The World Health Organization (WHO) defines adverse drug reaction as a response to a drug that is noxious and unintended, which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of disease or for the modifications of physiological function. Adverse cutaneous drug reactions (ACDRs) cause a major problem in drug therapy. Most of the reactions often are underreported, and many questions regarding the pathogenesis are yet to be addressed.
The cutaneous adverse drug reactions vary from transient maculopapular rash to fatal toxic epidermal necrolysis (TEN). Fatal reactions are almost always unpredictable, because of the complex underlying immunological mechanisms. The pattern of cutaneous adverse drug eruptions and the drugs responsible for them keep changing with time. The diagnosis of cutaneous drug eruptions is based on detailed history and correlation between the drug intake and the onset of rash. Prior sensitization is required which is usually silent. The subsequent exposure may produce symptoms within seconds to minutes of exposure. Various causality assessment scales are World Health Organization Collaborating Centre for International Drug Monitoring, the Uppsala Monitoring Centre (WHO-UMC), and Naranjo, among which WHO-UMC ADRs were categorized into certain, probable, possible, unlikely, and conditional. Naranjo’s causality assessment scale whereby the ADRs were classified into definite, probable, possible, and doubtful. Depending on the severity, ADRs were classified into mild, moderate, and severe reactions using the criterion developed by Hartwig–Siegel scale for severity assessment.
Materials and Methods
In this observational study, we have seen 2,96,544 patients in the skin department at a rural-based tertiary health-care hospital, out of which 728 cases were diagnosed to have ACDR from a time span of April 2010 to March 2021. After taking ethical approval from the institutional ethics committee (PSMC/HREC/ONCO No: 3), using a preformed proforma, basic demographic data was taken with chief complaints, onset of complaints, duration, and type of illness. Causative drug (self-medication or prescribed) and time between onset of symptoms after taking the drug were taken into evaluation. The causality assessment system proposed by the WHO-UMC, Naranjo probability scale, and Hartwigs score were calculated for each patient to assess whether there is a causal relationship between an identified untoward clinical event and a drug. Any significant past or family history of similar reaction to the same group of drugs or any other group was taken. A thorough clinical examination was performed. Descriptive statistics [mean (SD), frequency (%)] were used to depict the profile of study participants. The frequency (%) was used to present morphological types of ACDR and suspected drugs as well as various ACDR score’s components. The analysis was conducted using STATA (14.2).
The study was carried out from April 2010 to March 2021 in the skin department at a rural-based tertiary health-care hospital. Out of total OPD of 2,96,544 patients during the study duration, 728 cases were diagnosed to have ACDR (prevalence—2.4%), among which 50.96% (371) were males and 49.03% (357) were females with a male/female ratio 1.03:1. Majority were in the 21–30 years of age group (n = 183, 25.13%). The youngest age being a 2-year-old male child and the oldest being an 80-year-old female. [Table 1] The most common presenting complaint was erythematous rash (n = 155, 21.29%), followed by itching (n = 147, 20.19%) and eruption (n = 98, 13.51%) in our study.
Two hundred seventy-nine patients (38.43%) presented to the hospital within 12 h of appearance of skin lesion. Around 28.50% cases had gradual appearance and spread of lesions. Total 24.86% (n = 181) patients had taken drug for fever, followed by other complains like head injury/ road traffic accident (RTA)/stroke/epilepsy/seizure and upper respiratory tract infection (URTI), chronic obstructive pulmonary disease (COPD), asthma, etc.).
Antimicrobials were the most common drug group incriminated in 345 cases (47.39%), among which Ciprofloxacin (n = 82, 11.26%) and Metronidazole (n = 60, 8.2%) were the commonest. Other common causative drug groups were NSAIDs (n = 164, 22.52%) [Table 2]. The route of administration was oral in 653 patients and parenteral in 75 patients.
