|Year : 2017 | Volume
| Issue : 2 | Page : 69-72
A study of fixed-drug reactions at a rural-based tertiary care center, Gujarat
Rita V Vora1, Rochit R Singhal1, Rahulkrishna S Kota1, Bharat M Gajjar2
1 Department of Skin and VD, Pramukhswami Medical College, Shree Krishna Hospital, Karamsad, Gujarat, India
2 Department of Pharmacology, Pramukhswami Medical College, Shree Krishna Hospital, Karamsad, Gujarat, India
|Date of Web Publication||28-Dec-2017|
Dr. Rita V Vora
Department of Skin and VD, Shree Krishna Hospital, OPD Room No. 111, Anand, Karamsad - 388 325, Gujarat
Source of Support: None, Conflict of Interest: None
Context: Adverse cutaneous drug reactions (ACDRs) are very common due to a wide variety of drugs available in markets. Fixed-drug reaction (FDR) is a type of ACDR that dermatologists are facing frequently nowadays. There is a need to identify various drugs responsible for FDR and to ensure the safety of the patients with proper counseling. Aim and Objective: The aim and objective was to study the demographic details, clinical patterns, and the offending drugs causing FDR. Setting and Design: This was a cross-sectional, observational study. Materials and Methods: The study was carried out from April 2010 to March 2015 in the Department of Dermatology at a rural-based tertiary care center of Gujarat, India, after taking approval from the hospital's research ethical committee. A detailed history taking and thorough clinical examination were done for all the patients having FDR and were recorded in a predesigned pro forma. Analysis was done using frequencies, proportions, and Chi-square test. All the patients were educated regarding ACDRs and given a list of drugs causing FDR to avoid recurrence. Results: A total of 59 patients were studied for FDR among which 32 (54.23%) were males and 27 (45.76%) were females. Fever (20.34%) was the most common illness for which patients had taken the culprit drug. Antimicrobials (26 [44.07%]) were the most common group of drugs causing FDR followed by nonsteroidal anti-inflammatory drugs (21 [35.59%]). As a single molecule, diclofenac was the most common drug causing FDR followed by metronidazole 5 (8.47%) and cotrimoxazole, fluconazole, and ciprofloxacin 4 (6.78%) each. The most common complaint following intake of the culprit drug was pigmented patch (31 [52.54%]) followed by blisters (13 [22.03%]). Conclusion: FDR is one of the important ACDRs seen in patients. Antimicrobials are the most common group while diclofenac is the most common drug causing FDR.
Keywords: Antimicrobials, diclofenac, fixed-drug reaction, hyperpigmentation
|How to cite this article:|
Vora RV, Singhal RR, Kota RS, Gajjar BM. A study of fixed-drug reactions at a rural-based tertiary care center, Gujarat. Indian J Drugs Dermatol 2017;3:69-72
|How to cite this URL:|
Vora RV, Singhal RR, Kota RS, Gajjar BM. A study of fixed-drug reactions at a rural-based tertiary care center, Gujarat. Indian J Drugs Dermatol [serial online] 2017 [cited 2018 Feb 17];3:69-72. Available from: http://www.ijdd.in/text.asp?2017/3/2/69/221748
| Introduction|| |
Adverse cutaneous drug reactions (ACDRs) are common, comprising 10%–30% of all reported adverse drug reactions (ADRs)., Its incidence in hospitalized patients is estimated to be 2%–3%. Although the majority of ACDRs are mild and self-limiting, severe ACDRs such as Stevens–Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms are associated with significant morbidity and mortality.
Fixed-drug reaction (FDR) is the distinctive type of adverse cutaneous reaction that characteristically recurs at the same site or at different sites each time a particular drug is taken. Lesions are well defined, round or oval patches with erythema and edema, sometimes surmounted by a blister. Gradually, it becomes purplish or as brown patch. It can be seen over any part of the body such as face, upper limbs, lower limbs, trunk, genitals, and oral mucosa.
