Dermatologica Sinica

CASE REPORT
Year
: 2019  |  Volume : 37  |  Issue : 2  |  Page : 86--89

Toxic epidermal necrolysis in an infant induced by drug intake through breast milk


Yeh-Ni Chu1, Ming-Sheng Lee2, Shun-Cheng Yang2, Hui-Chun Tai3, Wen-Hung Chung4, Tsu-Man Chiu5,  
1 Department of Dermatology, Changhua Christian Hospital, Changhua, Taiwan
2 Department of Pediatrics, Changhua Christian Hospital, Changhua, Taiwan
3 Department of Pathology, Changhua Christian Hospital, Changhua, Taiwan
4 Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospitals, Taipei, Linkou and Keelung; College of Medicine, Chang Gung University; Chang Gung Immunology Consortium, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan; Whole-Genome Research Core Laboratory of Human Diseases, Chang Gung Memorial Hospital, Keelung, Taiwan
5 Department of Dermatology, Changhua Christian Hospital, Changhua; School of Medicine, Chung Shan Medical University, Taichung; Department of Biomedical Engineering, Chung Yuan Christian University, Taoyuan City, Taiwan

Correspondence Address:
Dr. Tsu-Man Chiu
Department of Dermatology, Changhua Christian Hospital, No. 135 Nanxiao Street, Changhua City, Changhua County 500
Taiwan

Abstract

Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening severe cutaneous adverse drug reactions, and SJS/TEN in infancy is rare. Here, we present a case of a 4-month-old infant with generalized exanthema, flaccid blisters, and mucosal erosions. He was diagnosed with TEN within 2 days using a granulysin quick screen test and subsequently verified with histopathologic findings. Transmission of cephalexin through breastfeeding was suspected to be a possible cause based on drug history, breastfeeding history, and lymphocyte transformation test. The patient survived with only skin hyperpigmentation remaining.



How to cite this article:
Chu YN, Lee MS, Yang SC, Tai HC, Chung WH, Chiu TM. Toxic epidermal necrolysis in an infant induced by drug intake through breast milk.Dermatol Sin 2019;37:86-89


How to cite this URL:
Chu YN, Lee MS, Yang SC, Tai HC, Chung WH, Chiu TM. Toxic epidermal necrolysis in an infant induced by drug intake through breast milk. Dermatol Sin [serial online] 2019 [cited 2022 Aug 12 ];37:86-89
Available from: https://www.dermsinica.org/text.asp?2019/37/2/86/259854


Full Text



 Introduction



Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening severe cutaneous adverse drug reactions that often require hospitalization.[1] SJS is defined as detachment of <10% skin of the whole-body surface area, whereas TEN is defined as detachment of >30% skin. Intermediate cases are known as SJS/TEN overlap. Here, we present a case of a 4-month-old infant who was diagnosed with TEN within 2 days using a granulysin quick screen test and subsequently verified with histopathologic findings. In addition, intake of cephalexin through breastfeeding was suspected to the cause based on drug history, breastfeeding history, and lymphocyte transformation test (LTT).

 Case Report



A 4-month-old male infant weighing 7.9 kg with no relevant history of travel, contact, or allergy was hospitalized in a regional hospital due to urinary tract infection with fever. He was treated with 250 mg cefazolin every 8 h for 8 days in addition to other medications, which were all discontinued upon discharge. A blistering rash on his trunk, face, and extremities (index day) with a fever of up to 40°C was noted by the outpatient department 9 days after discharge. During the following days, multiple flaccid blisters appeared over the infant's scrotum with erosion on the lips. The skin lesions rapidly progressed to the entire body and mucosa, and the patient was transferred to our hospital. Physical examination revealed generalized exanthema with flaccid blisters, erosions, and mucosal involvement (lips and external genital area including urinary meatus). The most severe lesions were concentrated in the trunk [Figure 1]a and [Figure 1]b. No target-like lesion was found, and the Nikolsky's sign was positive. Physical examination revealed no other findings. Laboratory test results showed a leukocyte count of 11,800 cells/μL with polymorphonuclear neutrophils 71.6%, eosinophils 1.1%, and an erythrocyte sedimentation rate of 26 mm/h. Biochemical studies for liver function and renal function showed serum alanine aminotransferase 23 U/L and creatinine 0.32 mg/dL. Serological testing for herpes simplex virus was positive for immunoglobulin G (IgG) (from the mother) but negative for IgM. Sera IgM and IgG for Mycoplasma pneumoniae were negative. A blood culture was positive for coagulase-negative Staphylococcus, which was considered a possible contaminant. The result of the granulysin quick screen test using fluid aspirated from the blisters was positive based on our 2008 study (>2 standard deviation [SD] above the mean of the control group).[2] The histopathological findings of skin biopsy revealed the separation of the epidermis from the underlying dermis with focal whole-layered necrosis and single-cell dyskeratosis of the epidermal layers, compatible with TEN [Figure 1]e and [Figure 1]f. Skin detachment of up to approximately 40% of the whole-body surface area was noted, in accordance with the pediatrician's opinion; therefore, the final diagnosis was TEN.{Figure 1}

A review of the infant's medication history revealed that in addition to the medications administered for urinary tract infection during the previous hospitalization, the mother consumed cephalexin for 2 days preceding the skin rash; therefore, drug passage through breast milk was suspected. Based on the infant's and his mother's drug history and breastfeeding history, cephalexin (transmitted through breast milk) was suspected as the possible cause.

After prompt withdrawal of the suspected drugs (stopping breastfeeding and avoiding cephalosporins), steroid therapy with intravenous (IV) methylprednisolone (4 mg) every 6 h was initiated, along with a single dose of IV Ig (15 mg) and daily teicoplanin (80 mg) to treat urinary tract infection due to Escherichia coli. Five days later, methylprednisolone was tapered to three times a day for 1 day, twice a day for 1 day, and once daily for 3 days. Blistering stopped within a few days, and over the following 15 days, the oral mucosa, genital mucosa, and skin gradually reepithelialized, enabling eventual discharge. The patient survived with the only remaining complication of skin hyperpigmentation [Figure 1]c and [Figure 1]d. LTT performed 4 weeks after cessation of systemic steroid therapy was positive for both cefazolin and cephalexin.

 Discussion



Granulysin is expressed in SJS/TEN, acute viral infection, graft-versus-host disease, and lichen planus but is not detectable in bullous pemphigoid, lupus, or psoriasis. The sensitivity of the granulysin quick screen test varies from 40% to 80%, and the specificity is approximately 96%. In our study conducted in 2008, blister fluids from participants with burn injuries or bullous pemphigoid were used as controls.[2] Blister fluids from participants with SJS-TEN showed high amounts of granulysin (6920.6 ± 12,050.2 ng/ml; range – 633.3–63,392.3 ng/ml). In contrast, the amount of granulysin in blister fluids of participants with burn injuries and bullous pemphigoid was 22.3 ± 24.8 and 22.1 ± 12.7 ng/ml, respectively. The granulysin quick screen test is regarded as positive when the value is higher than the mean +2 SD of the control value.[2] The granulysin quick screen test enabled us to diagnose the blistering rash as soon as possible.

Based on the clinical presentation, drug history, the result of the granulysin quick screen test, and histopathologic findings, a diagnosis of TEN was confirmed. Because cases of TEN in infants are rare, we could find only eight cases with comprehensive data to enable further discussion, which is summarized in [Table 1].[1],[3],[4],[5],[6],[7],[8],[9] We found that the most common etiology was antibiotics, with others including one of NSAIDs and one of an antiepileptic drug. We did not find any cases induced due to cephalexin or cefazolin, but three cases were possibly induced due to drugs belonging to the cephalosporin class.{Table 1}