Past history of drug reaction was present in 186 cases, out of which 89 patients had history to same drug in past. History of atopy/allergy was present in 30 patients (4.07%). The maximum number of patients (72.32%) had <50% body surface area involvement, whereas 13.97% cases had >75% body surface area involvement. Oral mucosa (n = 15, 2%) was the commonest mucosa involved followed by genital (n = 13, 1.7%) and conjunctival mucosa (n = 11, 1.6%).
Maculopapular rash [Figure 1a and b] was commonly seen in 182 (25%) cases followed by fixed drug eruptions (FDE) [Figure 2a and b] seen in 167 (22.93%) cases, urticaria was [Figure 3] in 160 (21.97%) cases and Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) [Figure 4a and b] were seen in 30 (4.12%) cases [Table 2].
In the causality assessment using WHO guidelines, there were 66 (9.1%) certain cases, 224 (30.83%) probable cases, and 436 (60%) possible cases. Naranjo score showed 73 (10%) definite cases, 255 (35%) probable cases, and 400 (55%) possible cases, while Hartwigs score showed level 2 in 122 (16.7%) cases and level 3 in 412 (56.7%) cases. [Table 3]
In the present study, a total of 728 cases were studied, among which 50.96% (371) were males and 49.03% (357) were females, which was similar to Jha et al.,Sasidharanpillai et al., Patel et al., and Agrawal et al. The most common age group affected was 21–30 years with 183 cases (25.13%) followed by the 31–40 years with 131 cases (18.01%), which was quite similar to Pudukadan et al. study, where most of the patients were in the age group of 20–39 years (52.2%) followed by 40–59 years of age group (24.4%). In the present study, the most common complaint was erythematous rash in 155 cases (21.29%) followed by itching in 147 cases (20.19%) and eruptions in 98 cases (13.51%), while the major presenting complaint was symptomatic rash (56.7%), followed by blistering (22%) in Pudukadan et al. study.
Time interval between the drug intake and the onset of reaction varies with the type of ACDR. It ranges from less than a day in urticaria to three weeks to 3 months in drug reaction with eosinophilia and systemic symptoms (DRESS). Most of the patients (38.43%) presented within 12 h of the drug eruption in our study, while in Sasidharanpillai et al. study, the latent period between the drug intake and the onset of symptoms varied from 12 h to 21 days and it was 2–5 days in Agrawal et al.
Most common illness for which the patients had taken the culprit drug was fever followed by other complains like head injury, RTA, stroke, epilepsy, seizure, and respiratory illness (URTI, COPD, asthma, etc.) in this study, while in Sasidharanpillai et al. study, 27.9% cases developed reaction following the drug intake for an infectious illness (antibiotics or NSAIDs).
All drugs are capable of producing any type and any severity of reaction in susceptible individuals, but some drugs are more likely to induce certain reaction patterns and this can give a clue regarding the likely causative drug. In the present study, antimicrobials were the most common drug group incriminated in 47.39% cases, among which Ciprofloxacin (n = 82, 11.26%) and Metronidazole (n = 60, 8.2%) were the commonest followed by NSAIDs in 22.52% cases. Similar to this, Pudukadan et al. study reported antimicrobials (60%) as the most common culprit group followed by antiepileptics (15.5%) and NSAIDS (15.5%). On contrary to this, the commonest drug group producing reactions were aromatic anticonvulsants (20/43, 46.5%) followed by antibiotics and NSAIDs in Sasidharanpillai et al. study.
In our study, a total of 186 (25.54%) cases had past history of drug reaction, out of that 89 (12.2%) cases had history to same drug in past and 27.7% had consumed the same drug earlier, 14.4% had a similar cutaneous reaction earlier in Pudukadan et al.study. Oral mucosa (2%) was the commonest mucosa involved followed by genital (1.7%) and conjunctival mucosa (1.6%), which is similar to Sasidharanpillai et al. study.
