|Year : 2022 | Volume
| Issue : 1 | Page : 33-37
Spectrum of severe cutaneous adverse drug reactions among pediatric population and management options
Sameer Abrol1, Rohini Sharma2
1 Department of Medicine, Government Medical College, Jammu, Jammu and Kashmir, India
2 Department of Dermatology, Government Medical College, Rajouri, Jammu and Kashmir, India
|Date of Submission||30-Jan-2021|
|Date of Decision||12-Oct-2021|
|Date of Acceptance||10-Nov-2021|
|Date of Web Publication||31-Dec-2021|
H No. 396 Shastri Nagar Jammu, Jammu and Kashmir - 180 004
Source of Support: None, Conflict of Interest: None
Background: Cutaneous adverse drug reactions (CADRs) have been seen to be one of the most common adverse drug reactions in various studies, and the incidence in developing countries is thought to be higher between 2% and 5%. Moreover, severe CADRs (SCADRs) constitute 2% of all CADRS and can be life-threatening. The pediatric population too is vulnerable, and like in adults, SCADRs are associated with serious mortalities and morbidity; hence, early diagnosis and prompt treatment are the cornerstone for better survival. Objective: This study was undertaken to assess the patterns of SCARDs among pediatric patients and to identify the causative drug/drugs and establish causality using Naranjo scale and also study various treatments given including the role of corticosteroids in their management. Materials and Methods: A total of 52 pediatric patients (</=18 years) were taken up for the study after written informed consent from the parents/guardian. The diagnosis of Steven-Johnson syndrome (SJS), SJS-toxic epidermal necrolysis (TEN), TEN, drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP) was established using the recommended criteria. Results: A total of 52 patients were taken up for the study. The youngest was 9 months old, whereas the oldest was 18 years old. There were 34 (65.3%) males and 18 (34.6%) females. The most common SCADR was SJS seen in 27 (51.9%), followed by TEN in 9 (173%), SJS-TEN overlap in 8 (15.3%), DRESS in 6 (11.5%), and AGEP in 2 (3.8%). Conclusion: There is a lack of studies on SCADRs among the pediatric population and more so dilemma still exists regarding management. Thus, multiple such studies need to be carried out to establish clear-cut recommendations for the management of SCADRs in children and also to assess the role of corticosteroids in their management, particularly in a resource-poor nation like India.
Keywords: Acute generalized exanthematous pustulosis, drug reaction with eosinophilia and systemic symptoms complex, pediatric, severe cutaneous adverse drug reactions, toxic epidermal necrolysis
|How to cite this article:|
Abrol S, Sharma R. Spectrum of severe cutaneous adverse drug reactions among pediatric population and management options. Indian J Paediatr Dermatol 2022;23:33-7
|How to cite this URL:|
Abrol S, Sharma R. Spectrum of severe cutaneous adverse drug reactions among pediatric population and management options. Indian J Paediatr Dermatol [serial online] 2022 [cited 2022 Jan 20];23:33-7. Available from: https://www.ijpd.in/text.asp?2022/23/1/33/334666
| Introduction|| |
Adverse drug reactions (ADRs) have been defined by the WHO as any response to a drug, which is noxious, unwanted, or unintended. The majority (75%–80%) of ADRs are caused by predictable and nonimmunologic effects, and the remaining 20%–25% of adverse drug events are caused by unpredictable effects that may or may not be immune-mediated. The immunological reactions account for 5%–10% of all drug reactions and include immunoglobulin E-dependent drug reaction, immune complex-mediated reaction, cytotoxic, and last, the cell-mediated immune reaction. Among the various ADRs, cutaneous ADRs (CADRs) have been seen to be one of the most common. Although the true incidence is difficult to quantify, still the incidence of CADRs is about 2.2% of all reported ADRs in India as reported in various studies. Out of the all reported CADRs 2% of these may be severe and few may even end in fatalities. The pediatric population too is vulnerable to CADRs, and various studies have shown that CADRs constitute 35% to 36% of ADRs in this population. Although the majority of these CADRs are benign and self-limiting, a small percentage of 2%–6.7% can be severe CADRs (SCADR's), which are life-threatening and need hospitalization., The term SCADRs encompasses Steven-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP). Like in adults, SCADRs are associated with serious mortalities and morbidity; hence, early diagnosis and prompt treatment are the cornerstone for better survival. There has been a paucity of studies among the pediatric population regarding SCADRs; hence, this study was undertaken to assess the patterns of SCARDs among pediatric patients and to identify the causative drug/drugs and establish causality using Naranjo scale and also study various treatments given including the role of corticosteroids in their management.