Almost any medicine can induce skin reaction, and certain drug classes, such as nonsteroidal anti-inflammatory drugs (NSAIDs), antibiotics, and anti-epileptics have drug eruption rates approaching 1%–5%. Early identification of skin reaction is very helpful to avoid severity and recurrence of ACDR. It is important that skin reactions should be identified and documented in the patient records so that their recurrence can be avoided. The need for this study is to identify the common drugs that are responsible for FDR.
| Materials and Methods|| |
An observational cross-sectional study was carried out from April 2010 to March 2015 at the Department of Dermatology, Venereology and Leprology of Shree Krishna Hospital, Pramukhswami Medical College, Karamsad, Gujarat, after taking approval from the hospital's research ethical committee. All patients diagnosed clinically as FDRs irrespective of age and sex attending the skin department were included in the study after taking written consent. In every case, a detailed history was elicited and a thorough clinical examination was carried out. To establish the etiologic agent, attention was paid to the drug history, temporal correlation with the drug, duration of the rash, morphology of the eruption, associated mucosal or systemic involvement, and improvement of lesions on withdrawal of drug. A diagnosis of ACDR was reached after exclusion of other etiologies. If more than one drug was thought to be responsible, the most likely offending agent was noted and the impression was confirmed by subsidence of the symptoms on withdrawing the drug.
All the information were carefully recorded in a predesigned pro forma. WHO causality categories, Naranjo ADR probability scale, and Hartwig severity assessment were used to establish the probability of association. All principles of good clinical practice were followed. Analysis was done using frequencies, proportions, and Chi-square test. All patients were educated regarding ACDRs and given a list of drugs causing FDR to avoid recurrence.
| Results|| |
A total of 59 patients were enrolled in the study, of which 32 (54.23%) were males and 27 (45.76%) were females. The prevalence of ACDR and FDR was noted to be 2.6% and 0.2%, respectively. Past history of FDR was seen in 26 (44.07%) patients, of which 10 (16.95%) were having FDR due to the same drug. The reaction that occurred was more severe than the previous one in all patients who had FDR from the same drug. The drugs were prescribed in 47 (79.66%) cases and self-administered in 12 (20.34%) cases. Fever (12 [20.34%]) was the most common illness for which patients had taken the culprit drug followed by respiratory illness (11 [18.64%]).
The most common age group affected was 21–30 years in 15 (25.42%) cases [Table 1]. The most common presenting complaint was hyperpigmented patch in 31 (52.54%) cases followed by blisters in 13 (22.03%) cases [Table 2]. Only skin was involved in 30 (50.84%) cases while the rest showed mucocutaneous involvement in 29 (49.16%) cases with genital lesions in 15 (25.42%), oral lesions in 11 (18.64%) cases, conjunctival involvement in 2 (3.39%) cases, and anal involvement in 1 (1.69%) case.
Antimicrobials were the most common group of drugs causing FDR in 26 (44.07%) cases followed by NSAIDs in 21 (35.59%) cases [Table 3]. As a single molecule, diclofenac was the most common drug causing FDR in 13 (22.03%) cases followed by metronidazole in 5 (8.47%) and cotrimoxazole, fluconazol [Figure 1], and ciprofloxacin in 4 (6.78%) each [Table 4].
According to the WHO causality categories, 5 cases were falling into certain 5 (8.4%), 28 (47.45%) into probable, and 26 (44.06%) into possible categories. Naranjo ADR probability scale showed probable in 40 (67.79%) cases, possible in 15 (25.42%) cases, and definite in 4 (6.77%) cases. Hartwig severity assessment showed level 2 in 27 (45.76%) cases, level 3 in 16 (27.11%), and level 4 in 6 (10.16%) patients.
| Discussion|| |
The prevalence of ACDR has been reported to be 1% and 2%–5% in outpatients and inpatients, respectively. FDRs range from 16% to 21% among all ACDRs. The actual frequency may be higher than the current estimates because of many unreported ACDRs due to over-the-counter medications and various nutritional supplements. Most of the studies have shown FDR as the second or third common ACDR.
