| Abstract|| |
Background: Few clinical studies are found in the literature about patients hospitalized with a diagnosis of cutaneous drug eruption. Aims: To determine the clinical types of drug eruptions and their causative agents in a hospital-based population. Materials and Methods: This retrospective study was performed in the Dermatology Department of Haseki General Hospital. Through 1751 patients hospitalized in this department between 2002 and 2009, inpatients diagnosed as drug eruption were evaluated according to WHO causality definitions. 106 patients composed of probable and possible cases of cutaneous drug eruptions were included in this study. Results: Seventy one females and 35 males were evolved. Mean age was 44.03±15.14. Duration between drug intake and onset of reaction varied from 5 minutes to 3 months. The most common clinical type was urticaria and/or angioedema in 48.1% of the patients, followed by maculopapular rash in 13.2%, and drug rash with eosinophilia and systemic symptoms in 8.5%. Drugs most frequently associated with cutaneous drug eruptions were antimicrobial agents in 40.5% of the patients, followed by antipyretic/anti-inflammatory analgesics in 31.1%, and antiepileptics in 11.3%. Conclusion: Urticaria and/or angioedema and maculopapular rash comprised majority of the drug eruptions. Rare reactions such as acute generalized exanthematous pustulosis, sweet syndrome, oral ulceration were also found. Antimicrobial agents and antipyretic/anti-inflammatory analgesics were the most commonly implicated drugs. Infrequently reported adverse reactions to myorelaxant agents, newer cephalosporins and fluoroquinolones were also detected. We suppose that studies on drug eruptions should continue, because the pattern of consumption of drugs is changing in every country at different periods and many new drugs are introduced on the market continuously.
Keywords: Adverse drug reaction, cutaneous drug eruption, skin rashes
|How to cite this article:|
Akpinar F, Dervis E. Drug eruptions: An 8-year study including 106 inpatients at a dermatology clinic in Turkey. Indian J Dermatol 2012;57:194-8
|How to cite this URL:|
Akpinar F, Dervis E. Drug eruptions: An 8-year study including 106 inpatients at a dermatology clinic in Turkey. Indian J Dermatol [serial online] 2012 [cited 2013 May 24];57:194-8. Available from: http://www.e-ijd.org/text.asp?2012/57/3/194/96191
| Introduction|| |
Cutaneous drug eruptions have relatively low morbidity but gain importance as they occur very frequently and require discontinuation of medication. Although there are many individual reports of cutaneous drug eruptions few reports on clinical series are found in the literature. ,,,,,,,,,,,, The objective of this study was to determine the clinical types of drug eruptions and their causative agents in a hospital-based population.
| Materials and Methods|| |
This retrospective study was performed in the Dermatology Department of Haseki General Hospital. Through 1751 patients hospitalized between 2002 and 2009, inpatients diagnosed as drug eruption were evaluated. Records were available in the patient files of the hospital. For each case, data regarding age and sex of the patient, name of suspected drugs, duration between drug intake and onset of reaction, clinical type of drug eruption was collected. For each case, records of medical history, physical examination, laboratory findings (complete blood count, ESR, CRP, liver function tests, renal function tests, VDRL, ELISA, HIV, IgE, urine examination) and histopathological examination in suspected cases (erythema multiforme minor, lichenoid drug eruption, Sweet syndrome) were analysed. Inpatients were included in the study according to the following criteria: ,
- The diagnosis of cutaneous adverse reaction should be in accordance with definition of adverse drug reactions provided by WHO. 
- No alternate explanation for the reaction.
- The time interval between the introduction of the drug and the onset of a reaction should be within a specific time described in the literature for each reaction (Maculopapular rash: <7 days, Urticaria: 7-21 days, SJS, TEN, Erythema multiforme: 1-3 weeks, Drug hypersensitivity syndrome: 2-6 weeks, Photodermatitis: up to 1 year, Exfoliative dermatitis: 1-6 weeks, Fixed drug eruption: 30 min-16 h). The reaction was not considered as drug-induced if the drug was administered after the onset of cutaneous reaction.
- Improvement in the condition of the patient after dechallenge/ withdrawal of the suspected drug.
The definitions as provided by the WHO collaborating center are given below:
A clinical event, including laboratory test abnormality, that occurs in a plausible time relation to drug administration, and which cannot be explained by concurrent disease or other drugs or chemicals. The response to the withdrawal of the drug (dechallenge) should be clinically plausible. The event must be definitive pharmacologically or phenomenologically, using a satisfactory rechallenge procedure if necessary.