In a breastfeeding infant, the amount of cephalexin is only small amount (if a mother takes 1 g cephalexin, the amount of drug in 90 ml breast milk is estimated to be about 0.05 mg 4–5 h later).[10] Further, the concentration we used in the LTT was 200 μg/ml for cefazolin and 18 μg/ml for cephalexin. LTT has a sensitivity of 64%–78% and a specificity of at least 85% which is probably higher for drugs such as lamotrigine, carbamazepine, and β-lactams. Therefore, ingestion of cephalexin through breast milk was suspected even though the amount of cephalexin was minimal. Skin eruptions caused due to medications in breast milk are rare, and we could not find any reports regarding cephalexin in breast milk and drug eruptions.[11],[12] This is the first report of TEN in an infant caused due to drug intake through human milk. A possible mechanism may have been initial sensitization of the infant's T-cells to cefazolin followed by induction of TEN due to cross-reactivity to cephalexin ingested through breast milk. LTT is a useful technique assisting in defining the causative agent in severe cutaneous adverse reactions. However, details of LTT in the context of drug intake through breast milk have not been specified. We could not rule out the possibility of a false-positive LTT result due to cross-reactivity, but our deduction is a reasonable explanation based on the clinical course. Although infection is another possible cause of TEN, we ruled out the possibility according to the negative laboratory findings and clinical manifestations in our case.

Drug ingestion is the most common cause of SJS/TEN. It is widely accepted that morbidity and mortality increase when the offending drug is withdrawn at a later stage. The granulysin quick screen test with fluid collected from blisters is useful to arrive at a diagnosis of SJS/TEN as soon as possible and to promptly withdraw possible causative drug(s).[2] In cases of breastfed patients, it is also necessary to review the drug history of the mother because even scant drug amounts in breast milk can induce SJS/TEN.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient's guardian have given the consent for the images and other clinical information to be reported in the journal. The patient's guardian understand that the patient's names and initials will not be published and due efforts will be made to conceal the patient's identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1Ferrándiz-Pulido C, García-Fernández D, Domínguez-Sampedro P, García-Patos V. Stevens-Johnson syndrome and toxic epidermal necrolysis in children: A review of the experience with paediatric patients in a university hospital. J Eur Acad Dermatol Venereol 2011;25:1153-9.
2Chung 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.
3de Groot R, Oranje AP, Vuzevski VD, Mettau JW. Toxic epidermal necrolysis probably due to Klebsiella pneumoniae sepsis. Dermatologica 1984;169:88-90.
4Hawk RJ, Storer JS, Daum RS. Toxic epidermal necrolysis in a 6-week-old infant. Pediatr Dermatol 1985;2:197-200.
5Scully MC, Frieden IJ. Toxic epidermal necrolysis in early infancy. J Am Acad Dermatol 1992;27:340-4.
6Morici MV, Galen WK, Shetty AK, Lebouef RP, Gouri TP, Cowan GS, et al. Intravenous immunoglobulin therapy for children with Stevens-Johnson syndrome. J Rheumatol 2000;27:2494-7.
7Lohmeier K, Megahed M, Schulte KW, Stannigel H, Mayatepek E, Schroten H, et al. Toxic epidermal necrolysis in a premature infant of 27 weeks' gestational age. Br J Dermatol 2005;152:150-1.
8Fernandes FR, Taguchi MR, Cabral JE, Ayres SS, Pimentel D, Sá LC, et al. Toxic epidermal necrolysis in newborn period: Case report. Allergol Immunopathol (Madr) 2011;39:240-1.
9Kim HY, Yang HK, Kim SH, Park JH. Ibuprofen associated acute vanishing bile duct syndrome and toxic epidermal necrolysis in an infant. Yonsei Med J 2014;55:834-7.
10Kafetzis DA, Siafas CA, Georgakopoulos PA, Papadatos CJ. Passage of cephalosporins and amoxicillin into the breast milk. Acta Paediatr Scand 1981;70:285-8.
11Yeung GT. Skin eruption in newborn due to bromism derived from mother's milk. Br Med J 1950;1:769.
12Matheson I, Lunde PK, Notarianni L. Infant rash caused by paracetamol in breast milk? Pediatrics 1985;76:651-2.