Stevens-Johnson syndrome/toxic epidermal necrolysis overlap following sulfadoxine-pyrimethamine overdose: a case report

¹Department of Pharmacology and Therapeutics, Ebonyi State University, Abakaliki, Ebonyi State, Nigeria, ²Division of Plastic Surgery, Department of Surgery, Alex-Ekwueme Federal University Teaching Hospital, Abakaliki, Ebonyi State, Nigeria, ³Department of Paediatrics, Alex-Ekwueme Federal University Teaching Hospital, Abakaliki, Ebonyi State, Nigeria, ⁴Department of Ophthalmology, Alex-Ekwueme Federal University Teaching Hospital, Abakaliki, Ebonyi State, Nigeria, ⁵Department of Community Medicine, Alex-Ekwueme Federal University Teaching Hospital, Abakaliki, Ebonyi State, Nigeria

^&Corresponding author
Chukwuma David Umeokonkwo, Department of Community Medicine, Alex-Ekwueme Federal University Teaching Hospital, Abakaliki, Ebonyi State, Nigeria

Introduction    

Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and Stevens-Johnson/toxic epidermal necrolysis overlap syndrome are all forms of a delayed-type drug hypersensitivity reaction and constitute medical emergency as they are associated with high morbidity and mortality [1]. They are rare but severe adverse drug reactions that present majorly as severe blistering skin rashes characterized by widespread necrosis of the skin and mucosa. What distinguishes between SJS, SJS/TEN overlap and TEN is the degree of body surface area involved (10% in SJS, 10%-30% in SJS/TEN overlap and >30% in TEN respectively) [1]. Currently, artemisinin-based combination therapy is the mainstay of malaria treatment [2]. Sulfadoxine-pyrimethamine is reserved for intermittent preventive treatment of malaria in pregnancy (IPTp). It is also used to treat toxoplasmosis [3]. The use of sulfadoxine-pyrimethamine, like other sulphonamides, is associated with the development of some forms of drug hypersensitivity reaction. It has been reported to cause a spectrum of SJS, TEN or SJS/TEN overlap [4]. This is idiosyncratic and needs to be continuously documented and reported to the relevant agencies and the general public. This will enhance pharmacovigilance and provide healthcare managers and health policymakers needed tool for improved evidence-based decision making. We, therefore, report this case of SJS/TEN overlap following the use of sulfadoxine-pyrimethamine.

Patient and observation     

We report the case of a 23kg 5-year old male child who was brought by the parents to the Children Emergency Room of Alex Ekwueme Federal University Teaching Hospital Abakaliki on account of four-day history of blisters and ulcers scattered over the body (limbs, trunk, face, labial mucosa and eyelids), and a three-day history of fever. The blistering preceded the onset of fever by one day. Fever was low grade (38°C) and persistent initially. These symptoms developed 10 days after he received sulfadoxine-pyrimethamine at a dose of two tablets every 12 hours for 3 days (an over-dosage about 12-fold) following a community-organized screening of primary school children for malaria using malaria rapid diagnostic test (MRDT). The screening was conducted by a community health extension worker in his locality. He tested positive to the screening alongside his elder sister. Following the onset of these symptoms, the child was taken to a secondary level privately-owned hospital where he was managed for 2 days without significant improvement. The elder sister who also took the same dosage of the drug as the child had a similar reaction but a much milder one that did not necessitate hospitalization. His father also has a history of allergic reaction (itching and rashes) to sulfadoxine-pyrimethamine some years beforehand. Patient was reviewed by a multidisciplinary team comprising of paediatricians, dermatologists, ophthalmologists and plastic surgeons. Physical examination revealed an anxious febrile (38°C) child, anicteric, acyanosed but in some painful distress. The vital signs were stable. There was extensive mucocutaneous blistering and ulcers exudating serosanginous fluid scattered over the limbs, the trunk and the face. Body surface area affectation was estimated at 19% with labial congestion, oral mucosal blistering and ocular involvement.

On admission, the random blood glucose was normal while serum electrolytes, urea and creatinine levels were within normal range except for mild hyponatremia and mild metabolic acidosis. Full blood count was normal (packed cell volume-36%, neutrophils-58%, lymphocytes-28%, monocytes-14%). Blood film also showed monocytosis which in this case is suggestive of underlying parasitic (malarial) infection. The Naranjo Adverse Drug Reaction Probability Scale [5] score of 6 was gotten suggesting a probable relationship between ingestion of the sulfadoxine-pyrimethamine and the adverse drug reaction seen. The patient was not taking any other drug concomitantly with the sulfadoxine-pyrimethamine prior to onset of symptoms. The severity-of-illness score of toxic epidermal necrolysis (SCORTEN) [6] was given as only one out the seven parameters was presents (initial detachment of the epidermis being 19%). Skin biopsy could not be done for logistic reasons. A diagnosis of Stevens-Johnson syndrome/toxic epidermal necrolysis overlap with ocular involvement following sulfadoxine-pyrimethamine administration was made. The differential diagnosis considered were toxic epidermal necrolysis, maculopapular eruptions, epdermiolysis bullosa and staphylococcal scalded skin syndrome. He received 10% dextrose saline initially as he could not take orally due to the oral mucosa involvement. Wound dressing was done and analgesics were given for the pain. He also received zinc gluconate (20mg orally daily for 14 days), antibiotics (ciprofloxacin - 200mg orally 12 hourly for 7 days and ceftriaxone - 900mg orally 12 hourly for 7 days), loratadine (10mg orally per day for 7 days), vitamins A, C and E, hydrocortisone (22.5mg orally 6 hourly for 3 days), omeprazole (10mg orally daily for 3 days) and dexamethasone/neomycin/polymyxin ophthalmic solution and ointment. On commencement of treatment the fever subsided and normalized and the blisters and ulcers started healing. He recovered fully and was discharged home after 13 days of admission. He had residual scars. The caregivers were strongly advised to avoid sulfadoxine-pyrimethamine particularly and other sulpha-containing drugs (which were enumerated for them) for the child, his siblings and father. The patient was given an appointment for a follow-up in four weeks´ time. When he came, he had fully recovered without any complications. There is no written patient/guardian´s assessment of outcome.