A clinical event, including laboratory test abnormality, with a reasonable time relation to administration of the drug, unlikely to be attributed to the concurrent disease or other drugs or chemicals and which follows a clinically reasonable response on withdrawal (dechallenge). Rechallenge information is not required to fulfill this definition.
A clinical event, including laboratory test abnormality, with a reasonable time relation to administration of the drug, but which could also be explained by concurrent disease or other drugs or chemicals. Information on the drug withdrawal may be lacking or unclear.
A clinical event, including laboratory test abnormality, with a temporal relation to administration of the drug, which makes a causal relation improbable, and in which other drugs, chemicals or underlying disease provide plausible explanations. Conditional/unclassified: A clinical event, including laboratory test abnormality, reported as an adverse reaction, about which more data is essential for a proper assessment or the additional data is being examined.
A report suggesting an adverse reaction that cannot be judged, because information is insufficient or contradictory and cannot be supplemented or verified.
Rechallenge was not carried out in any of the patients in this study. A total of 106 patients composed of 84 possible and 22 probable cases were considered for analysis.
| Results|| |
Inpatients diagnosed as probable and possible cases of drug eruption composed of 106 (6.05%) patients were evaluated. There were 71 females and 35 males (age 9-74 years, mean age 44.03±15.14). A majority of the patients (58.4%) was in the age group of 20-50 years, 38.8% of the patients were older than 50 years and 7.6% of the cases consisted of children.
Duration between drug intake and onset of reaction varied from 5 minutes to 3 months. The drug eruptions began during the first 2 weeks in 84.6% of the cases. In 3.7% of the cases, drug eruptions developed due to radiocontrast agents and the duration was 5 minutes-6 hours. Penicillins caused drug eruptions 3-4 days after the last exposure in most cases. Duration between antipyretic/anti-inflammatory analgesic intake and induction of reaction was 2-3 days. The reaction time was 1-3 months in 7.5% of the cases and the causative drugs were antiepileptics and sulfasalazine.
The most common clinical type was urticaria and/or angioedema in 48.1% of the patients, followed by maculopapular rash in 13.2%, and drug rash with eosinophilia and systemic symptoms (DRESS) in 8.5%. The clinical types of drug eruptions and their causative agents are shown in [Table 1].
|Table 1: The clinical types of drug eruptions and their causative agents|
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Antimicrobial agents were the main drugs inducing skin reactions in this study (40.5%). Antipyretic/anti-inflammatory analgesics (31.1%) followed by antiepileptics (11.3%) were the next. Penicillins, mainly amoxicillin were the most common drugs causing eruptions. Fluoroquinolones, naproxen sodium and phenytoin were the other most commonly implicated drugs in this study. Most commonly implicated drugs are shown in [Table 2].
There was 1 patient with hyperthyroidism, 1 patient with depression, 1 patient with chronic myeloid leukemia, and there were 3 patients with hypertension, 4 patients with rheumatoid arthritis, 12 patients with epilepsy. Others had taken medicine for pain, fever, and infection. None of the cutaneous drug reactions resulted in death in this study.
Urticaria and/or angioedema occurred most commonly due to antimicrobial agents (41.1%), mainly penicillins (amoxicillin), and antipyretic/anti-inflammatory analgesics (35.2%), mainly acetylsalicylic acid, diclofenac, methamizole and meloxicam. Half of the patients who developed urticaria and/or angioedema due to antimicrobial agents had a history of upper respiratory tract infection one week before the reaction. None of the patients had acute infection symptoms during the reaction. Six cases were induced by ticlopidine, methimazole, paroxetine, lansoprazole, lisinopril and doxazosin. Two cases were due to myorelaxant drugs, thiocolchicoside and phenyramidol HCl. Two of the 51 urticaria and/or angioedema cases were atopic. They had history of allergic asthma and high levels of IgE.
Maculopapular rash was induced by antibiotics (78.5%), mainly penicillins, antipyretic/ anti-inflammatory analgesics (14.2%) and antiepileptics (7.1%).
Erythroderma was most commonly caused by antipyretic/anti-inflammatory analgesics (62.5%), mainly naproxen sodium. Other drugs were amoxicillin, levofloxacin, and imatinib.