The majority (nearly 95%) of ADRs are Type A (augmented) reactions which are dose dependent and predictable from the primary and secondary drug pharmacology while Type B (bizarre) reactions are idiosyncratic, unpredictable from drug pharmacology, and determined by patient-specific susceptibility factors. Genetically, FDR has been linked with HLA-B22., Although the exact mechanism is unknown, a cell-mediated process is involved in initiating both the active and quiescent lesions. The offending drug acts as a hapten that preferentially binds to basal keratinocytes, leading to an inflammatory response. Through liberation of cytokines such as tumor necrosis factor-alpha, keratinocytes upregulate expression of the intercellular adhesion molecule-1 (ICAM-1). ICAM-1 acts as stimulus in activating CD8+ effector/memory T-cells. CD8+ effector/memory T-cells play an important role in the reactivation of lesions with re-exposure to the offending drug., They produce a large amount of interferon-gamma and tumor necrosis factor alpha and cause tissue damage.
FDR can occur in any age. In our study, majority of patients belonged to 20–39 years' age group which correlates with other studies. In this study, antimicrobials (26 [44.07%]) were the most common group of drugs causing FDR, followed by NSAIDs (21 [35.59%]), antifungals drugs (9 [15.25%]), antiepileptics and antitubercular drugs (2 [3.39%] each), and antiretroviral drugs and antispasmodics (1 [1.69%] each). A study conducted by Ghosh et al. showed similar results, antibiotics as the most frequent cause of adverse cutaneous reactions though antiepileptics were second common in causing adverse cutaneous reactions. Raksha et al. reported NSAIDs with 21% followed by sulfa drugs with 14% as the cause of FDR.
In this study, diclofenac was found to be most commonly associated with FDR (13 [22.03%]) followed by metronidazole (5 [8.47%] cases), and cotrimoxazole, fluconazole, ciprofloxacin 4 (6.78%) each. Pudukadan and Thappa reported cotrimoxazole in 22.25% of patients followed by dapsone in 17.7% of patients as the most common offenders. Cotrimoxazole was the most common antimicrobial in studies by Singh et al. and Shrivastava et al. as the cause of FDR.,
In this study, 29 (49.16%) patients showed mucocutaneous involvement with genital lesions in 15 (25.42%) cases and oral lesions in 11 (18.64%) cases in contrast to study by Kanodia et al. in which 78.95% were having mucocutaneous involvement.
In our study, when multiple drugs are implicated in causing FDR, the most likely offending agent was noted and the impression was confirmed by subsidence of the symptoms on withdrawing the drug. Re-challenge/provocation tests, intradermal tests, or skin prick tests are of significant value in identifying the culprit drug, but they are time consuming, need expertise, or may even re-precipitate life-threatening ADRs that may raise ethical issues. However, drug patch test can be used to detect ACDRs as it is easy to perform, relatively safe, and the only in vivo challenge test available.
Alanko et al. first used patch testing for determining the causative drugs in FDR. The basic principle and methodology for drug patch test remains same as that in patch testing for contact dermatitis. Pure drug form should be used for patch testing whenever possible in concentrations of 1%–10% in petrolatum, water, or alcohol. The most immunologic drug reactions are due to anticonvulsants (carbamazepine, phenytoin, phenobarbitone, or lamotrigine), sulfonamides, NSAIDs, and betalactum antibiotics (amoxicillin and ampicillin). Patch testing should preferably be performed on a previously involved skin or else a false-negative result is likely. The overall sensitivity of drug patch test is low between 11% and 38%. In cases of negative patch test results, oral provocation test is considered to be the only reliable method to identify the culprit drug. The drug patch testing is recommended as a first line of investigation in many patterns of ACDRs but particular to FDR, it is useful in cases of FDR caused by NSAIDs.
The limitation of the study was no objective test was conducted to confirm the culprit drug. Also, only that drug which was most likely to cause drug reaction was recorded instead of mentioning all the drugs in a given patient.
| Conclusion|| |
FDR is an important type of ACDR frequently seen nowadays due to a wide variety of drugs available in markets. Antibiotics, analgesics, and antiepileptics are the main group of drugs causing FDR. There is a need of ACDR reporting and monitoring system to reduce the cases of ACDR. Patients should also be counseled about drug reactions and should be given drug list of that respective ACDR to avoid recurrence.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Arulmani R, Rajendran SD, Suresh B. Adverse drug reaction monitoring in a secondary care hospital in South India. Br J Clin Pharmacol 2008;65:210-6.
