Viral exanthems in childhood. Part 3: Parainfectious exanthems and those associated with virus-drug interactions

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1 506 Review Article DOI: /j x Viral exanthems in childhood. Part 3: Parainfectious exanthems and those associated with virus-drug interactions Regina Fölster-Holst 1, Hans Wolfgang Kreth 2 (1) University Clinic Schleswig-Holstein Campus Kiel, Clinic for Dermatology, Venerology and Allergology (Director: Prof. Dr. T. Schwarz), Germany (2) Pediatric Clinic and Polyclinic, University Clinic of Würzburg (Director: Prof. Dr. C. P. Speer), Germany JDDG; : Submitted: Accepted: Keywords parainfectious exanthems Gianotti-Crosti syndrome pityriasis rosea pityriasis lichenoides DRESS Summary Viruses cause not only direct infectious exanthems, but also parainfectious exanthems, which provoke skin alterations via interactions with the immune system. These distinct exanthems, for instance Gianotti-Crosti syndrome and pityriasis lichenoides group, do not reflect a specific pathogen but can occur in the course of many viral infections. In addition, some exanthems result from the interaction between viruses and drugs. Gianotti-Crosti syndrome Since the early 1990s, Gianotti-Crosti syndrome (GCS) has collectively referred to the clinically indistinguishable hepatitis B-associated acrodermatitis papulosa eruptiva infantilis and the non-hepatitis- B-associated infantile papulovesicular acrolocated syndrome [1]. GCS is a parainfectious exanthem. The prevalence of the disease is unknown. An average of patients with the disorder visit our clinic each year. Yet, because most affected children remain under their primary caregiver, the actual number of patients is surely much higher. GCS typically manifests during early childhood. The infectiousness of the disease is low. The exanthem seen in GCS is usually associated with Epstein-Barr virus (HHV-4). Other infectious agents include human herpes virus 6, parvovirus B19, Coxsackie, respiratory syncytial, parainfluenza, and hepatitis-b viruses [2]. In Northern Europe, hepatitis B virus is not a significant trigger of GCS, but in Mediterranean countries, especially Italy, it is one of the most important. The exanthem may also appear as an expression of a vaccine reaction, including the hepatitis B vaccine [3, 4]. A monomorphic papular (frequently lichenoid) or papulovesicular exanthem on the cheeks (Figure 1), extensor aspects of the extremities (Figure 2) and gluteal areas support the diagnosis. The exanthem is rarely accompanied by pruritus, hepatitis, or lymphadenopathy. Patients are positive for the Köbner phenomenon, which is noticeable with tight clothing (including elastic in socks). Other disorders which should be excluded include lichen ruber, atopic eczema, ictus, and drug-induced exanthem. Unlike Gianotti-Crosti syndrome, these are accompanied by pruritus; they also have different predilection sites. Hepatitis serology should be obtained in patients who have not been vaccinated against hepatitis B. If there is uncertainty, or for scientific purposes, more comprehensive serological tests and/or direct virus detection methods may be appropriate. is not necessary. It is important to educate the parents about the disorder, including its duration, as the disease can persist for several months. Pityriasis rosea Pityriasis rosea (PR) is a common, parainfectious, self-limited disease that affects adolescents and young adults.

2 Viral exanthems in childhood Part 3 Review Article 507 Figure 1: 2-year-old boy with Gianotti-Crosti syndrome. Red papules and plaques in the center of the cheek. Figure 2: Nearly 2-year-old girl with Gianotti- Crosti syndrome. Multiple lentil-sized papules disseminated along the extensor surfaces of the lower extremities. The exanthem and the course of disease are characteristic. The exact prevalence is unknown. Some authors have reported an association between PR and human herpes viruses, especially HHV-6 and HHV-7 [5 7]. Other authors have disputed this finding [8, 9]. There are no signs of an association with other viral agents. The exanthem may be preceded by malaise, fatigue, fever, and headache. The rash begins with a herald patch, an up to 6 cm large oval, red plaque (primary plaque). Within 1 2 weeks smaller, morphologically identical lesions (secondary plaques) erupt on the trunk and proximal extremities. Other clinical features include a ring of scales around the periphery of the lesion (collarette of scales) (Figure 3), which is found in the primary plaque as well as the secondary lesions, as well as the distribution of the rash along the lines of cleavage of the skin. PR is also characterized by an extremely irritable skin, which is especially apparent after bathing, and can lead to eczema and severe pruritus, and also determines the duration of the disorder (3 weeks to 6 months). Other erythematous squamous dermatoses should be considered in the Figure 3: 17-year-old boy with pityriasis rosea. A few pale red-brown, flat plaques showing typical collarette scaling. differential diagnosis. These include tinea corporis, psoriasis