INTRODUCTION:

An adverse drug reaction (ADR) is any noxious, unintended, and undesired effect of a drug that occurs at doses used for prophylaxis, diagnosis, or therapy or for modification of physiological function¹.

The skin is the largest organ in the body and skin reactions due to drug exposure are a common problem. Any medicine can induce dermatological reactions and certain drug classes, such as non-steroidal anti-inflammatory drugs, antibiotics and antiepileptic, have drug eruption rates approaching 1% – 5%².

An adverse cutaneous reaction caused by a drug is any undesirable change in the structure or function of the skin, its appendages or mucous membranes and it encompasses all adverse events related to drug eruption, regardless of the etiology³.

Cutaneous adverse drug reactions (CADRs) are among the most common adverse drug reactions (ADRs) associated with drugs in which any type of skin reaction can be mimicked, induced or aggravated⁴. Cutaneous ADRs may vary from mildly discomforting to those that are life-threatening⁵. They account for patients' suffering, hospitalization and economic burden, and can sometimes be fatal. Cutaneous adverse drug reactions are among the most frequent adverse drug events, approximately 2.9% - 5.6% of the hospital admissions are due to ADR and 35% of the hospitalized patients experience at least one ADR during their stay in the hospital⁶.

Studies have found the overall incidence of CADRs in developed countries as 1-3%, while the incidence in developing countries is reported to be between 2-5%⁷.

Maculopapular rashes, fixed drug eruptions were observed to be the most common of the cutaneous ADRs⁸.

ADRs (occurring in approximately 1 in 1,000 hospitalized patients⁹) endangering patient's life are:

· Stevens-Johnson syndrome (SJS)

· Toxic epidermal necrolysis (TEN)

· Drug reaction with eosinophilia and systemic symptoms (DRESS)

· Acute generalized exanthematouspustulosis (AGEP).

Dermatologists and physicians usually come across many cases of suspected CADRs. Therefore, they should be familiar with different types of skin reactions to enable early diagnosis and prompt withdrawal of the causative drugs to prevent morbidity and mortality¹⁰.

Pharmacovigilance is defined as “the pharmacological science relating to the detection, assessment, understanding and prevention of adverse effects, particularly long-term and short-term adverse effects of medicines”¹¹. Pharmacovigilance is majorly known as drug safety. It is main integral part of clinical research, both clinical trials safety and post marketing. Pharmacovigilance is critical throughout the drug life cycle¹².Thisprogramme operates through a spontaneous reporting system to monitor adverse drug reactions. Prospective intensive monitoring can overcome the drawbacks of under-reporting of ADRs. To determine the cause of a drug eruption clinically, a logical approach based on clinical characteristics, chronologic factors, and generation of a focused differential diagnosis is required. It is essential to report serious suspected CADR to a pharmacovigilance network if the involved drug is a newly marketed medication or unusually related to cutaneous reactions¹³.

There are only a few studies conducted in India related to cutaneous ADRs. By conducting this study, we can identify the most common type of CADR that is seen in the hospital. We can assess the most common type of drug that causes CADRs and observe the range of severity of the reaction in different patients. This will help doctors in identifying the causative drug quicker and take appropriate action to treat the patient and give a replacement drug if necessary. This will also help the patients, who can be on the lookout for the symptoms and seek medical aid early.

Hence, this study was carried out to assess the pattern and the causative agents implicated in cutaneous ADRs in a tertiary health care teaching hospital in Southern India.

AIMS AND OBJECTIVES:

1. To study the pattern of various types of cutaneous adverse drug reactions.

2. Determine prevalence of each type of CADR in a tertiary health care teaching hospital.

3. To determine the causative drug(s) involved in causing the cutaneous ADR.

MATERIALS AND METHODS:

This prospective study was done in the department of dermatology in association with the department of pharmacology. Patients diagnosed with cutaneous adverse drug reactions were considered for this study. Patients were taken from the Dermatology OPD and the Anti-Retroviral (ART) Center. This study was carried out only after obtaining the consent of the patient and after receiving clearance from the Institutional Ethics Committee. This study was done over a period of two months in a tertiary care hospital in Hyderabad.

All patients who are diagnosed with cutaneous adverse drug reactions by a dermatologist in the tertiary health care teaching hospital were considered for the study.

