Abstract:


            Objectives

         To study cutaneous adverse drug reactions (ADR) seen in the Emergency Department of Al-Farwaniya hospital


            Materials
           All patients consulting for drug eruptions between 1st Jan 2004 to 31st Dec 2004 were included in the study.

            Methods

          In every case, a detailed history was elicited and a thorough clinical examination was done.

            Results
      
        The total number of cases in this series was 208, the most common types of adverse drug eruptions seen in the ED were exanthematous eruptions, urticaria and fixed drug eruptions. The most common groups of causative drugs were antimicrobial agents, antipyretic/anti-inflammatory analgesics and drugs acting on the central nervous system.

            Conclusions

           the clinical patterns and the drugs causing adverse drug eruptions are remarkably similar to those observed in other countries except for minor variations.
           
Introduction

         The commonly used definition of drug induced disorders states that an Adverse Drug Reaction (ADR) is an adverse drug event (ADE) or drug interaction that results in an undesirable or unexpected event that requires some change in the clinician's care of the patient; such as discontinuing a drug, modifying a dosage, prolonging hospitalization or administering supportive treatment. ADRs do not include drug withdrawal, drug-abuse syndromes, accidental poisonings or complications of drug overdose. This definition relies on a combination of the definitions of the World Health Organization (WHO) and the American Society of Health-System Pharmacists (ASHP)(1, 2). Cutaneous drug eruptions are the most frequent type of adverse drug reactions 3 the overwhelming majority of which are thought to be allergic in origin. Some studies revealed data indicating that 2 to 3 percent of medical inpatients experience cutaneous eruptions to prescribed medications(4). Drug-induced disorders have historically been classified as type A and type B reactions(5). Type A reactions are the normal pharmacologic effects of a drug that are exaggerated to the point of being undesirable. These reactions are usually dose-dependent and are fairly predictable. Type A reactions are the most common type of drug-induced disorders. Although their incidence and morbidity are high, these reactions are rarely life threatening. Clinicians should be aware that these reactions may occur at any time during drug therapy. On the other hand, type B reactions include the effects of a drug that are unrelated to its known pharmacologic actions. These reactions may or may not be dose-related. They are unpredictable and include idiosyncratic, immunologic and allergic reactions as well as carcinogenic and teratogenic events. The incidence of type B reactions is relatively low, but the mortality is high. Categories of drugs most commonly implicated are antimicrobial agents, non-steroidal anti-inflammatory drugs and anticonvulsants(6), although all drugs can be suspects in the setting of cutaneous eruptions. Cutaneous side effects of drugs may depend on toxic reactions, such as overdosage, accumulation, interaction of various drugs, idiosyncrasy or anaphylactoid reaction due to histamine liberation. Drug sensitivity, however, is the most common cause of cutaneous reactions(7); an eruption may be the sole symptom or it may be accompanied by others. Early recognition and management of drug related cutaneous reactions is important to prevent serious sequelae of drug hypersensitivity.


Patients and Methods


      The study was carried out at the Emergency Department. of Farwaniya Hospital in Kuwait between the 1st of January and the 31st of December 2004. All patients consulting for drug eruptions were included in the study. A detailed history was elicited in every case and a thorough clinical examination was carried out as suggested by Sacerdots et al(8). To establish the etiologic agent for a particular type of reaction, attention was paid to the drug history, temporal correlation with the drug, duration of the rash, approximate incubation period, morphology of the eruption, associated mucosal or systemic involvement, improvement of lesions on withdrawal of drug and recurrence of lesions on rechallenge. The severity of the reaction was graded according to the University of Virginia Health System Adverse Drug Reaction Reporting Program criteria as follows:


        1. Mild:
  

       A reaction that does not require treatment or prolongation of hospital stay.

        2. Moderate:
 

       A reaction that is potentially life-threatening or contributes to the death of the patient, is permanently disabling, requires intensive medical care (including extended hospitalization), or results in a congenital anomaly, cancer, or unintentional overdose(9). All the information was carefully recorded in a specially designed proforma. All the patients were investigated for complete blood account (CBC), liver function test (LFT), renal function tests (RFT) and eosinophil count. The total number of cases was 208. There were 106 male patients and 102 female patients. The age range was from 1 to 70 years. The mean age was 32 years. In some cases, the patient history and the clinical picture was so typical that no further evidence was needed. A provocation test was performed for some cases with the suspected drug in order to confirm the causative agent.

       3. Severe:
 

       A reaction that requires treatment and/or prolongs hospitalization by at least one day.
 