DRESS was triggered by antiepileptics (77.7%), mainly phenytoin and carbamazepine. There was one case caused by sulfasalazine (a 52 year-old female patient using sulfasalazine for rheumatoid arthritis). One of the patients developed DRESS due to ceftriaxone. All cases of DRESS in this study had fever, lymphadenopathy, and skin rash. Elevated hepatic transaminase levels returned to normal after treatment. The causative antiepileptic drugs were withdrawn and levetiracetam was used instead.
Eczematous eruption was associated with itraconazole, terbinafine, cefuroxime axetyl, and carbamazepine.
Fixed drug eruption developed due to levofloxacin, cotrimoxazole, naproxen sodium and methamizole.
Erythema multiforme minor diagnosed histopathologically was induced by antiepileptics, antipyretic/anti-inflammatory analgesics, and antimicrobial agents. Two of these cases were caused by flurbiprofen. None of the patients had a history of herpes labialis infection before the reaction.
Stevens-Johnson syndrome More Details (SJS) cases were induced by naproxen sodium. These were severe reactions with more than one mucosal site involvement.
Lichenoid drug eruption was seen due to cilazapril, phenytoin, and gabapentin. Biopsy specimens supported the reactions. The eruptions disappeared after removal of the suspected drugs.
Oral ulceration developed due to methotrexate.
Acute generalized exanthematous pustulosis (AGEP) with acute onset, small, non-follicular pustules on an erythematous background, fever, rapid recovery and without history of psoriasis were caused by cefazolin sodium and clindamycin.
One patient developed sweet syndrome due to flurbiprofen. She experienced similar reactions twice with the same drug before. Diagnosis was confirmed histopathologically.
The suspected drug was promptly withdrawn in all cases as a first line treatment. In most cases, short term systemic corticosteroid together with antihistaminics were administered. Severe cases, such as SJS, DRESS, angioedema, erythroderma required long-term high dose systemic corticosteroid treatment to control the reaction.
| Discussion|| |
Anamnesis and clinical examination are useful in diagnosis of drug eruption, whereas laboratory and skin tests are of limited value. Consistent with this data, we could not find any laboratory abnormalities except elevated liver enzymes in patients with DRESS and increased IgE levels in patients with urticaria and/or angioedema. Although skin biopsy can be useful, it does not identify the responsible drug. The oral provocation test is for identifying the causative agent.  It must be interpreted carefully, because the reaction may be more severe and even potentially fatal.  Further studies should be performed to find another reliable method which is safer than the oral provocation test.
The incidence of drug eruptions in this study (6.05%) does not reflect the incidence in general population. Because only inpatients and through them, only cases defined as 'probable' and 'possible' were included. Thus, the real incidence is expected to be higher.
There was female preponderance, as reported by other studies. ,,,, This finding may have two explanations: 1) Females take medicine more frequently than males.  2) Number of beds for females is two times the number of beds for males in our clinics. However, males were affected more than females in various studies. ,,,
Drug eruptions are not age related,  but some reports suggest that drug eruptions are more frequent in children and older adults, possibly because of a dysfunctional immunity or the metabolism of the drugs,  while some other studies reveal the opposite. , Elderly patients take more medicine because of their underlying diseases.  This increases the risk of development of cutaneous drug reaction. Age distribution of this study was consistent with the literature. ,,,
Consistent with the literature,  skin lesions appeared during the first 2 weeks in 84.6% of the cases in this study.
Urticaria and/or angioedema (48.1%) were the most frequent cutaneous manifestation which was in accordance with the study by Adısen et al.  The most common clinical type was maculopapular rash in various studies. ,,,,, Previous studies conducted in India , and Finland  reported fixed drug eruption as the most frequent type. This different finding in our study which includes hospitalized patients suggests that maculopapular rash and fixed drug eruption are not usually very severe reactions that require hospitalization.
Consistent with the literature, ,,,,, antimicrobial agents (40.5%), followed by antipyretic/anti-inflammatory analgesics (31.1%) and antiepileptics (11.3%) were responsible for the majority of drug eruptions in this study. Penicillins, mainly amoxicillin were the most common drugs as reported by previous studies. ,,, However, cotrimoxazole was found to be the common cause in various Indian studies. ,, and in a Finn study.  Similar to the study by Sushma et al,  fluoroquinolones were found to be on rise in this study. This may be due to increased prescription of newer drugs.