| Materials and Methods|| |
This was a descriptive study undertaken for a period of 6 months at a tertiary center of North India. In this study, a total of 52 patients presenting with SCADRs were taken up. The pediatric age group was defined as </=18 years. The study was conducted over a period of 6 months at a tertiary care center of North India. Written informed consent was taken from the parents/guardian of the children. Inclusion criteria included children who presented with SJS, TEN, DRESS, and AGEP with a prior drug intake history of 1 month or less and met the European Registry of SCARs (RegiSCAR), were taken up. Cases where no drug history could be elicited were excluded from the study. Furthermore, other CADRs were also excluded from the study. In the case of SJS, the diagnosis was made when there was epidermal detachment <10% of the total body surface area (BSA) with skin lesions in the form of atypical and typical targets, macules, bullae, and erosions with involvement of the two or more mucous membranes. In the case of TEN, diagnoses were made based on the sheets of erosions with confluence of skin lesions such as macules, atypical targets, and >30% of the BSA involved, and SCORTEN scoring was also done. BSA involvement between 10% and 30% and with similar lesions such as in SJS and TEN were labeled as SJS/TEN overlap. The diagnosis of DRESS was confirmed by the DRESS RegiSCAR score including the following features: Mucocutaneous rash, fever, lymphadenopathy, and hematological anomalies such as eosinophilia, atypical lymphocytes, and internal organ involvement. Using the above score, a score of </=2 was categorized as “no DRESS,” 2–3 as “possible DRESS,” 4–5 as “probable DRESS,” and >5 as “DRESS.” The diagnosis of AGEP was made according to the clinical characteristics in the form of nonfollicular pustules over and erythematous base following the drug exposure and the presence of atypical lesions such as bullae and purpura. The diagnosis was further endorsed using the European Study of Severe Cutaneous Adverse Reactions scoring system with a score <0 points is labeled as not AGEP, 1–4 points as possible AGEP, 5–7 points as probable AGEP, and 8-12 points as definite AGEP. To further substantiate, a detailed clinical history regarding take of drug/drugs, time gap between drug intake and cutaneous eruption, any associated systemic symptoms, temporal association, and improvement after withdrawal of drugs/drugs was noted down. Past and family history of drug reactions were noted. A detailed general physical examination, cutaneous eruption regarding morphology, pattern and distribution of eruption, and mucosal examination was performed. Causality was assessed using Naranjo probability scale. All the laboratory investigations relevant to patients were done. Patch tests could not be done in view of refusal from the ethical committee. The data were statistically analyzed using the SPSS 22.0 statistical software package (SPSS Inc., Chicago, Ill, USA).
| Results|| |
A total of 52 patients were taken up for the study. The youngest was 9 months old, whereas the oldest was 18 years old. There were 34 (65.3%) males and 18 (34.6%) females. The most common SCADR was SJS seen in 27 (51.9%), followed by TEN in 9 (173%), SJS-TEN overlap in 8 (15.3%), DRESS in 6 (11.5%), and AGEP in 2 (3.8%). The duration between drug intake and drug eruption ranged from 3 to 5 weeks. The most common class of drug implicated was antimicrobials seen in 24 (45.1%), nonsteroidal anti-inflammatory drugs (NSAIDs) in 14 (26.9%), and antiepileptics in 13 (25%). Using the Naranjo probability scale, 24 patients had a probable association, 22 highly probable, and six had a possible association. The past history of similar complaints was taken up in five patients, and family history in none. No associated comorbidity was seen in any patient.