Results

       The male to female ratio was approximately equal (1:0.96). The mean age of the patients was 32 years (range, 1-70 years). One hundred and eleven (53.37%) were in the age group of 21-40 years, 54 (25.96%) were less than 20 years, 24 (11.54%) were 41-60 years, while 19 (9.13%) patients were above 60 years old. The mean duration of drug intake prior to the onset of the rash was 10 days and most of the patients developed the rash while taking the incriminated drug. Mild adverse cutaneous reactions were observed in 39.9% (83/208) of the patients, moderate adverse cutaneous reactions in 25.96% (54/208), and severe reactions in 34.13% (71/208). Most of our patients (137/208) had 0-10% body surface area involvement; 47 patients had 35-90%, 19 had 11-34%, while only 5 had more than 90% body surface area involvement. The most common clinical types of drug eruption in this study were exanthematous eruption, urticaria, and fixed drug eruption (FDE) occurring in 79, 48 and 30 cases, respectively. The remaining 51 patients had other types of drug eruptions (erythema multiforme, erythroderma, etc) (Table 1).

 

 About 32.7% of the patients (68/208) had mucosal involvement, the manifestations of which varied according to the type of rash. Mucosal involvement in maculopapular drug rash and erythroderma manifested either as a bright red erythema of the mucosae or as conjunctival congestion. In urticaria, mucosal involvement was in the form of edema of the lips and laryngeal mucosa, while in Erythema Multiform(EM), Toxic Epidermal Necrolysis (TEN), Stevens-Johnson Syndrome (SJS) and Fixed Drug Eruption (FDE), mucosal involvement manifested as erosions, Systemic manifestations were present in only 26.44% (55/208). Fever was recorded in most patients with maculopapular rash, SJS, TEN and erythroderma. Major systemic complications were more frequently observed in cases of TEN (5/8 patients) and SJS (7/9 patients). Complications included 5 patients with septicemia, 3 with urinary tract infections, one with ocular involvement, one with oral candidiasis and two with renal involvement. Commonly incriminated drugs in our study included Co-trimoxazole (14.9%), followed by Penicillins (11.54%), Phenytoin (8.65%), antipyretic/anti-inflammatory drugs (8.17%) and Carbamazepine (7.69%). The drugs causing cutaneous reactions are shown in Table 2.

 

The details of the clinical types and their causative agents are shown in table 3,

 

which demonstrates that Penicillin is the most common single causative agent for exanthematous eruption and urticaria (16.46% and 22.92% respectively), whereas Co-trimoxazole is the most common for fixed drug eruption (40.0%). A comparison of the clinical types of drug eruption observed in this study with those found in previous studies is shown in table 4,

 

and a comparison of the causative agents of drug eruption found in this study with those observed previously is shown in table 5.  

Discussion
 

     Our study showed an equal male to female sex ratio as was observed in another study(10). Adverse cutaneous drug reactions vary in their patterns of morphology and distribution. In this study, the most common morphologic patterns were exanthematous, urticarial and/or angioedema and fixed drug eruption. The same morphological pattern was observed in previous studies(6). Another study from North India found maculopapular rash to be the most common type of adverse cutaneous drug reactions (ACDR)(11). This variation could be due to different patterns of drug usage and different ethnic group characteristics. Cotrimoxazole and NSAID's were more commonly involved in non-severe drug eruptions. In our study, antimicrobials represented the major causative group (43.26%), followed by antiepileptics (19.22%) and NSAID's (8.17%). This is in concordance with an earlier report(11). Antimicrobials, followed by NSAID's and central nervous system depressants were the most common drugs implicated in another study(6) . The majority of our patients were in the 21-40 years age group. Another study observed that adults aged 20-49 years were at greatest risk of antibiotics-related drug eruptions, probably due to increased exposure to antibiotics(12); while another study noted that the elderly are more commonly affected(13). The difference in various studies may be related to the regional variation in the health care seeking behavior of the population(11). Drug eruption may be easily diagnosed from the history and clinical picture; however, most patients receive many drugs at the same time. The problem then is to find which drug was the cause of the cutaneous eruption. Many efforts have been made to identify the causative agents, e.g. radioallergo-sorbent test (RAST), lymphocyte transformation test, etc., but the results are mostly unsatisfactory. Oral provocation is still the only reliable clinical method for identifying the causative agent. The procedure involves only a minimal risk when performed rationally and with caution. Stubb et al(14) concluded that verifying the drug responsible for the eruption is of paramount importance, and oral provocation is the proper method for detecting the causative agent. It is better to induce a mild reaction under controlled circumstances than to allow the patient to suffer repeated severe reactions at home. However, further studies should be performed to find other reliable, safer methods for identification of the causative agent. The mean absolute eosinophil count was abnormal in most eruptions, with values more than 500 cells/mm3, except in cases of acneiform eruptions, urticaria/ angioedema, and eczematoid, lichenoid and fixed drug eruption patients. Guidelines of the American Academy of Dermatology state that eosinophil counts more than 1000 cells/mm3 indicate a serious drug-induced cutaneous eruption(15). According to Romagosa et al(16), a peripheral eosinophil count carries little diagnostic value in the setting of adverse cutaneous drug eruptions. In our study, the absolute eosinophil counts were consistently higher in the so-called serious adverse cutaneous reactions. It may be concluded that the clinical patterns and the drugs causing ADR are remarkably similar to those observed in other countries(11,14,17,18) except for minor variations.