CM E

Comorbid Infections of Pediatric Inflammatory Skin Diseases

LeAnna Lane, MD; and Jonathan Dyer, MD

CM E EDUCATIONAL OBJECTIVES S. aureus binds to the superfi cial for severe impetiginized eczema include 1. Identify and discuss commonly epidermis largely via fi bronectin and poorly controlled AD with involvement encountered bacterial and viral fi brinogen, extracellular matrix proteins of signifi cant body surface area.8 Devel- infections associated with atopic that are exposed when the epidermis is opment of pustules, crusting, erythema, dermatitis in children. disrupted by infl ammation or scratch- edema, or local lymphadenopathy are all 2. Determine effective strategies ing. The prominent Th2 cytokine, IL-4, clinical signs that a patient with AD has for prevention of infectious complications in atopic dermatitis. has been shown to induce production of developed a secondary bacterial infec- fi bronectin by skin fi broblasts.3 Numer- tion, most commonly with S. aureus or 3. Outline treatment options for infections in children with atopic ous studies during the past several years Streptococcus pyogenes (see Figure 1). dermatitis. have demonstrated decreased presence While methicillin-resistant S. aureus of resident cutaneous antimicrobial (MRSA) is becoming more common, Both authors are with the Department peptides in atopic dermatitis (AD) com- clinical and epidemiologic factors are of Dermatology, University of Missouri- pared with psoriasis, including beta- not always reliable in distinguishing Columbia. LeAnna Lane, MD, is a PGY3. defensins hBD2 and hBD3, cathlecidin MRSA from methicillin-sensitive S. au- Jonathan Dyer, MD, is Assistant Professor. LL-37, and calgranulins.4,5 reus (MSSA) in patients with AD.9 The Address correspondence to Jonathan Dyer, S. aureus contributes directly to most important clue may be lack of im- MD, via email: [email protected]. AD infl ammation in a variety of ways. provement while taking beta-lactam an- Drs. Lane and Dyer have disclosed no Staphylococcal enterotoxin B (SEB) and tibiotics such as cephalexin. relevant fi nancial relationships. alpha toxin act as superantigens, leading Diagnosis and antibiotic susceptibil- doi: 10.3928/00904481-20111209-07 to massive stimulation of T cells and ity profi les are best obtained from cul- production of IgE-specifi c antibodies ture of clinically infected lesions. While taphylococcus aureus is the most that contribute to mast cell degranula- it may seem intuitive that AD patients common infective agent of the skin tion and symptoms of pruritus and acute should be more susceptible to develop- Sin patients with atopic dermatitis. infl ammation.6 SEB and alpha-toxin are ing MRSA infections because of their Roughly 80% to 90% of atopic dermatitis also more potent stimulators of IL-22 repeated exposure to antibiotics, several patients are colonized with S. aureus com- secretion in patients with AD compared recent studies suggest that AD patients pared with only 5% of healthy controls. with patients with psoriasis and healthy are not at increased risk for developing Disease activity and severity have been as- controls, which may help explain the MRSA and may, in fact, have a lower sociated with S. aureus density, with acute role of S. aureus in eczema fl ares.7 risk than general pediatric patients.10,11 lesions having more S. aureus than chronic While such data appear reassuring, lesions, unaffected atopic skin, and normal STAPHYLOCOCCAL AD patients can and do become colo- nonatopic skin.1,2 Extensive research has ‘SUPERINFECTIONS’ nized with MRSA, which can lead to revealed S. aureus colonization to be both a As staphylococcal colonization is fl aring of AD or progress to true infec- consequence and a cause of the underlying nearly universal in AD, superinfection of tion. Monitoring bacterial cultures in infl ammation of atopic dermatitis. skin lesions is also common. Risk factors patients with refractory to standard oral

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Figure 1. Superinfected atopic dermatitis. Source: Lane L, Dyer J. Reprinted with permission. Figure 2. Eczema herpeticum. Source: Lane L, Dyer J. Reprinted with permission.