Among the patients of SJS, the youngest was 9 months old and the oldest 14 years [Figure 1]. The most common class of drug was antimicrobials (16, 59.2%), followed by NSAIDs in 7 (3.7%), antiepileptics in 3 (11.1%), and multivitamins in one patient. Among antimicrobials, cephalosporin plus clavulanic acid combination was the most common and among NSAIDs, ibuprofen was the most common. All drugs implicated in each class are shown in [Table 1]. Using the Naranjo ADR scale, in 11 (40.7%) patients, drug came out to be a probable cause and in 16 (59.2%), the drug was highly probable. Mucocutaneous involvement was seen in all patients with oral mucosa involved in all and ocular in 18 patients. Liver function tests were altered in 19 patients and eosinophilia was seen in 25 patients. In all the patients, the causative or suspected drug/drugs was stopped immediately, followed by the initiation of the supportive therapy. Systemic steroids were given to all patients for a short period of 1–2 weeks. In 19 (76%) patients, the condition improved drastically. In six patients, patients had to be referred to a center for intravenous immunoglobulins (IVIgs) and were given both steroids and IVIgs.
In nine patients of TEN, the most common class of drug implicated was antiepileptics (6, 6.6%), followed by NSAIDs in 3 (33.3%) patients. All causative drugs are shown in [Table 2]. The youngest patient was 7 years and the oldest 15 years. In four patients (44.4%), drug came out to be highly probable cause and in rest, probable. There was >30% cutaneous involvement in all patients with oral and ocular mucosal involvement also present. SCORTEN scoring system showed five patients with, three patients with a score of 3, and 1 with a score of 6. The offending drug was stopped in all the patients, and all patients were managed under intensive care unit with utmost care. Systemic steroids were given to all patients in the very beginning with eight patients showing recovery whereas one patient died. Among eight patients of SJS-TEN overlap, antimicrobials were the causative drugs in five and NSAIDs in three. Drugs implicated are shown in [Table 3]. The youngest patient was 5 years and the oldest 12 years [Figure 2]. Cutaneous involvement was 10%–30% in both including mucosal involvement. Drug came out to be highly probable in 1 (12.5%) and probable in 4 (50%) patients, possible in 3 (37.5%). Systemic involvement was also seen in both the patients. Both patients improved after stopping the offending drug, and administration of systemic steroids resulted in faster improvement.
|Table 3: Drugs implicated in Steven-Johnson syndrome - toxic epidermal necrolysis|
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|Figure 2: Patient of Steven-Johnson syndrome/toxic epidermal necrolysis overlap|
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Among six patients of DRESS, antiepileptics were seen as the causative drugs in 4 (66.6%) patients, NSAIDs (piroxicam) in 1 (16.6%), and antimicrobial (dapsone) in 1 (16.6%) patients. This is shown in [Table 4]. The youngest patient was 11 years old and the oldest was 18 years old [Figure 3]. Probable, highly probable, and possible association with drug etiology was seen in two patients (33.3%) each. All six patients presented with fever with rash, facial edema, and eosinophilia. Rash was in the form of maculopapular rash in four patients and two patients presented with SJS-like features. Four patients had lymphadenopathy, and liver function tests were deranged in all. Renal function tests were deranged in one patient, whereas another patient presented with pulmonary involvement. Patients with severe symptoms had greater eosinophilia >1500 and liver enzymes raised to about 20–40 times. Rapid withdrawal of the drugs was done in all the patients. Short course of corticosteroids was given in all patients and all recovered.