Naldi L, Conforti A, Venegoni M, Troncon MG, Caputi A, Ghiotto E, et al.
Cutaneous reactions to drugs. An analysis of spontaneous reports in four Italian regions. Br J Clin Pharmacol 1999;48:839-46.
Bigby M, Jick S, Arndt K. Drug-induced cutaneous reactions: A report from the Boston Collaborative Drug Surveillance Programme on 15 438 consecutive inpatients, 1975-1982. J Am Med Assoc 1986;256:3358-63.
Roujeau JC, Stern RS. Severe adverse reactions to drugs. N Engl J Med 1994;333:1272-85.
Bigby M. Rates of cutaneous reactions to drugs. Arch Dermatol 2001;137:765-70.
Krähenbühl-Melcher A, Schlienger R, Lampert M, Haschke M, Drewe J, Krähenbühl S, et al.
Drug-related problems in hospitals: A review of the recent literature. Drug Saf 2007;30:379-407.
Lee AY. Fixed drug eruptions. Incidence, recognition, and avoidance. Am J Clin Dermatol 2000;1:277-85.
Friedmann PS, Ardern-Jones M. Patch testing in drug allergy. Curr Opin Allergy Clin Immunol 2010;10:291-6.
Pellicano R, Ciavarella G, Lomuto M, Di Giorgio G. Genetic susceptibility to fixed drug eruption: Evidence for a link with HLA-B22. J Am Acad Dermatol 1994;30:52-4.
Pellicano R, Lomuto M, Ciavarella G, Di Giorgio G, Gasparini P. Fixed drug eruptions with feprazone are linked to HLA-B22. J Am Acad Dermatol 1997;36:782-4.
Mizukawa Y, Shiohara T. Fixed drug eruption: A prototypic disorder mediated by effector memory T cells. Curr Allergy Asthma Rep 2009;9:71-7.
Shiohara T. Fixed drug eruption: Pathogenesis and diagnostic tests. Curr Opin Allergy Clin Immunol 2009;9:316-21.
Ghosh S, Acharya LD, Rao PG. Study and evaluation of various cutaneous drug reactions in Kasturba Hospital, Manipal. Indian J Pharm Sci 2006;68:212-5. [Full text]
Patel RM, Marfatia YS. Clinical study of cutaneous drug eruptions in 200 patients. Indian J Dermatol Venereol Leprol 2008;74:430. [Full text]
Pudukadan D, Thappa DM. Adverse cutaneous drug reactions: Clinical pattern and causative agents in a tertiary care centre in South India. Indian J Dermatol Venereol Leprol 2004;70:20-4.
] [Full text]
Singh KK, Shrinivas CR, Krupashankar DS, Naik RP. Study of thirty three cases of fixed drug eruption. Indian J Dermatol Venereol Leprol 1990;56:123-4. [Full text]
Shrivastava D, Kumar A, Singh SK. Adverse drug reaction monitoring in patients attending skin. O.P.D at a teaching hospital. Indian J Pharmacol 2004;36:S42.
Kanodia SK, Seth AK, Shukla SR. A Study on Genital Fixed Drug Eruption in a Tertiary Care Hospital. J Clin Diagnostic Res 2011;5:700-2.
Mahajan VK, Handa S. Patch testing in cutaneous adverse drug reactions: Methodology, interpretation, and clinical relevance. Indian J Dermatol Venereol Leprol 2013;79:836-41.
] [Full text]
Alanko K, Stubb S, Reitamo S. Topical provocation of fixed drug eruption. Br J Dermatol 1987;116:561-7.
Romano A, Viola M, Mondino C, Pettinato R, Di Fonso M, Papa G, et al.
Diagnosing nonimmediate reactions to penicillins by in vivo
tests. Int Arch Allergy Immunol 2002;129:169-74.
[Table 1], [Table 2], [Table 3], [Table 4]