antibiotic therapy is necessary to guide at the end of treatment. Larger, high- as the nares, perineum, or axilla.14 Dilut- their therapy effectively. quality randomized controlled trials are ed bleach baths may also be employed needed to better defi ne the benefi ts and with great success and minimal com- CONTROLLING STAPH risks of antistaphylococcal treatment. plications (as they frequently are by the COLONIZATION authors) in patients requiring repeated While colonization is an obvious risk EFFICACY OF ANTIBIOTICS antibiotic courses. factor for infection, decreasing or eradi- In patients with AD that is resistant Recently, the role of group A strep- cating S. aureus colonization is chal- to appropriately applied topical anti- tococcus (GAS) in skin and soft tissue lenging. A recently published review on infl ammatory agents, and in those who infections in AD patients has been high- interventions to reduce S. aureus colo- have clinical signs suggestive of el- lighted.15 Importantly, in a retrospective nization found that both topical corti- evated bacterial burden or infection, the review, the presence of GAS was asso- costeroids and antibacterial agents can simple addition of short courses of ap- ciated with a higher incidence of fever, decrease the S. aureus bacterial load on propriate antibiotics that target typical cellulitis, and hospitalization in patients the skin of patients of AD, but found no gram-positive infectious agents (fi rst- or with AD. In a number of patients with convincing evidence that a decrease in second-generation cephalosporins, ami- proven GAS infection, the clinical lesions colonization leads to demonstrable clini- nopenicillins) often leads to rapid and mimicked disseminated herpes simplex cal improvement. Additionally, patients dramatic improvement in cutaneous le- virus (HSV). Additionally, while stan- quickly revert to previous levels of colo- sions, without any other alteration in dard MSSA antibiotics are also effective nization when interventions are discon- treatment. In such AD patients, unless against GAS, trimethoprim/sulfamethox- tinued.12,13 Included in this review was MRSA is suspected, it is reasonable to azole — which is being used more fre- a recent report demonstrating improve- treat empirically with the above agents, quently in suspected MRSA infections ment in the severity of moderate/severe reserving bacterial cultures for patients — is not reliably effective for GAS. This AD with use of intranasal mupirocin who do not respond. report again highlights the need to follow (twice daily for 5 consecutive days per If MRSA is present or suspected be- cutaneous bacterial cultures in diffi cult or month) and diluted bleach baths (one- cause of clinical appearance, then appro- treatment-resistant AD patients.15 half cup of common household bleach priate antibiotics such as trimethoprim/ diluted in approximately 40 gallons of sulfamethoxazole or clindamycin can be VIRAL INFECTIONS water for a fi nal bleach concentration of used. Topical antibiotics such as mupiri- Patients with infl ammatory skin disease 0.005%, used as a 5- to 10-minute soak cin can be helpful for superfi cial or mild such as AD, Darier-White disease, Hailey- twice weekly). However, even in these limited skin infections, or for decreasing Hailey disease, certain ichthyoses, and patients, S. aureus was cultured from colonization at body sites that are com- pemphigus foliaceous are also susceptible both the skin and the nares of patients mon reservoirs of Staphylococcus, such to cutaneous viral infections.16

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Some of the same factors that in- crease the risk for bacterial infection also contribute to viral infections such as HSV, herpes vaccinatum, and mollus- cum contagiosum. These factors include disrupted epidermal barrier leading to enhanced viral penetration; decreased antimicrobial peptides; and prominence of T-helper type 2 (Th2) cytokines. These also contribute to viral infections such as HSV, herpes vaccinatum, and molluscum contagiosum.