A pro forma was used to collect data of demography, diagnosis, investigations, adverse reactions, their clinical morphology, causative drugs with dosage, route, frequency, and duration of administration, lag period to develop reaction (period between administration of drugs and appearance of lesions), its treatment and cost, outcome, severity, and concomitant medications¹⁴.

Inclusion Criteria:

1. All cases related to CADRs.

2. Cases with a relevant and complete history.

3. Patients >12 years of age are included.

Exclusion Criteria:

1. Patients who consumed alternative system of medicine¹⁵.

2. Patients who developed reactions that were not related to the drug.

Statistical Analysis:

The data collected from the case records is entered is MS Excel spreadsheet and analyzed as percentages.

The Naranjo Scale is used to assess the causality of the adverse drug reaction and the causative drug. It classifies ADRs into “definite”, “probable”, “possible” or “doubtful”. This algorithm assesses whether there is a causal relationship between an identified untoward clinical event and a drug using a simple questionnaire to assign probability scores. There is a total of ten questions that are answered as “Yes”, “No” or “Do not know”. Different point values (-1, 0, +1 or +2) are assigned to each answer. Total scores range from -4 to +13¹⁶.

Score	Interpretation of Score ¹⁶
Total Score ≥ 9	Definite - the reaction (1) followed a reasonable temporal sequence after a drug or in which a toxic drug level had been established in body fluids or tissues, (2) followed a recognized response to the suspected drug, and (3) was confirmed by improvement on withdrawing the drug and reappeared on re-exposure.
Total Score 5 to 8	Probable - the reaction (1) followed a reasonable temporal sequence after a drug, (2) followed a recognized response to the suspected drug, (3) was confirmed by withdrawal but not by exposure to the drug, and (4) could not be reasonably explained by the known characteristics of the patient’s clinical state.
Total Score 1 to 4	Possible. The reaction (1) followed a temporal sequence after a drug, (2) possibly followed a recognized pattern to the suspected drug, and (3) could be explained by characteristics of the patient’s disease.
Total Score ≤ 0	Doubtful. The reaction was likely related to factors other than a drug.

The severity of the drug reaction is measured using the Modified Hartwig and Siegel scale. There are seven levels as per their severity and they are classified amongst adverse drug reactions into mild, moderate and severe.

1. Mild: Level 1 and 2

2. Moderate: Level 3 and 4

3. Severe: Level 5, 6 and 7

OBSERVATIONS AND RESULTS:

A total of 110 cases have been reported in the Dermatology Out-Patient Department and the Anti-Retroviral Therapy (ART) Centre over a period of two months (September-November).

Age:

Figure 1: Distribution of Cases based on Age

From the data collected over the course of two months between September to November, it is clear that the majority of the patients that come with drug-related reactions fall under the age category of 31-40 years were 33 cases (30%). It is followed by the age groups 21-30 years (25.45%), 11-20 years (18.18%), 41-50 years (17.27%) in descending order. Very few cases have been recorded in the extremes of the age distribution graph.

From figure 1, it is clear that the affected population are the adolescents, the young adults and middle aged people. When the graph was plotted, the mean age for the CADRs was found to be 33 years of age.

Gender:

Figure 2: Distribution of cases based on Gender

Figure 2 shows the male-to-female proportion of patients that show the percentage of having suffered an adverse event due to usage of drug(s). The number of females that are suffering from a drug reaction constitute about 60% of the patient pool. Males contribute only 40% of the cases. There seems to be no clear reason why this seems to be the case¹.

Distribution of Cases:

Figure 3: Distribution of cases between the Dermatology OPD and ART Centre

We can see from figure 3, majority of the cases were recorded from the Dermatology OP (80.9%), while the rest were recorded from the Anti-Retroviral (ART) Centre (19.1%).

Both the departments showed various patterns of the adverse drug reactions. The cases that were recorded in the ART Centre are mild (Level 1) as per the modified Hartwig and Seigel scale. Cases from the Dermatology OPD showed a greater variation in the type of CADR recorded and also showed a variation in their severity.