guttata, parapsoriasis en plaques, pityriasis lichenoides chronica (described by Juliusberg and involving scaling papules), drug-related exanthems (skin changes resembling those seen in pityriasis-rosea have been reported after use of angiotensin converting enzyme (ACE) inhibitors, hydrochlorothiazide, allopurinol, and acetylsalicylic acid [10]). Secondary syphilis, pityriasis versicolor (hyperpigmented form), and nummular eczema should also be considered, although the above-named diseases do not involve the appearance of a primary plaque, the typical collarette of scales, or dissemination along the cleavage lines of the skin. The diagnosis is made based on clinical features (see above). To exclude other disorders, a skin biopsy may be taken for histological analysis (PR: focal parakeratosis, dermal lymphohistiocytic infiltrate). Secondary syphilis should also be considered (treponemal hemagglutination [TPHA] test), and is particularly The Authors Journal compilation Blackwell Verlag GmbH, Berlin JDDG /2009/0706 JDDG (Band 7)

3 508 Review Article Viral exanthems in childhood Part 3 relevant in pregnant women. For the purposes of scientific research, other tests may be appropriate for identification of potential causative agents (see above). The most important part of treatment is to inform the patient that skin irritation, such as caused by vigorous washing, can trigger eczema and delay healing. In difficult-to-treat disease, a combination of mild topical glucocorticoids and low-dose UVB radiation (for patients aged 12 years and older) may be considered [11]. Some authors also have reported the effective use of antibiotics (erythromycin [12]) and antiviral drugs (administration of acyclovir within a week of disease onset) [13]. Pityriasis lichenoides Pityriasis lichenoides (PL) is a benign inflammatory skin disorder which predominantly affects children and young adults. It may also manifest as acute pityriasis lichenoides et varioliformis acuta (PLEVA or Mucha Habermann disease) or, in its chronic form, as pityriasis lichenoides chronica (PLC). The distinction between acute and chronic refers to the highly variable morphological appearance of individual lesions. The acute and chronic forms of disease are merely endpoints on a continuum of a range of clinical features. This explains the overlap and the similarities between histological appearances. Peak incidence of pityriasis lichenoides in adults is in the third decade of life and, in children, in the 5 th and 10 th years of life [14]. One retrospective analysis of 124 children reported that PLEVA was found in 57.3 % and PLC in 37 %, while in 8.7 % the diseases existed concomitantly [15]. The etiology of the disease is unknown. It is most likely due to the induction of a benign reactive proliferation of lymphocytes (primarily cytotoxic T cells) caused by infectious agents; associations with Toxoplasma gondii, herpes viruses (Epstein-Barr virus, VZV, CMV), HIV, parvovirus B19, and bacterial (staphylococcal and streptococcal) infections have been reported [14]. The outbreak of epidemics, especially during the winter or fall, age of manifestation, the self-limited Figure 4: 4-year-old boy with pityriasis lichenoides et varioliformis acuta (PLEVA). Bright red papules, some papulovesicles and plaques, resembling an arthropod assault reaction. course, and accompanying infection of the upper respiratory system support the theory of a causative infectious pathogen being the responsible trigger in PL [15]. Against the background of positive direct immunofluorescence, it has also been hypothesized that that etiopathogenesis may involve primary immune complex vasculitis. The resemblance with lymphomatoid papulosis and sporadic detection of a monoclonal rearrangement of the beta T-cell receptor gene (PLEVA, PLC) support the view of those who regard PL as a primary lymphoproliferative process [14]. The development of malignant lymphoma from PL has also been reported. Whether elevated tumor necrosis factoralpha (TNF- ) is relevant in terms of pathogenesis or, rather, is a reflection of the inflammation, remains unclear [16]. PLEVA: The exanthem begins abruptly either as a parainfectious process or postinfection, with the eruption of red maculae that evolve into papulovesicles (Figure 4). These can become necrotic, ulcerate, and/or hemorrhage (histology: perivascular and diffuse lymphohistiocytic infiltrates, erythrocyte extravasation, edema, basal vacuolar degeneration, epidermal necrolysis). The lesions, which have a predilection for the trunk, are polymorphic. Residual scarring and Figure 5: 5-year-old boy with chronic pityriasis lichenoides. Multiple, red-brown macules measuring a few millimeters in diameter and plaques with fine scales. pigmentary disorders (hyperpigmentation or hypopigmentation) are common. The exanthem is often accompanied by pain and sometimes pruritus, fever, and joint pain. PLC: The lesions appear as red-brown maculae (Figure 5) or lichenoid papules with a characteristic scaling (histologically similar, yet much more discreet than PLEVA). Unlike PLEVA, subjective symptoms are usually lacking.