Eczema Herpeticum HSV is the most common viral co-infection in AD patients. Dissemi- Figure 3. Molluscum contagiosum infection. Source: Sugarman J. Reprinted with permission. nated cutaneous infection with HSV is termed eczema herpeticum (EH). Past estimates for EH frequency in patients EH may have severe complications Because histologic exam cannot differ- with AD were roughly 3% to 15%, such as keratoconjunctivitis, leading to entiate HSV-1, HSV-2, or varicella, the although a recent large population blindness, meningitis, encephalitis, and diagnosis is often best established with a study suggested a higher rate, closer secondary bacterial sepsis. Before the combination of the above methods. to 50%.17 Patients who developed EH availability of acyclovir, EH mortality were more likely to have severe skin approached 75%. Viral culture has been HSV-1 and HSV-2 disease, earlier age of onset, more se- considered the gold standard for diagno- In the clinic, the diagnosis of dis- vere Th2 polarity, greater serum IgE sis but is limited by its low sensitivity. seminated HSV infection can require levels, greater allergen sensitization, Yields are highest when the viral culture a high index of suspicion. Some cases and signifi cantly higher incidence of S. is obtained from the base of a new ves- may be subtle clinically, which may aureus infections.17 icle less than 48 hours old.19 A Tzanck explain the variation in estimated EH HSV reactivation in response to smear is quick and easy to perform, but incidence. It is less clear what the as- sunlight, trauma, stress, or immuno- specifi city and sensitivity are highly sociated morbidity is from milder EH suppression is often preceded by a variable; multinucleated giant cells and outbreaks, but given the speed with prodrome of burning or pruritus and intranuclear inclusions are seen with Gi- which HSV infection can spread or leads to “outbreaks” in the distribution emsa or Wright stain. Serology is most become severe in these patients, an ag- of the involved nerve. useful in differentiating primary HSV gressive approach is essential. EH is believed to develop more infections from reactivation using com- When HSV is confi rmed in an AD commonly from primary HSV infec- parison of acute and convalescent titers patient, often, empiric antiviral therapy tion rather than reactivation. Classi- separated by 2 to 4 weeks. is initiated at this time, as waiting for cally, HSV presents as grouped mono- Polymerase chain reaction (PCR) and viral culture/PCR results without treat- morphic vesicles on an erythematous direct fl uorescence antigen (DFA) detec- ment could lead to greater morbidity. base with rupture of the vesicles, pro- tion are newer methods and are less stud- Oral acyclovir is the treatment of choice ducing punched out ulcers (Figure 2, ied in cutaneous HSV. Both methods have and carries a pediatric indication. While see page e2). In patients with poorly high sensitivity and allow differentiation neither valacyclovir nor famciclovir car- controlled AD, EH may be diffi cult to of HSV-1 and HSV-2, but DFA is less ries an indication for use in children and detect or misdiagnosed as a bacterial expensive, more widely available, and only come in pill forms, recent shortages infection (especially GAS)14 or con- is the preferred molecular technique.18 in acyclovir have necessitated their use; tact dermatitis; any fl are of AD should Histologic examination is less commonly they have been shown effective and safe prompt examination for EH. Systemic performed and may show an intraepider- in pediatric patients.20 symptoms such as fever, malaise, and mal vesicle, multinucleated cells, nuclear Hospitalization with intravenous acy- poor appetite are common.18 molding, or cells with steel gray nuclei. clovir may be necessary in rapidly pro-