|Table 4: Drugs implicated in drug reaction with eosinophilia and systemic symptoms|
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In two patients of AGEP, terbinafine and azithromycin were implicated in each as shown in [Table 5]. Probable and possible association was seen in one patient each. The cutaneous lesions were in the form of generalized erythema with pustules, which at places were coalescing with petechiae and purpura. Fever with eosinophilia was seen in one patient. The drugs were stopped, and antihistamines with topical steroids were initiated. In one patient, oral steroids were needed to be given.
| Discussion|| |
A total of 52 patients were taken up for the study and males outnumbered the females. The most common SCADR was SJS seen in 27 (51.9%), followed by TEN in 9 (173%), SJS-TEN overlap in 8 (15.3%), DRESS in 6 (11.5%), and AGEP in 2 (3.8%). Although there has been a dearth of studies to assess SCADR's in pediatric population, few studies have reported SJS/TEN in 60.4% of the patients, DRESS in 27.6%, and AGEP in 12%. The most common class of drugs was antimicrobials, followed by NSAIDs and antiepileptics as the causative agents in SJS-TEN spectrum with cephalosporin plus clavulanic acid being the most common drug. This has been reported in various other studies as well.,, Recently, the role of granulysin has been the front runner. Systemic involvement along with mucocutaneous involvement was seen in our patients along with the SJS-TEN spectrum and one patient died. Various studies have also reported lower mortality rate in children. In our study, immediate withdrawal of the offending drugs along with supportive treatment in the form of corticosteroids resulted in rapid improvement in most of the patients. Only six patients needed additional IVIgs. Although the role of corticosteroids is controversial; however, their beneficial role has been documented in some studies.
Among six patients of DRESS, antiepileptics were seen as the causative agents in the majority followed by piroxicam and dapsone. Various studies have found similar results. However, another study reported antibiotics as the main etiologic agent. Systemic involvement was seen in all patients in the form of altered liver function tests, altered kidney function tests, and pulmonary involvement. Another study reported the liver to be the most common organ affected. Lymphadenopathy was seen in four patients. It was seen that prompt withdrawal and early administration of systemic steroids resulted in marked improvement in patients. Although no morbidity was seen in our patients, various studies have shown a morbidity of 5.8%–11%., Regarding AGEP in children, not much data exists, but aminopenicillins have been reported to be the most common etiologic agent, which stands in contrast to our study which reported terbinafine and azithromycin as the causative agents. Furthermore, in consortium with other studies, symptomatic treatment in the form of topical steroids along with antihistamines came out to be successful in our patients as well.,
Thus, in addition to prompt withdrawal, early administration of corticosteroids led to better outcomes in the majority of the patients.
| Conclusion|| |
In summary, there is a lack of studies on SCADRs among the pediatric population, and more so dilemma still exists regarding management. Thus, multiple such studies need to be carried out to establish clear-cut recommendations for the management of SCADRs in children and also to assess the role of corticosteroids in their management, particularly in a resource-poor nation like India.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Ghosh S, Acharya LD, Rao PG. Study and evaluation of the various cutaneous adverse drug reactions. Indian J Pharm Sci 2006;68:212-5. [Full text]
Nayak S, Acharjya B. Adverse cutaneous drug reaction. Indian J Dermatol 2008;53:2-8.
] [Full text]
Sharma VK, Dhar S. Clinical pattern of cutaneous drug eruption among children and adolescents in north India. Pediatr Dermatol 1995;12:178-83.
Patel RM, Marfatia YS. Clinical study of cutaneous drug eruptions in 200 patients. Indian J Dermatol Venereol Leprol 2008;74:430. [Full text]
Grover S. Severe cutaneous adverse reactions. Indian J Dermatol Venereol Leprol 2011;77:3-6.
] [Full text]
Noguera-Morel L, Hernández-Martín Á, Torrelo A. Cutaneous drug reactions in the pediatric population. Pediatr Clin North Am 2014;61:403-26.
Teo YX, Walsh SA. Severe adverse drug reactions. Clin Med (Lond) 2016;16:79-83.
Hoetzenecker W, Nägeli M, Mehra ET, Jensen AN, Saulite I, Schmid-Grendelmeier P, et al.