Anti-Retroviral Therapy (ART) Centre:

Figure 4: CADRs recorded in the ART Centre (TLD/TLE Regimen)

Table 1: Prevalence of cases seen in the ART Centre

S. No	Type of CADR in ART Center	Most likely drug	No. of Cases	% of Cases
01	Skin Allergy	TLD/TLE Regimen	4	19%
02	Skin Problem	TLD/TLE Regimen	5	23.8%
03	Itching	TLD/TLE Regimen	2	9.5%
04	Skin Allergy	DTG/LPV/Rit	1	4.8%
05	Discoloration (fair to dark)	TLD/TLE Regimen	2	9.5%
06	Skin Problem	Antibiotics	1	4.8%
07	Skin Rashes	TLD/TLE Regimen	2	9.5%
08	Rashes on Hand	ZLD Regimen	1	4.8%
09	Heat balls	TLD/TLE Regimen	2	9.5%
10	Skin white patches	TLD/TLE Regimen	1	4.8%

Many of the cases that have been recorded in the ART centre are those which showed mild cases of skin allergies, itching, rashes and skin discoloration due to usage of the TLD/TLE regimen for treatment of HIV. This is clearly illustrated in Figure 4. The reactions are mild (Level 1), according to the Modified Hartwig and Siegel scale. They did not require any change in treatment of the disease. The patients are usually prescribed with paraffin oil and chlorpheniramine tablets to help alleviate the symptoms.

Table 1 depicts the individual distribution of cases in the ART Centre in percentage. The most common cause of these reactions are the TLD/TLE Regimen (85.7%). Few cases were also recorded with the ZLD regimen (4.8%), DTG regimen (4.8%) and antibiotics (4.8%). The Naranjo’s scale was used to determine the casualty of the CADRs. Using this measurement, 5 probable cases and 16 possible cases were seen among the recorded CADRs.

Dermatology OPD:

Figure 5: Percentage vs. Diagnosis for CADRs in Dermatology OPD

Figures 5 discusses the cases that have been recorded from the Dermatology OPD. Most of the cases that came to the OPD were found to be benign ADRs. It is clear that the majority of the patients from the pool have been diagnosed with Tinea incognito (50.6%) while quite a few of the remaining cases are observed to be related to excessive use of topical steroids. The next most common CADRs are steroid modified tinea (12.4%), steroid induced acne (4.5%), bullous fixed drug eruptions (FDE) (3.4%), Irritant Contact Dermatitis (ICD) (3.4%) for mild cases. These patients were advised to discontinue the offending drug(s) before receiving the appropriate treatment to alleviate their symptoms.

In serious CADRs, maximum number of cases were seen with Steven-Johnson Syndrome (SJS) (3.4%), chronic urticaria with angioedema (3.4%), 2 cases each with possible Drug-induced Lupus Erythematosus (DLE) and extensive Tinea corporis (2.2% each). A single case each of maculopapular rash (1.1%), urticarial drug eruption (1.1%), steroid-induced Tinea corporis (1.1%) and Baboon syndrome (1.1%) were also recorded.

Table 2: Prevalence of CADRs in Dermatology OPD

Diagnosis	No. of Cases	Percentage
T. incognito	45	50.60%
Steroid modified tinea	11	12.40%
Bullous FDE	3	3.40%
Steroid induced acne	4	4.50%
SJS	3	3.40%
Steroid induced T.corporis	1	1.10%
Chronic Urticaria with Angioedema	3	3.40%
DLE?	2	2.20%
Extensive T.corporis	2	2.20%
Baboon syndrome	1	1.10%
Irritant Contact Dermatitis	3	3.40%
Diagnosis	No. of Cases	Percentage
Urticarial drug eruption	1	1.10%
Maculopapular rash	1	1.10%
Steroid induced hyperpigmentation	1	1.10%
Steroid use topically	1	1.10%
Acquired melanocyte nevi (cosmetics)	1	1.10%
Steroid induced buffalo hump	1	1.10%
Itchy lesions (RVD+ZLN Regimen)	1	1.10%
AV-III and Acneiform eruptions	1	1.10%
RVD+ ART regimen Hansen's	1	1.10%
secondary AD and steroid-induced dermatitis	1	1.10%
ART management	1	1.10%

The most common causative drug for CADRs was found to be over-the-counter topical corticosteroid cream. When the patients were asked about any drugs that they had taken prior to coming to the hospital, many of them admitted to applying corticosteroid cream in order to alleviate itching or inflammation that had arisen. This further complicated the diagnosis of tinea as the use of corticosteroid, while decreasing the inflammation and alleviating the symptoms, caused further exacerbation of disease and increased treatment time. It was recorded in one case that long term use of this corticosteroid cream has led to atrophy of the skin. Other drugs like NSAIDs were also seen.