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gressing or severe cases. Extreme cau- ployed to treat MC. These differ in EV Presentation and Diagnosis tion must be taken in cases with facial effi cacy and in the amount of patient EV presents with a characteristic distri- and periocular involvement, given the discomfort associated with treatment. bution involving the face, neck, antecubi- risk for corneal scarring from HSV kera- Curettage of lesions can be effective tal and popliteal fossae; it tends to present toconjunctivitis. Topical antiviral thera- but is often uncomfortable and even most commonly in areas of active derma- py has no place in the treatment of active frightening for younger patients. titis, although it can also involve normal EH due to complete lack of established Cryotherapy with liquid nitrogen is skin and become confl uent and dissemi- effi cacy. Viral culture with investigation similarly effective but uncomfortable. nated. EV begins as papules that evolve of antiviral sensitivities is important in Topical cantharidin, a topical vesicant into prominently umbilicated vesicles or patients resistant to treatment, as thymi- made from the Chinese blister beetle, pustules that may form crusts, often on dine kinase-resistant HSV has been re- has been used as a relatively painless erythematous and edematous bases. Im- ported in AD patients.21 and effective treatment for decades. portantly, all the lesions are in the same However, reactions to the agent are stage of development, and in untreated Molluscum Contagiosum less predictable and it cannot be ob- patients, may come in periodic crops. This poxvirus is distinct from vaccin- tained from any pharmacy in the US Lesions typically resolve in 21 days, ia and variola. Molluscum contagiosum because it lacks FDA approval. Other leaving depressed scars that may be (MC) infection is common in childhood, agents such as topical tretinoin or oral severe.26 Vesicular lesions in an AD pa- appearing with greater frequency and se- cimetidine are less well studied.22 tient with possible exposure to a small- verity in AD patients. pox/vaccinia vaccinee should raise sus- MC lesions typically appear on af- ECZEMA VACCINATUM picion of EV. Diagnosis is made most fected AD skin but may also affect Eczema vaccinatum (EV) results readily with the use of PCR, which can uninvolved skin, possibly due to auto- from the dissemination of the vac- differentiate vaccinia, variola, and other inoculation. Umbilicated, skin-colored cinia virus (VV), a live virus used in orthopoxviruses. Cytopathic effect can papules are the classic fi ndings. Sec- the smallpox vaccine. Currently, a past be noted on viral culture, but this is not ondary reactions to MC infection are history of AD or active AD are contra- specifi c for vaccinia. Guarnieri bodies, common. A secondary “molluscum indications to vaccination due to con- or type-B inclusions, are eosinophilic dermatitis” occurs in many cases and cern over EV. During the decades of blobs noted in the cytoplasm of cells may be diffi cult to discern from the widespread smallpox vaccination in infected with poxvirus that can be seen surrounding eczematous patches (Fig- the US, EV occurred in roughly 10 to on histologic examination. ure 3, see page e3). There are no as- 38 cases per million, with fatality rates sociated systemic fi ndings. ranging from 30% to 40% in untreated CONCLUSION Diagnosis of MC is usually made patients, with most deaths occurring Cutaneous infections frequently clinically with dermoscopy, helping in small children.23,24 Since the rein- complicate the picture of infl ammatory to highlight the central umbilication stitution of smallpox vaccination of skin diseases. Because of the higher in questionable cases. If the diagnosis US military personnel and designated likelihood of developing disseminated remains in question, biopsy of a lesion public offi cials in 2002, a single case or more severe disease compared with will show epidermal invagination and of EV has been reported, occurring in normal or even psoriatic skin, cutane- the pathognomonic Henderson-Pater- a 28-month-old male with severe AD ous infections should be taken seri- son bodies. Management of MC in the who contracted the virus from his re- ously in the pediatric patient popula- AD patient can be diffi cult. The pres- cently vaccinated military father. The tion. Goals of therapy should be aimed ence of active dermatitis can lead to patient’s father had been vaccinated no at properly treating the infection and easier spread of the virus itself and can fewer than 21 days before exposing his gaining improved control of the under- also interfere with the assessment and family, a time when in most, the virus lying infl ammatory disease to reduce treatment of lesions. would no longer have been present. risk for recurrent infection. Often, a reasonable initial approach The father’s personal history of AD is to calm any existing AD/MC der- may help explain his prolonged viral REFERENCES matitis with topical anti-infl ammatory shedding. The patient’s mother also 1. Leung D. Infection in atopic dermatitis. Curr Opin Pediatr. 2003;15(4):399-404. agents (eg, 2.5% hydrocortisone) in developed signs of vaccinia infection, 2. Lin YT, Wang CT, Chian BL. Role of bacterial addition to directly treating the MC. confi rmed with PCR, and his siblings pathogens in atopic dermatitis. Clinic Rev Al- A variety of therapies have been em- showed positive serology.23,25 lergy Immunol. 2007;33(3):167-177.

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