Adverse cutaneous drug eruptions: Current understanding. Semin Immunopathol 2016;38:75-86.
Chung WH, Wang CW, Dao RL. Severe cutaneous adverse drug reactions. J Dermatol 2016;43:758-66.
Mockenhaupt M. International Registry of Severe Cutaneous Adverse Reactions (SCAR) to Drugs and Collection of Biological Sample, Study Protocol [Internet] RegiSCAR Study Group; 2010. Available from: http://www.regiscar.org/pdf/regiscarprotocol100312.pdf
. [Last accessed on 2018 Nov 05].
Dibek Misirlioglu E, Guvenir H, Bahceci S, Haktanir Abul M, Can D, Usta Guc BE, et al.
Severe cutaneous adverse drug reactions in pediatric patients: A multicenter study. J Allergy Clin Immunol Pract 2017;5:757-63.
Kardaun SH, Sidoroff A, Valeyrie-Allanore L, Halevy S, Davidovici BB, Mockenhaupt M, et al.
Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: Does a DRESS syndrome really exist? Br J Dermatol 2007;156:609-11.
Sidoroff A, Halevy S, Bavinck JN, Vaillant L, Roujeau JC. Acute generalized exanthematous pustulosis (AGEP) – A clinical reaction pattern. J Cutan Pathol 2001;28:113-9.
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.
Mockenhaupt M, Viboud C, Dunant A, Naldi L, Halevy S, Bouwes Bavinck JN, et al.
Stevens-Johnson syndrome and toxic epidermal necrolysis: Assessment of medication risks with emphasis on recently marketed drugs. The EuroSCAR-study. J Invest Dermatol 2008;128:35-44.
Chung WH, Hung SI, Yang JY, Su SC, Huang SP, Wei CY, et al.
Granulysin is a key mediator for disseminated keratinocyte death in Stevens-Johnson syndrome and toxic epidermal necrolysis. Nat Med 2008;14:1343-50.
Yamane Y, Matsukura S, Watanabe Y, Yamaguchi Y, Nakamura K, Kambara T, et al.
Retrospective analysis of Stevens-Johnson syndrome and toxic epidermal necrolysis in 87 Japanese patients – Treatment and outcome. Allergol Int 2016;65:74-81.
Del Pozzo-Magana BR, Lazo-Langner A, Carleton B, Castro-Pastrana LI, Rieder MJ. A systematic review of treatment of drug-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in children. J Popul Ther Clin Pharmacol 2011;18:e121-33.
Kardaun SH, Sekula P, Valeyrie-Allanore L, Liss Y, Chu CY, Creamer D, et al.
Drug reaction with eosinophilia and systemic symptoms (DRESS): An original multisystem adverse drug reaction. Results from the prospective RegiSCAR study. Br J Dermatol 2013;169:1071-80.
Skowron F, Bensaid B, Balme B, Depaepe L, Kanitakis J, Nosbaum A, et al.
Drug reaction with eosinophilia and systemic symptoms (DRESS): Clinicopathological study of 45 cases. J Eur Acad Dermatol Venereol 2015;29:2199-205.
López-Rocha E, Blancas L, Rodríguez-Mireles K, Gaspar-López A, O'Farrill-Romanillos P, Amaya-Mejía A, et al.
Prevalence of DRESS syndrome. Rev Alerg Mex 2014;61:14-23.
Sidoroff A, Dunant A, Viboud C, Halevy S, Bavinck JN, Naldi L, et al.
Risk factors for acute generalized exanthematous pustulosis (AGEP)-results of a multinational case-control study (EuroSCAR). Br J Dermatol 2007;157:989-96.
Ingen-Housz-Oro S, Hotz C, Valeyrie-Allanore L, Sbidian E, Hemery F, Chosidow O, et al.
Acute generalized exanthematous pustulosis: A retrospective audit of practice between 1994 and 2011 at a single centre. Br J Dermatol 2015;172:1455-7.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]