4 Viral exanthems in childhood Part 3 Review Article 509 In addition to the classic distinction based on morphology (acute and chronic forms), the disease is also classified by dissemination of lesions (diffuse, central, peripheral) [17]. The majority of patients have the diffuse form (trunk and extremities) [15]. Complications: One complication of PLEVA is febrile ulceronecrotic PLEVA. This variant is characterized by pronounced necrosis and ulceration as well as secondary infection of the skin lesions, high fever, and severely diminished overall health. Extracutaneous symptoms include sore throat and abdominal pain, diarrhea, central nervous system disorders, splenomegaly, arthritis, sepsis, interstitial pneumonitis, and conjunctival ulcers. Mortality reportedly ranges around 25 % [18]. Both PLEVA and PLC can progress to malignant lymphoma. The differential diagnosis of PLEVA includes varicella (compared with PLEVA more commonly with mucous membrane involvement, multinucleate giant cells in cutaneous specimens) and lymphomatoid papulosis (preponderance of CD4 cells, CD30-positive). Gianotti- Crosti syndrome and ictus should also be considered. In PLC, other erythematous squamous skin disorders which should be considered are psoriasis guttata (family history, Auspitz and Köbner phenomena), pityriasis rosea (primary plaque, collarette scaling, following skin folds) and stage 2 syphilis (often involving palmoplantar regions). In suspected pityriasis lichenoides, regardless of the variant, a skin biopsy should be taken for histological, and if needed, immunohistochemical (predominance of CD8 cells, usually CD30- negative) and molecular genetic tests (Tcell receptor rearrangement). Occasionally (in patients with severe disease, unusual age of manifestation, protracted course) and for scientific research, additional studies may be ordered to identify potential infectious agents (see above). Similar to pityriasis rosea, a TPHA test should be done in patients with pityriasis lichenoides to exclude secondary syphilis. Figure 6: 19-year-old patient with amoxicillin-related exanthem. Bright red morbilliform exanthem. Phototherapy (especially PUVA and UVB) has proved very effective, especially in treating chronic disease. In children under age 12, it should be reserved for exceptional circumstances. Success with photodynamic therapy in PLC has also been recently reported [19]. Treatment was with a pulsed dye laser (595 nm). Although there was clearance of lesions after only a single session, this mode of treatment should still be regarded as an experimental treatment measure. For treatment of pediatric PL, oral erythromycin is recommended as monotherapy or with topical corticosteroids [15]. A recently published comparative study has shown that children respond more poorly to therapeutic measures than adults [20]. This observation seems to contradict our own experience, however, in which children in particular have responded well. Febrile ulceronecrotic PLEVA requires intensive medical care. Under antiobiotic cover, methotrexate given as monotherapy or with systemic corticosteroids has been shown to be highly effective [21]. Based on current knowledge of disease pathogenesis (see above), the use of TNF- antagonists could also be effective, although they have not yet been used. Exanthems related to ampicillin/amoxicillin use While only 10 % of children with infectious mononucleosis develop an exanthem, administration of ampicillin or amoxicillin in infectious mononucleosis necessarily causes an exanthem. In most children, after the disease has run its course, the exanthem is not reproducible after re-exposure to the aminopenicillins, although sensitization may occur over the course of infection [22]. One or two days after beginning antibiotic therapy, a morbilliform exanthem first appears on the trunk (Figure 6) and then spreads as a generalized rash. There is a noticeably marked tendency toward confluent lesions, resembling measles. Other exanthems associated with herpes viruses The combination of exanthem, fever, eosinophilia, lymphadenopathy, and elevated liver enzymes characterize a disorder known as drug rash with eosinophilia and systemic symptoms (DRESS), which apparently can lead not only reactivation of the herpes virus (especially HHV-6), but may also trigger it [23, 24]. Potential responsible agents are the anticonvulsant drugs carbamazepine, phenytoin or phenobarbital, allopurinol, dapsone, minocycline, and nevirapine [25]. The resulting exanthem is characterized by a broad morphological spectrum (including morbilliform or resembling erythema multiforme exudativum, erythrodermia or toxic epidermal necrolysis). Typical features include severe facial edema at the beginning and rapid desquamation, reminiscent of generalized contact dermatitis. <<< Conflict of interest None. The Authors Journal compilation Blackwell Verlag GmbH, Berlin JDDG /2009/0706 JDDG (Band 7)