Urticaria and/or angioedema occurred most commonly due to antimicrobial agents and antipyretic/anti-inflammatory analgesics as reported by earlier studies. ,,,, The incidence of radiocontrast agents (3.7%) was higher compared to other studies. , This can be explained by admission of patients developing radiocontrast agent-induced cutaneous reaction from multiple medical imaging centers around our hospital and Radiology Department of our hospital. Duration between the injection of the radiocontrast agent and induction of the reaction was only 5 minutes to 6 hours. Thus, the medical staff should be careful about such kind of a reaction during the process.
Maculopapular rash was induced by antibiotics, antipyretic/ anti-inflammatory analgesics and antiepileptics, which was in accordance with other studies. ,,,,,,
There were recent case reports about imatinib-induced erythroderma in the literature. , In the study by Adısen et al ,  erythroderma was caused by antimicrobial agents, mainly penicillins, then cephalosporins, flurbiprofen, phenytoin, carbamazepine and allopurinol. The responsible drugs were fluoroquinolones, cephalosporins, antituberculosis drugs, macrolides, phenytoin and nimesulide in an Indian study. 
Dapson was more common than antiepileptics as the cause of DRESS in an Indian study.  Few cases of sulfasalazine-induced DRESS have been reported in the literature , as one case in our study. Ceftriaxone induced DRESS case has been supported by a Turkish case report informing about DRESS like severe drug rash with eosinophilia, atypical lymphocytosis and fever secondary to ceftriaxone. 
We could not encounter any published study in pub med searching about eczematous eruptions due to antifungal agents. Nevertheless, they were involved in the etiology of AGEP.  In the study by Apaydin et al,  eczematous eruptions developed due to penicillins, methamizole, and diclofenac while Puavilai et al, reported penicillins, cotrimoxazole, allopurinol, and phenobarbital.
Fixed drug eruption cases were hospitalized because of generalized lesions and developed due to antimicrobial agents and antipyretic/anti-inflammatory analgesics as cited in the literature. , Outpatients should also be considered to calculate the real percentage of fixed drug eruption. Cotrimoxazole caused majority of fixed drug eruption in the study by Apaydin et al, and in various Indian studies. ,,, Tetracycline was the most common cause in the study by Puavilai et al.  Cotrimoxazole was the leading causative agent, followed by naproxen sodium, methimazole, enolic acids and other rare causes in the study by Ozkaya-Bayazit E. 
Erythema multiforme minor was induced by antiepileptics, antipyretic/anti-inflammatory analgesics, and antimicrobial agents as reported by earlier studies. ,,,,, Two of these cases were caused by flurbiprofen similar to an Indian study in which the most common cause was ibuprofen. 
Antimicrobial agents, mainly sulphonamides , and fluoroquinolones,  antiepileptics , and antipyretic/anti-inflammatory analgesics ,, were the implicated drugs causing Stevens-Johnson syndrome in the literature.
Cephalexin, cloxacillin, cotrimoxazole and phenytoin-induced lichenoid drug eruption in the studies by Puavilai et al. ,
Similar cases of oral ulceration due to methotrexate were found in the literature.  Antipyretic/anti-inflammatory analgesics, azathioprine, penicillamine, gold compounds, tiopronin, ACE inhibitors, AT 2 receptor blockers, antiagregans, antidepressants, AIDS therapy were reported as the other causes of oral ulceration in the literature. 
Penicilin and carbamazepine-induced AGEP in the study by Adısen et al .  Previous studies implicated antibiotics, antifungal agents (terbinafine), diltiazem, hydroxychloroquine, carbamazepine in the etiology of AGEP. 
Medications implicated in drug-induced Sweet syndrome include granulocyte-colony stimulating factor, minocycline, cotrimoxazole, antiepileptics, antihypertensives, oral contraceptives, or retinoids. 
As this was a study including hospitalized patients, we did not obtain any information about drug eruptions which can be treated without hospitalization like acneiform pustules, pigmentation, and alopecia.
It is necessary that patients diagnosed as drug eruption should be informed about the suspected drugs.
We suppose that studies on drug eruptions should continue, because the pattern of consumption of drugs is changing in every country at different periods and many new drugs are introduced on the market continuously.
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[Table 1], [Table 2]