Discussion     

The culprit drug had been stopped before the patient presented. The ongoing hypersensitivity reaction was managed using immunosuppressants to stop further immunological reactions. Vitamins and zinc were administered to aid wound healing. Also, fluid loss from the blistering was corrected, adequate pain relief and wound care were given. The eye involvement was taken care of using appropriate eyedrops and ointments. The Stevens-Johnson syndrome/toxic epidermal necrolysis seen in this patient is most likely due to his genetic predisposition to hypersensitivity reaction to sulfur-containing drugs (in this case, sulfadoxine component of the sulfadoxine-pyrimethamine) as his father has had a history of hypersensitivity reaction on taking the drug in the past. The elder sister also had a similar history when given same drug at the same time as the index patient. This scenario underscores the need for healthcare workers to always pay close attention to family history of drug allergy of every patient as it has been shown that patients with SJS/TEN have genetic predisposition [1]. It also highlights the need to introduce basic pharmacogenetic testing in our health systems, especially in Sub-Saharan Africa where this is almost non-existent. A lot of adverse drug reactions we see in clinical practice would not occur if we begin to screen patients for their susceptibility to drug hypersensitivity (especially to certain drugs known to cause notorious adverse reactions). It is more cost-effective to undertake pharmacogenetic/genomic test-guided individualized therapy than treating the adverse effects associated with giving such medications without prior testing [7]. For this index patient, the time spent in the hospital was 13 days. The fact that the parents were always on ground looking after him constituted loss of productive man-hours as both parents are civil servants. Not only that, this resulted in catastrophic health expenditure for the family as they are not currently covered by any health insurance like the majority of the Nigerian populace.

Adverse drug reactions which are said to be a cause of morbidity, disability, mortality as well as economic drain in the health system, accounts for about 4.9% of hospital admissions worldwide [8]. However, it is under-reported mostly in developing countries and even in developed countries [9]. It therefore, behooves on health workers to promptly and proactively report any incidence of adverse drug reactions as recommended by the World Health Organisation [10]. Regulatory agencies like the Nigerian National Agency for Food and Drug Administration and Control of Nigeria, should also step up post-marketing surveillance of drugs to identify such adverse drug reactions and in turn let the populace be in the know to curtail further incidences. The prescription of the sulfadoxine-pyrimethamine by the community health extension worker in this context is both outside his/her job description and normal expectation for the cadre of health worker. No doubt, community health extension workers have an important role to play in the health sector especially in middle and low-income countries, however they must be seen to demonstrate adequate knowledge and skills requisite for their jobs as well as being conscious of their job description and adhere to it. While the community health extension worker was authorized to carried out malaria rapid diagnostic test on suspected malaria cases it was not recommended by the national malaria guideline to use sulfadoxine-pyrimethamine as the first line option for treating asymptomatic malaria in children. It is imperative for health workers to keep abreast of new developments and policy guidelines in clinical practice. Particularly, health policymakers and administrators should educate community health extension workers on the current treatment guidelines for common diseases like malaria, diarrhea, et cetera. There is also a need to closely supervise the activities of this cadre of health workers to ensure they operate within their job description.

Conclusion     

There is need for health workers to pay close attention to patient's family drug allergy history before administering any medications. Also, basic pharmacogenetic testing should as a matter of policy, be introduced into health facilities, especially for drugs known to cause serious adverse drug reactions. Furthermore, health workers should keep abreast with updates on treatment guidelines and also dutifully report all cases of adverse drug reactions to relevant bodies.

Competing interests     

The authors declare no competing interests.

Authors' contributions     

Emeka Donald Ogiji and Charles Chidiebele Maduba conceptualized the work. Ugochukwu Uzodimma Nnadozie, Uchechukwu Chukwuebuka Ukoh, Gabriel Maduwuike Okorie, Edak Ezeanosike and Charles Chidiebele Maduba managed the patient. Emeka Donald Ogiji, Chukwuma David Umeokonkwo, Uchechukwu Chukwuebuka Ukoh and Charles Chidiebele Maduba drafted the manuscript. All the authors read and approved the final manuscript.

References