5 510 Review Article Viral exanthems in childhood Part 3 Correspondence to Prof. Dr. med. Regina Fölster-Holst Universitätsklinikum Schleswig-Holstein, Campus Kiel Dermatologie, Venerologie und Allergologie Schittenhelmstraße 7 D Kiel Tel.: /1579/1501 Fax: rfoelsterholst@dermatology.uni-kiel.de References 1 Caputo R, Gelmetti C, Ermacora E, Gianni E, Silvestri A. Gianotti-Crosti syndrome: a retrospective analysis of 308 cases. J Am Acad Dermatol 1992; 26: Brandt O, Abeck D, Gianotti R. Burgdorf W. Gianotti-Crosti syndrome. J Am Acad Dermatol. 2006; 54: Haug S, Schnopp C, Ring J, Fölster- Holst R, Abeck D. Gianotti-Crosti syndrome following immunization. Hautarzt 2002; 53: Karakaş M, Durdu M, Tuncer I, Cevlik F. Gianotti-Crosti syndrome in a child following hepatitis B virus vaccination. J Dermatol 2007; 34: Drago F, Ranieri E, Malaguti F, Battifoglio ML, Losi E, Rebora A. Human herpesvirus in patients with pityriasis rosea. Dermatol 1997;195: Watanabe T, Kawamura T, Jacob SE, Aquilino EA, Orenstein JM, Black JB, Blauvelt A. Pityriasis rosea is associated with systemic active infection with both human herpes virus-7 and human herpes virus-6. J Invest Dermatol 2002; 119: Broccolo F, Drago F, Careddu AM, Foglieni C, Turbino L, Cocazza CE, Gelmetti C, Lusso P, Rebora AE, Malnati MS. Additional evidence that pityriasis rosea is associated with reactivation of HHV-6 and HHV-7. J Invest Dermatol 2005; 124: Kempf W, Adams V, Kleinhans M, Burg G, Panizzon R, Campadelli- Fiume G, Nestle F. Pityriasis rosea is not associated with human herpesvirus 7. Arch Dermatol 1999; 135: Chuh AA, Chan HL, Zawar V. Is human herpesvirus 7 the causative agent of pityriasis rosea? a critical review. Internat J Dermatol; 2004; 43: Atzori L, Pinna AL, Ferreli C, Aste N. Pityriasis rosea-like adverse reaction: review of the literature and experience of an Italian drug-surveillance center. Dermatol Online J. 2006; 27; 12(1): Valkova S, Trashlieva M, Christova P. UVB phototherapy for Pityriasis rosea. J Eur Acad Dermatol Venereol 2004; 18: Sharma Erythromycin in pityriasis rosea: A double-blind, placebo-controlled clinical trial. J Am Acad Dermatol 2000; 42: Drago F, Vecchio F, Rebora A. Use of high dose acyclovir in pityriasis rosea. J Am Acad Dermatol 2006; 54: Bowers S, Warshaw EM. Pityriasis lichenoides and its subtypes. J Am Acad Dermatol. 2006; 55: Ersoy-Evans S, Greco MF, Mancini AJ, Subaşi N, Paller AS. Pityriasis lichenoides in childhood: a retrospective review of 124 patients. J Am Acad Dermatol. 2007; 56: Tsianakas A, Hoeger PH. Transition of pityriasis lichenoides et varioliformis acuta to febrile ulceronecrotic Mucha- Habermann disease is associated with elevated serum tumour necrosis factoralpha. Br J Dermatol 2005; 152: Gelmetti C, Rigoni C, Alessi E, Ermacora E, Berti E, Caputo R. Pityriasis lichenoides in children: a longterm follow-up of eighty-nine cases. J Am Acad Dermatol. 1990; 23: Khachemoune A, Blyumin ML. Pityriasis lichenoides: pathophysiology, classification, and treatment. Am J Clin Dermatol. 2007; 8: Fernández-Guarino M, Harto A, Reguero-Callejas ME, Urrutia S, Jaén P. Pityriasis lichenoides chronica: good response to photodynamic therapy. Br J Dermatol. 2008; 158: Wahie S, Hiscutt E, Natarajan S, Taylor A. Pityriasis lichenoides: the differences between children and adults. Br J Dermatol. 2007; 157: Ito N, Ohshima A, Hashizume H, Takigawa M, Tokura Y. Febrile ulceronecrotic Mucha-Habermann's disease managed with methylprednisolone semipulse and subsequent methotrexate therapies. J Am Acad Dermatol 2003; 49: Renn CN, Straff W, Dorfmüller A, Al- Masoudi T, Merk HF, Sachs B. Amoxicillin-induced exanthema in young adults with infectious mononucleosis: demonstration of drug specific lymphocyte reactivity. Br J Dermatol 2002; 147: Mitani N, Aihara M, Yamakawa Y, Yamada M, Itoh N, Mizuki N, Ikezawa Z. Drug-induced hypersensitivity syndrome due to cyanamide associated with multiple reactivation of human herpesviruses. J Med Virol 2005; 75: Tohyama M, Hashimoto K, Yasukawa M, Kimura H, Horikawa T, Nakajima K, Urano Y, Matsumoto K, Iijima M, Shear NH. Association of human herpesvirus 6 reactivation with the flaring and severity of drug-induced hypersensitivity syndrome. Br J Dermatol. 2007; 57: Wurps G, Ott H, Schlüter A, Häusler M. DRESS-Syndrom nach Carbamazepin. Hautarzt 2007; 58: