|Year : 2014 | Volume
| Issue : 2 | Page : 96-99
Cutaneous adverse drug reaction to antiretroviral therapy in children
K Bhumesh Kumar, A Geeta Kiran
Department of Dermatology, Venereology and Leprosy, Gandhi Medical College, Hyderabad, Andhra Pradesh, India
|Date of Web Publication||27-Aug-2014|
K Bhumesh Kumar
Department of Dermatology, Venereology and Leprosy, Gandhi Medical College, Hyderabad 500 003, Andhra Pradesh
Source of Support: None, Conflict of Interest: None
HIV-infected patients have a higher risk of developing cutaneous reactions than the general population, which has a significant impact on patients' current and future care options. The severity of cutaneous adverse reactions varies greatly, and some may be difficult to manage. HIV-infected patients just at the beginning of antiretroviral therapy can frequently show a wide variety of adverse drug effects such as erythema multiforme, urticarial reaction, drug rashes, Stevens-Johnson syndrome, and toxic epidermal necrolysis.
Keywords: Antiretroviral therapy, cutaneous adverse drug reactions, human immuno deficiency virus infection in the child
|How to cite this article:|
Kumar K B, Kiran A G. Cutaneous adverse drug reaction to antiretroviral therapy in children. Indian J Paediatr Dermatol 2014;15:96-9
|How to cite this URL:|
Kumar K B, Kiran A G. Cutaneous adverse drug reaction to antiretroviral therapy in children. Indian J Paediatr Dermatol [serial online] 2014 [cited 2020 Oct 21];15:96-9. Available from: https://www.ijpd.in/text.asp?2014/15/2/96/139513
| Introduction|| |
Adverse drug reactions (ADRs) are common and important public health problem, may be life-threatening. An ADRs is defined by the World Health Organization as a noxious and unintended response to a drug that occurs at a dose normally used in man.  The most frequently observed are cutaneous reactions and range from generally trivial manifestation, such as pigmentation, to severe life-threatening reactions, such as Steven-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), exfoliative dermatitis and drug hypersensitivity syndrome. Their impact is significant in terms of cost and health service resources. The incidence of ADRs in immuno competent children is only 1.5%, whereas it is 20-30% in adults. HIV-infected patients have a higher risk of developing ADRs irrespective of age, which has a significant impact on patient care. Antiretroviral therapy (ART) manifest a wide variety of ADRs ranging from maculopapular rash to TEN. ,,,
Here, we report three different manifestations of cutaneous ADRs (CADRs) to ART in children.
| Case Reports|| |
A 2-year-old female child presented with an itchy rash all over the body including palms and soles without mucosal involvement, 2 weeks after ART (Azidothymidine [AZT] + lamivudine [3TC] + nevirapine [NVP]) [Figure 1]. No history of constitutional symptoms. Cutaneous examination revealed mild to moderate maculopapular rash all over the body, predominantly on trunk and extremities. ART was stopped, and symptomatic treatment was given on an outpatient basis. Child was asymptomatic after 10 days of therapy. After a gap of 2 weeks same ART regimen was initiated, and now the child is doing well.
|Figure 1: (a) and (b) Itchy maculopapular rash all over the body including palms and soles without mucosal involvement, 2 weeks after antiretroviral therapy. (c) Child was normal after 10 days|
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A 12-year-old female child developed red colored rash all over the body including palms and soles, 12 days after starting ART (AZT + 3TC + NVP) [Figure 2]. Patient continued ART without consulting doctor following which she developed oral lesions with constitutional symptoms. The patient reported to us with skin and mucosal lesions. On examination, extensive maculopapular rash present all over the body including palms and soles with involvement of oral and conjunctival mucosa, diagnosed as SJS. Child was admitted in the hospital and investigated. All routine parameters were found to be normal. Patient was treated with antibiotics, steroids, intravenous (IV) fluids, etc., She recovered in 2 weeks and discharged safely. NVP was substituted with efavirenz (EFV) after 2 weeks of recovery. At present, the child is doing well with substituted regimen.
|Figure 2: (a) and (b) Erythmatous maculopapular rash all over the body including palms and soles, 12 days after antiretroviral therapy|
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A 12-year-old female child developed extensive painful, red colored skin lesions 20 days after starting ART (AZT + 3TC + NVP) associated with constitutional symptoms [Figure 3]. On examination, tender erythematous to hyperpigmented macules and patches with epidermal peeling, leaving erosions seen over trunk and limbs. Erythematous macules present over palms and soles. Oral and conjunctival mucosa involved. Nikolsky's sign was positive. The patient was diagnosed as TEN and admitted in the hospital. Child was investigated, and all routine parameters were within normal limits. Antibiotics, steroids and IV fluids were given. Child recovered in 3 weeks and discharged safely. NVP was substituted with EFV after 2 weeks of recovery and the child tolerated the changed regimen without any symptoms.
|Figure 3: (a) and (b)Extensive erythematous, tender skin with positive Nikolsky's sign with mucosal involvement, 20 days after antiretroviral therapy|
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| Discussion|| |
In the 1 st year of treatment ADRs are the most common reasons for the discontinuation of ART among HIV-infected patients. The cutaneous manifestations are the most common in ADRs. The majority are simple maculopapular rash (immune-mediated). Severe skin eruptions such as SJS and TEN develop in <0.5% of patients. Diagnosis is based on history and clinical criteria. Usually, the onset of an ADR is delayed, between 1 and 6 weeks after commencing the drug. Rash or fever occurring more than 3 months after onset of therapy is almost always due to another agent. ,,,
Genetic polymorphisms that alter drug metabolism or immune responses in some individuals increase susceptibility to certain drugs or to certain severe CADRs (SCADRs).  Viral infections may play a concomitant pathologic role in SCADRs. 
| Clinical manifestation of severe cutaneous adverse drug reactions|| |
Steven-Johnson Syndrome and Toxic Epidermal Necrolysis
Patients initially develop pain, tenderness or a burning sensation in the skin. These symptoms often begin abruptly and are associated with fever and general malaise. Over the next 1-3 days, ill-defined erythematous macules or a diffuse erythema develops over the trunk and extremities. As the red areas enlarge, central dusky necrotic sites develop with subsequent bullae formation. As the disease progresses, sheets of full-thickness epidermis detach, revealing dark red, moist dermis (resembling severe second-degree burns). , A positive Nikolsky sign is an important diagnostic clue and precedes the onset of a life-threatening event. SJS involves <10% epidermal detachment and TEN involves more than 30% of epidermal detachment. Various differences of SJS & TEN are shown in [Table 1]. Between 10% and 29% epidermal detachment is diagnosed as SJS/TEN overlap. However, there was a report of a case of SJS that only presented with mucous membrane lesions, without skin lesions, in 14-year-old boy.  The presenting sign of mucous membrane involvement occurs in 85-95% of SJS and TEN patients, appearing on the conjunctivae, mucous membranes of the nares, mouth, oropharynx, anorectal junction, vulvovaginal region and urethral meatus. [Table 2] shows the detailed SJS and TEN differences. ,
Antiretroviral Therapy Associated Hypersensitivity Reactions
Antiretroviral therapy has been in the following groups: Nucleoside reverse transcriptase inhibitors (NRTIs), non-NRTIs, protease inhibitors and the newer group, the fusion inhibitors. The categories of ART together with examples are listed in [Table 3]. 
Nevirapine rash is the most frequently reported adverse reaction. Usually mild to moderate maculopapular rash (immune-mediated), occur most frequently within the first 6 weeks of therapy. Development of the rash is more rapid and severe with NVP rechallenge. The reaction appears more frequently and is more severe amongst non-HIV-infected individuals receiving prophylactic NVP. Delay in discontinuing NVP after onset of mild to moderate rash may result in more severe reaction. Mild NVP rash is usually a self-limited reaction that can be treated symptomatically.
Moderate to severe NVP rash, with or without hepatitis, requires discontinuation of NVP. HLA-B*3505 allele is a strong predictor for NVP induced skin ADR in HIV-infected. NVP was the causative agent in all our three cases, and all were females.
General Management Tips 
When a hypersensitivity reaction is suspected or occurs, the suspected causative drug should be withdrawn immediately. In mild hypersensitivity reactions, antihistamines are the recommended treatment. In severe hypersensitivity reactions that correspond with anaphylaxis, adrenaline should be administered promptly via intramuscular or IV routes. Glucocorticosteroids have an anti-inflammatory effect that may reduce prolonged reactions or later relapses. The management of SJS and TEN should preferably occur in an Intensive Care Unit (ICU). Care should be taken to warm the environment, correct electrolyte disturbances, ensure high caloric intake and maintain strict antiseptic measures. Regular assessment of liver function is important as these patients are at risk of developing hepatic failure. The effectiveness of IV immunoglobulins is still being debated, despite their widespread use. Specialized nursing care and topical management had dramatically reduced morbidity and permitted more rapid healing of the skin lesions.  Avoidance of the specific drug that caused the hypersensitivity reaction is required.
When to Discontinue Drugs
Therapy should be stopped if there is mucosal involvement, blistering, exfoliation, an elevation in alanine aminotransferase >5 times the upper limit of normal or elevation in transaminases associated with symptoms such as jaundice and upper abdominal pain, fever >39°C, or intolerable pruritus. It is also important to note that in abacavir hypersensitivity, rash may be a late or absent feature, and discontinuation should be based on progressive constitutional symptoms.  Reactions may worsen temporarily after cessation of drug therapy, particularly with drugs with longer half-lives such as NVP. 
Management of skin rashes due to nevirapine 
Based on the type and severity of symptoms:
- Mild rash (erythema, pruritus)
- Self-limited (90%), symptomatic treatment under supervision
- Mild to moderate rash, without systemic symptoms (diffuse erythematous macular or maculopapular rash)
- Symptomatic and supportive treatment under supervision
- Discontinuation of NVP for 1-2 weeks then restarted.
Moderate to Severe Rash, with or without Systemic Symptoms
Discontinuation of NVP, symptomatic and supportive treatment under supervision. Consider substituting NVP to EFV after rash resolves.
The prophylactic use of corticosteroids or antihistamines to prevent hypersensitivity reactions to NVP has not been shown to be of benefit, and could, in fact, increase the risk of developing the rash. ,,
To summarize, CADRs are common with ART (NVP) and its pathophysiology is complex and multifactorial. Monitoring and managing ADRs to ART are crucial to establish a successful HIV regimen. Early withdrawal of the causative agent is essential to prevent the progression of the reaction. Most crucial interventions in SJS-TEN are discontinuation of the offending drug and intensive supportive care in ICU. However, the real key to prevention of death and morbidity depends upon stopping the progression during the acute phase. SCADRs pose a challenge to the medical community since our knowledge regarding their pathogenesis is limited and hence the management.
| References|| |
|1.||World Health Organization. International drug monitoring: the role of national centres. World Health Organ Tech Rep Ser 1972;498:1-25. |
|2.||Champion RH, Burton JL, Burns DA, Breathnach SM. Textbook of dermatology. 6 th ed. Oxford: Blackwell Science Publishing 1998;2085-7. |
|3.||Irwin MF, Arthur ZE, Klauss WK, Frank A, Lowell AG, Stephen K. Fitzpatrick's dermatology in general medicine. 5 th ed. New York: McGraw Hill 1999. p. 138. |
|4.||Roujeau JC, Stern RS. Severe adverse cutaneous reactions to drugs. N Engl J Med 1994;331:1272-85. |
|5.||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;48:839-846. |
|6.||Chia FL, Leong KP. Severe cutaneous adverse reactions to drugs. Curr Opin Allergy Clin Immunol 2007;7:304-9. |
|7.||Bachot N, Roujeau JC. Physiopathology and treatment of severe drug eruptions. Curr Opin Allergy Clin Immunol 2001;1:293-8. |
|8.||Criado PR, Criado RF, Vasconcellos C, Pegas JR, Cera PC. Severe cutaneous adverse reactions to drug-relevant aspect to diagnosis and treatment. An Bras Dermatol 2004;79:471-88. |
|9.||Caproni M, Torchia D, Schincaglia E, Volpi W, Frezzolini A, Schena D, et al. Expression of cytokines and chemokine receptors in the cutaneous lesions of erythema multiforme and Stevens-Johnson syndrome/toxic epidermal necrolysis. Br J Dermatol 2006;155:722-8. |
|10.||Demoly P, Viola M, Gomes ER, Romano A. Drug hypersensitivity. Basel;Karger AG 2007:2-17. |
|11.||Phillips E, Mallal S. Drug hypersensitivity in HIV. Curr Opin Allergy Clin Immunol 2007;7:324-30. |
|12.||Irwin MF, Arthur ZE, Klauss WK, Frank A, Lowell AG, Stephen K. Fitzpatrick's dermatology in general medicine. 5 th ed. New York: McGraw Hill 1999. p.138. |
|13.||Jesse BH, Gregory AS, Lawrence DHW. Principles of Critical Care, 3 rd ed. NewYork: McGraw-Hill Companies 2005 (accesed October 7, 1007 at http:// www.accessmedicine. com/ content.aspx?aID=2281931 [Last accessed on 1007 Oct 07] |
|14.||Vanfleteren I, Van GD, De BC. Stevens-Johnson syndrome: a diagnostic challenge in the absence of skin lesions. Pediatr Dermatol 2003;20:52-6. |
|15.||Mirakian R, Ewan PW, Durham SR, et al. BSACI guidelines for the management of drug allergy. Clin Exp Allergy 2009;39:43-61. |
|16.||Temesgen Z, Beri G. HIV and drug allergy, Immunol Allergy Clin NAm 2004;24:521-31. |
|17.||Schnyder B. Approach to the patient with drug allergy. Immunol Allergy Clin N Am 2009;29:405-18. |
|18.||Davis CM, Shearer WT. Diagnosis and management of HIV drug hypersensitivity. J Allergy Clin Immunol. 2008;121:826-32.e825. |
|19.||Carr A, Cooper DA. Adverse effects of antiretroviral therapy. Lancet 2000;356:1423-30. |
|20.||Wit FW, Wood R, Horban A, Beniowski M, Schmidt RE, Gray G, et al. Prednisolone does not prevent hypersensitivity reactions in antiretroviral drug regimens containing abacavir with or without nevirapine. AIDS 2001;15:2423-9. |
|21.||Montaner JS, Cahn P, Zala C, Casssetti LI, Losso M, Hall DB, et al. Randomized, controlled study of the effects of a short course of prednisone on the incidence of rash associated with nevirapine in patients infected with HIV-1. J Acquir Immune Defic Syndr. 2003;33:41-6. |
|22.||Barreiro P, Soriano V, Casas E, Estrada V, Tellez MJ, Hoetelmans R, et al. Prevention of nevirapine-associated exanthema using slow dose escalation and/or corticosteroids. AIDS. 2000;14:2153 |
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]