Maculopapular rash was commonly seen in 182 (25%) cases followed by FDE seen in 167 (22.93%) cases and urticaria in 160 (21.97%) cases in this study, which is similar to Agrawal et al. The most common pattern of cutaneous drug reactions observed in Patel et al. study was FDE (30.5%) followed by urticaria in 18.5% and morbilliform rash in 18% of the patients.
In the modern era, due to changing lifestyle, people are prone to develop multiple medical illnesses for which they have to take a lot many drugs which put them at a higher risk of developing ACDR. Multiple medical problems may also increase the chance of developing ACDR. In the causality assessment using WHO guidelines, there were 66 (9.1%) certain cases, 224 (30.83%) probable cases, and 436 (60%) possible cases, which is similar to Bharani et al., where out of 231 cases, 3 (1.3%) cases were classified certain, 68 (29.4%) cases as probable, and 160 (69.3%) cases as possible. In our study, Naranjo score showed 73 (10%) definite cases, 255 (35%) probable cases, and 400 (55%) possible cases, which was similar to Jadhav et al. Hartwigs score showed level 2 in 122 (16.7%) cases and level 3 in 412 (56.7%) cases, which is similar to Patel et al.
Maculopapular rash was the commonest presentation of cutaneous adverse drug reactions. Antimicrobial agents were most commonly associated with it. According to the Naranjo scale, the majority of the cutaneous drug reactions have a “possible” association with the offending drugs. Usual or unusual, all types of drug reactions are to be notified by clinicians to a responsible body, a watchdog which will help in formulating preventive measures and help both the patients and the treating physicians in long run.
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Conflicts of interest
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1. Wiffen P, Gill M, Edwards J, Moore A Adverse drug reactions in hospital patients: A systematic review of the prospective and retrospective studies. Bandolier 2002.
2. Roujeau JC, Allanore L, Liss Y, Mockenhaupt M Severe cutaneous adverse reactions to drugs (SCAR): Definitions, diagnostic criteria, genetic predisposition. Dermatol Sin 2009: 27; 203–9.
3. Sharma VK, Sethuraman G, Kumar B Cutaneous adverse drug reactions: Clinical pattern and causative agents—A six-year series from Chandigarh, India. J Postgrad Med 2001: 47; 95–9.
4. Hotchandani SC, Bhatt JD, Shah MK A prospective analysis of drug-induced acute cutaneous reactions reported in patients at a tertiary care hospital. Indian J Pharmacol 2010: 42; 118–9.
5. Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981: 30; 239–45.
6. Hartwig SC, Siegel J, Schneider PJ Preventability and severity assessment in reporting adverse drug reactions. Am J Hosp Pharm 1992: 49; 2229–32.
7. Jha N, Alexander E, Kanish B, Badyal DK A study of cutaneous adverse drug reactions in a tertiary care center in Punjab. Indian Dermatol Online J 2018: 9; 299–303.
8. Sasidharanpillai S, Riyaz N, Khader A, Rajan U, Binitha MP, Sureshan DN Severe cutaneous adverse drug reactions: A clinicoepidemiological study. Indian J Dermatol 2015: 60; 102.
9. Patel RM, Marfatia YS Clinical study of cutaneous drug eruptions in 200 patients. Indian J Dermatol Venereol Leprol 2008: 74; 430.
10. Agrawal A, Ghate S, Gupta AK, Dhurat R Clinical spectrum of cutaneous adverse drug reactions. Indian J Drugs Dermatol 2018: 4; 61–6.
11. 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.
12. Patel TK, Thakkar SH, Sharma DC Cutaneous adverse drug reactions in Indian population: A systematic review. Indian Dermatol Online J 2014: 5; S76–86.
13. Bharani KR, Chandel NR, Goyal CA Dermatological adverse drug reactions in tertiary care hospital: An analysis of causality and severity. Int J Basic Clin Pharmacol 2018: 7; 1620–5.
14. Jadhav A, Patil S, Manchanda I, Hasija R, Patil A Cutaneous adverse drug reactions in a tertiary teaching hospital: A prospective, observational study. Indian J Dermatol 2021: 66; 573.