Hospital Consult

Outpatient Management and Follow-up Recommendations for Adverse Drug Reactions: Guidelines for Posthospitalization Care

In partnership with the Society for Dermatology Hospitalists

Cutis. 2019 May;103(05):254-256, 258

Acute generalized exanthematous pustulosis (AGEP), drug rash with eosinophilia and systemic symptoms (DRESS) syndrome, and Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) are types of adverse drug reactions (ADRs), each with their own set of characteristic symptoms and sequelae. Although guidelines for inpatient management of these conditions exist, guidelines for outpatient follow-up are lacking. Based on the existing literature, we propose guidelines for outpatient follow-up of AGEP, DRESS, and SJS/TEN.

PDF Download

Practice Points

In the setting of an adverse drug reaction (ADR), discontinuing the concerning medication is the first and most important step.
Acute generalized exanthematous pustulosis, drug rash with eosinophilia and systemic symptoms (DRESS) syndrome, and Stevens-Johnson syndrome/toxic epidermal necrolysis all require specific outpatient follow-up after discharge.

References

Preventable adverse drug reactions: a focus on drug interactions. US Food and Drug Administration website. https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm110632.htm. Updated March 6, 2018. Accessed April 12, 2019.
Thienvibul C, Vachiramon V, Chanprapaph K. Five-year retrospective review of acute generalized exanthematous pustulosis. Dermatol Res Pract. 2015;3:1-8.
Lee HY, Chou D, Pang SM, et al. Acute generalized exanthematous pustulosis: analysis of cases managed in a tertiary hospital in Singapore. Int J Dermatol. 2010;49:507-512.
Ropars N, Darrieux L, Tisseau L, et al. Acute generalized exanthematous pustulosis associated with primary Epstein-Barr virus infection. JAAD Case Rep. 2014;1:9-11.
Hattem S, Beerthuizen G, Kardaun S. Severe flucloxacillin‐induced acute generalized exanthematous pustulosis (AGEP), with toxic epidermal necrolysis (TEN)‐like features: does overlap between AGEP and TEN exist? clinical report and review of the literature. Br J Dermatol. 2014;171:1539-1545.
Tajmir-Riahi A, Wörl P, Harrer T, et al. Life-threatening atypical case of acute generalized exanthematous pustulosis. Int Arch Allergy Immunol. 2017;174:108-111.
Feldmeyer L, Heidemeyer K, Yawalkar N. Acute generalized exanthematous pustulosis: pathogenesis, genetic background, clinical variants and therapy. Int J Mol Sci. 2016;17:E1214.
Szatkowski J, Schwartz RA. Acute generalized exanthematous pustulosis (AGEP). a review and update. J Am Acad Dermatol. 2015;73:843-848.
Totonchy MB, McNiff JM, Bunick CG. Koebnerization of Hailey-Hailey disease into a cutaneous drug eruption of acute generalized exanthematous pustulosis associated with systemic symptoms. J Cutan Pathol. 2016;43:1031-1035.
Husain Z, Reddy BY, Schwartz RA. DRESS syndrome: part II. management and therapeutics. J Am Acad Dermatol. 2013;68:709.e1-e9; quiz 718-720.
Kano Y, Shiohara T. Long-term outcome of patients with severe cutaneous adverse reactions. Dermatologica Sinica. 2013;31:211-216.
Bolognia J, Jorizzo JL, Schaffer JV, eds. Dermatology. Vol 1. Philadelphia, PA: Elsevier Saunders; 2012.
Ushigome Y, Kano Y, Ishida T, et al. Short- and long-term outcomes of 34 patients with drug-induced hypersensitivity syndrome in a single institution. J Am Acad Dermatol. 2013;68:721-728.
Ljungman P, Wang FZ, Clark DA, et al. High levels of human herpesvirus 6 DNA in peripheral blood leucocytes are correlated to platelet engraftment and disease in allogeneic stem cell transplant patients. Br J Haematol. 2000;111:774-781.
Asano Y, Kagawa H, Kano Y, et al. Cytomegalovirus disease during severe drug eruptions: report of 2 cases and retrospective study of 18 patients with drug-induced hypersensitivity syndrome. Arch Dermatol. 2009;145:1030-1036.
Kano Y , Tohyama M, Aihara M, et al. Sequelae in 145 patients with drug‐induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms: survey conducted by the Asian Research Committee on Severe Cutaneous Adverse Reactions (ASCAR). J Dermatol. 2015;42:276-282.
Morita C, Yanase T, Shiohara T, et al. Aggressive treatment in paediatric or young patients with drug-induced hypersensitivity syndrome (DiHS)/ drug reaction with eosinophilia and systemic symptoms (DRESS) is associated with future development of type III polyglandular autoimmune syndrome [published online October 27, 2018]. BMJ Case Rep. doi:10.1136/bcr-2018-225528.
Chiang A, Shiu J, Elsensohn AN, et al. Classic autoimmune type 1 diabetes mellitus after a case of drug reaction with eosinophilia and systemic symptoms (DRESS). JAAD Case Rep. 2018;4:295-297.
Lew TT, Creamer D, Mackenzie J, et al. Post-traumatic stress disorder following drug reaction with eosinophilia and systemic symptoms. Br J Dermatol. 2015;172:836-837.
Kumar R, Das A, Das S. Management of Stevens-Johnson syndrome-toxic epidermal necrolysis: looking beyond guidelines! Indian J Dermatol. 2018;63:117-124.
Yang CW, Cho YT, Chen KL, et al. Long-term sequelae of Stevens-Johnson syndrome/toxic epidermal necrolysis. Acta Derm Venereol. 2016;96:525-529.
Lee HY, Walsh SA, Creamer D. Long‐term complications of Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN): the spectrum of chronic problems in patients who survive an episode of SJS/TEN necessitates multidisciplinary follow‐up. Br J Dermatol. 2017;177:924-935.
Hsu M, Jayaram A, Verner R, et al. Indications and outcomes of amniotic membrane transplantation in the management of acute Stevens-Johnson syndrome and toxic epidermal necrolysis: a case-control study. Cornea. 2012;31:1394-1402.
Sant’ Anna AE, Hazarbassanov RM, de Freitas D, et al. Minor salivary glands and labial mucous membrane graft in the treatment of severe symblepharon and dry eye in patients with Stevens-Johnson syndrome. Br J Ophthalmol. 2012;96:234-239.
Hefez L, Zaghbib K, Sbidian E, et al. Post-traumatic stress disorder in Stevens-Johnson syndrome and toxic epidermal necrolysis: prevalence and risk factors. a prospective study of 31 patients [published online October 3, 2018]. Br J Dermatol. doi:10.1111/bjd.17267.
Knight L, Todd G, Muloiwa R, et al. Stevens Johnson syndrome and toxic epidermal necrolysis: maternal and foetal outcomes intwenty-two consecutive pregnant HIV infected women [published online August 12, 2015]. PLoS One. doi:10.1371/journal.pone.0135501.
Tchetnya X, Ngwasiri CA, Munge T, et al. Severe eye complications from toxic epidermal necrolysis following initiation of nevirapine based HAART regimen in a child with HIV infection: a case from Cameroon. BMC Pediatr. 2018;18:108.
Antoon JW, Goldman JL, Lee B, et al. Incidence, outcomes, and resource use in children with Stevens-Johnson syndrome and toxic epidermal necrolysis. Pediatr Dermatol. 2018;35:182-187.
Basu S, Shanbhag SS, Gokani A, et al. Chronic ocular sequelae of Stevens-Johnson syndrome in children: long-term impact of appropriate therapy on natural history of disease. Am J Ophthalmol. 2018;189:17-28.
Pinho A, Marta A, Coutinho I, et al. Long‐term reproducibility of positive patch test reactions in patients with non‐immediate cutaneous adverse drug reactions to antibiotics. Contact Dermatitis. 2017;76:204-209.
Barbaud A, Collet E, Milpied B, et al. A multicentre study to determine the value and safety of drug patch tests for the three main classes of severe cutaneous adverse drug reactions. Br J Dermatol. 2013;168:555-562.

