome. Natl J Physiol Pharm Pharmacol 2017;7(5):476-481.
Source of Support: Nil, Conflict of Interest: None declared.
Jayanthi C R, Ankita Bedwal, Kavitha Rajarathna
Department of Pharmacology, Bangalore Medical College and Research Institute, Bengaluru, Karnataka, India
Correspondence to: Ankita Bedwal, E-mail: firstname.lastname@example.org
Received: December 06, 2016; Accepted: December 25, 2016
Table 1: Demographic details Variables Characteristics Number of CADRs N=230 (%) Age (years) 0-20 32 (13.9) 21-40 131 (57) 41-60 52 (22.6) >60 15 (6.5) Gender Male 129 (56.1) Female 101 (43.9) CADR: Cutaneous adverse drug reactions Table 2: Therapeutic classes of drugs causing CADRs Therapeutic Number of CADRs N=230 (%) classes of drugs Antimicrobial agents 87 (37.8) NSAIDs 40 (17.4) Antiepileptic drugs 31 (13.5) Antiretroviral agents 31 (13.5) Corticosteroids 12 (5.2) Antifungal agents 4 (1.7) Gastrointestinal agents 4 (1.7) Miscellaneous 21 (9.13) Table 3: Antimicrobial agents causing CADRs Class of Antimicrobial Number of CADRs (N=87) antimicrobials agents Beta-lactams Ceftriaxone 29 Cefixime 5 Cefotaxime 5 Amoxicillin-clavulanic 5 acid Piperacillin-tazobactum 3 Cefuroxime 1 Fluoroquinolones Ofloxacin 14 Ciprofloxacin 10 Levofloxacin 1 Antitubercular drugs Rifampicin 8 Isoniazid 1 Macrolides Azithromycin 1 Erythromycin 1 Sulfa drugs Cotrimoxazole 1 Dapsone 1 Antiamoebic drugs Metronidazole 1 CADR: Cutaneous adverse drug reactions Table 4: Drugs causing severe CADRs Severe CADRs Drugs SJS (11) Phenytoin (5), diclofenac (2), ceftriaxone (1), cefuroxime (1), nevirapine (1), carbamazepine (1) TEN (3) Phenytoin (2), aceclofenac (1) Drug hypersensitivity (5) Phenytoin (3), dapsone (1), carbamazepine (1) Erythema multiforme (4) Paracetamol (1), clobazam (1), diclofenac (1), phenytoin (1) Angioedema (2) Efavirenz (1), ceftriaxone (1) Exfoliative dermatitis (1) Ambroxol (1) SJS: Stevens-Johnson syndrome, TEN: Toxic epidermal necrolysis
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|Title Annotation:||RESEARCH ARTICLE|
|Author:||Jayanthi, C.R.; Bedwal, Ankita; Rajarathna, Kavitha|
|Publication:||National Journal of Physiology, Pharmacy and Pharmacology|
|Date:||May 1, 2017|
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