DISCUSSION:

Drug reactions are seen throughout the medical profession. Of those, cutaneous ADRs are the most common drug reactions according to various literature⁴.

This study focused on the patterns of cutaneous ADRs in a tertiary care hospital. This study was conducted in a tertiary care teaching hospital in Telangana. A total of 110 cases were recorded in this study. 80.9% of these cases were taken from the Dermatology OPD while 19.1% came from the ART Center.

In the present study, females show preponderance towards CADRs (60% of the total cases). This is corresponding to previous studies conducted by Chatterjee et al¹⁷. However, other studies have shown a male preponderance^12->18or that both sexes were equally affected¹⁹. While there is no clear reason why this variation exists, a possible explanation could be the different health care seeking patterns in different regions^12->18.A possible reason for female preponderance may be due to more concern of female towards their skin and hence dermatological ADRs maximally reported by female¹⁵.

Studies conducted by Sharma et.al, Shah et.al, Sushma et.al, Pudukadan et.al and Dimple et.al showed male preponderance^{8,18,20,21,22}.

In this study, cutaneous ADRs were most commonly found in the age group 31-40 years (30.0%). This is followed by the age group 21-30 years (25.45%). Other studies conducted on CADRs have shown similar results, with theanalysis being that patients that fall under the category of 20-49 years show the most likelihood of developing drug reactions²³.

In a study conducted by Patel et al²⁴, 38 different types of CADRs were observed. Maculopapular rash (32.39%), FDEs (20.13%) and urticaria (17.49%) were the commonly reported CADRs. Severe CADRs constituted 8.17% in all. The most common severe CADR was SJS/TEN-6.84%. Other studies on CADRs like those by Sumit et al, Ghosh et al and Dubey et al^15,25,26also show a high incidence of rashes.

In the current study, about 25 different types of CADRs were observed. The most commonly reported ADRs are Tinea incognito (40.90%), skin reactions due to TLD/TLE Regimen (21.79%) and steroid modified tinea (10%). Severe CADRs were found to be 2.72% of the total patient pool in this study. The most common type of severe CADR was found to be SJS.

According to various studies, including one conducted by Anal Modi et al²⁷in a regional ADR monitoring centre, the most common causal drug groups were antimicrobials (45.72%) followed by NSAIDs (18.02%) and anti-epileptics (9.66%). Among antimicrobial group, antiretroviral, anti-tubercular, and fluoroquinolones were the most common causal drug groups.

This is not corresponding to the results of the current study. The most common causal drug group was found to be topical corticosteroid creams. A few cases of NSAIDs, anti-epileptics, antimicrobials and antifungals were also recorded. Even vaccinations like COVISHIELD have shown a development in CADRs.

CONCLUSION:

In medical practice, ADRs are a common problem to deal with. Dermatologists deal with the most common type of ADR, cutaneous adverse drug reactions.

Out of the 110 CADRs recorded in this study, many of the cases have shown a misuse of corticosteroids. Patients buy over-the-counter corticosteroid cream which, while alleviates the symptoms the patients are suffering from, are also responsible for exacerbating the current infection. This has led to the dissemination of the infection, which requires even more careful monitoring and an increase in treatment time. While this makes the doctors’ job harder to fulfill, it is also mentally taxing to the patient due to the increase in cost of the treatment and its duration.

It is important for dermatologists and primary health care workers to be able to identify a CADR. If the CADR is mild, then the doctor must be able to reassure the patient of the circumstances. If it is severe, the doctor must be able to provide prompt medical care and advice to the patient.

ADRs must be continuously reported, monitored and analyzed as their prevalence may change based on the current medical practices and the different types of drugs available in the market.

Being aware of the spectrum of skin reactions will enable a dermatologist to enable an early diagnosis, withdrawal of the drugs and management accordingly²⁸. It will also allow them to counsel the patient about the drug reactions they might observe during the course of treatment and discourage the misuse of drugs.

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

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Received on 29.08.2022 Modified on 31.01.2023

Research J. Pharm. and Tech 2024; 17(1):131-136.

DOI: 10.52711/0974-360X.2024.00021