It has been estimated that 2 million serious adverse drug reactions (ADRs) occur annually in the United States, resulting in 100,000 deaths.¹ Although the acute morbidity and mortality of these ADRs are readily apparent, postdischarge sequalae are critical aspects of a patient’s care. Herein, we present an approach to outpatient dermatologic follow-up of 3 ADRs: acute generalized exanthematous pustulosis (AGEP), drug rash with eosinophilia and systemic symptoms (DRESS) syndrome, and Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). For these ADRs, the first step is prompt diagnosis and discontinuation of any potentially causative medications.

ACUTE GENERALIZED EXANTHEMATOUS PUSTULOSIS

Ninety percent of the time, AGEP is caused by medications, most commonly antibiotics, and less often it is caused by viruses.^2-4 It presents as a cutaneous eruption with nonfollicular sterile pustules, fever, and leukocytosis, usually within 5 days after starting a causative medication.⁵ After stopping the medication, cutaneous findings generally improve within 1 week, and leukocytosis often resolves within 1 week.³

Notable Sequelae

Although AGEP typically is considered benign,² there have been reports of severe sequelae including death from a systemic inflammatory response and complications such as bacterial superinfection and sepsis.^6,7 Visceral involvement can be seen in up to 20% of AGEP patients, with systemic symptoms similar to those seen in DRESS syndrome. Mortality has been reported in up to 5% of cases, mainly in patients with comorbidities and notable mucosal involvement.⁸ More severe disease can be seen in patients with known dermatologic disease, as AGEP can provoke an isomorphic phenomenon.⁹ Laboratory alterations typically seen in AGEP include neutrophilia, eosinophilia, and elevated liver enzymes.²

Follow-up Recommendations

Patients should be informed of the expected timeline for resolution and should be counseled on the possibility of rare systemic symptoms. Laboratory abnormalities should be monitored every 2 to 4 weeks until normalized.

DRESS SYNDROME

DRESS syndrome is characterized by a morbilliform eruption that can be accompanied by fever; eosinophilia; purpura; facial edema; lymphadenopathy; and liver, renal, or other organ dysfunction. DRESS syndrome most often presents within 8 weeks of exposure to a causative drug.^10,11 The most common causative agents are anticonvulsants, antimicrobials, and allopurinol.¹² Treatment includes topical corticosteroids and systemic corticosteroids for internal organ involvement.¹⁰

Short-term Sequelae

Several potential sequelae may occur within 6 months of resolution of DRESS syndrome, resulting from both the ADR itself and/or systemic corticosteroids that often are required for treatment.¹³ Complications secondary to herpesviruses have been reported.¹⁴ Cases of cytomegalovirus-induced gastric ulcers can lead to gastrointestinal tract bleeds.¹⁵

Infections including Cryptococcus species and herpes zoster also have been reported.¹⁶ Patients, particularly those treated with systemic corticosteroids, should be monitored with close follow-up for infectious complications and treatment-related adverse effects.¹³