REVIEW URRENT C OPINION
What’s new with common, uncommon and rare rashes in childhood James G. Dinulos a,b
Purpose of review Children with rashes account for many of the outpatient visits to a general pediatrician. As such, pediatricians are often the first to identify and treat these rashes. Establishing an approach to common, uncommon and rare pediatric rashes assists in accurate assessment. This review highlights newly identified clinical patterns and disease severity. Recent findings Group A b-hemolytic streptococci (GABHS) have been shown to be an important cause of intertrigo and to cause more widespread disease in some instances. Superficial skin infections with GABHS have been associated with strains secreting exfoliating toxins, whereas deeper infections have been associated with superantigen toxins. Hand-foot-and-mouth disease (HFMD) outbreaks have occurred with more virulent strains, causing more widespread disease that may be confused with eczema herpeticum or varicella. Mycoplasma pneumoniae has been shown to be an important cause of common disorders such as urticaria, and less common disorders such as Stevens–Johnson syndrome and Mycoplasma-associated mucositis. Recurrent toxin-mediated erythema is a recently described entity that must be differentiated from Kawasaki disease. Summary The number of rashes acquired in childhood is vast, requiring the pediatrician to be able to identify worrisome rashes from those with a more benign course. Key clinical signs may assist in clinical diagnosis and treatment. Keywords enterovirus, hand-foot-and-mouth disease, Mycoplasma-induced mucositis, recurrent toxin-mediated erythema, streptococcal intertrigo
INTRODUCTION Children with rashes account for many of the outpatient visits to a general pediatric practice. As such, pediatricians are on the front lines, requiring a firm understanding of the various causes and treatments for common, uncommon and even rare rashes (listed below). Examples of common pediatric rashes:
(10) (11) (12) (13) (14) (15) (16)
Molluscum contagiosum Scabies Folliculitis Intertrigo Insect bite reactions Fungal/bacterial/viral infections Acne
Examples of uncommon pediatric rashes: (1) Drug-induced exanthems (morbilliform, urticaria, petechial) (2) Classic exanthems (measles, scarlet fever, erythema infectiosum, exanthem subitum) (3) Other viral exanthems (varicella, hand-footand-mouth disease (HFMD), herpes simplex) (4) Pityriasis rosea (5) Atopic dermatitis (6) Contact dermatitis (7) Seborrheic dermatitis (8) Psoriasis (9) Urticaria
(1) Gianotti–Crosti syndrome (2) Pityriasis lichenoides (3) Henoch–Schonlein purpura a
Geisel School of Medicine at Dartmouth, Hanover, New Hampshire and University of Connecticut, Farmington, Connecticut, USA
b
Correspondence to James G. Dinulos, MD, Seacoast Dermatology, 330 Borthwick Avenue, Suite 303, Portsmouth, NH 03801, USA. Tel: +1 603 431 5205; fax: +1 603 436 4257; e-mail: [email protected] Curr Opin Pediatr 2015, 27:261–266 DOI:10.1097/MOP.0000000000000197
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KEY POINTS Consider GABHS intertrigo in infants when standard therapies fail or when the rash is well demarcated, foul-smelling and lacks satellite pustules. Deep furuncles and abscesses due to Staphylococcus aureus and GABHS have been associated with superantigen-mediated disease, placing children at risk for toxic shock syndrome. HFMD caused by EV-A6 has been associated with widespread rash mimicking eczema herpeticum or varicella. Mycoplasma pneumoniae may be associated with mucositis in the absence of cutaneous skin findings. Recurrent erythema of the perineum has been associated with toxin-producing strains of GABHS and Staphylococcus aureus.
(4) Kawasaki syndrome (5) Mycoplasma-induced mucositis Examples of rare pediatric rashes: (1) Drug rash with eosinophilia and systemic symptoms (DRESS) (2) Syphilis (3) Leukemia cutis (4) Netherton syndrome (5) Neonatal lupus (6) Zinc deficiency dermatitis (7) Langerhans cell histiocytosis (8) Recurrent toxin-mediated erythema Rashes can engender extreme anxiety on the part of parents and caregivers, especially if the rashes are itchy, painful or widespread. This article will focus on four distinct clinical entities with recent findings in the literature. The two common rashes to be discussed are group A b-hemolytic streptococci (GABHS) intertrigo and HFMO. The uncommon rash to be covered is Mycoplasma pneumoniae-associated mucositis (MPAM) and the rare rash discussed is recurrent toxin-mediated erythema (RTME). Special emphasis will be placed on differential diagnosis and when to recommend specialty care.
COMMON PEDIATRIC RASHES Intertrigo occurs when two cutaneous surfaces touch each other in the setting of increased friction and moisture. Neonates and infants are particularly susceptible because of the deep folds on the neck, extremity and inguinal areas. Intertriginous skin 262
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commonly becomes secondarily infected with Candida albicans. Bacterial pathogens such as GABHS, Staphylococcus aureus, Pseudomonas aeruginosa, Proteus vulgaris and Proteus mirabilis may cause intertrigo as a single agent or in combination [1]. Satellite pustules – pustules immediately adjacent to bright red weepy plaques – are suggestive of candidal intertrigo, although rarely GABHS may also produce satellite pustules. A bright red, foul-smelling, well demarcated intertriginous rash favors the diagnosis of GABHS intertrigo [1,2]. Infants may become fussy with a low-grade fever. Diagnosis should be confirmed with surface swabs for bacterial and yeast culture. A streptococcal rapid antigen test should also be considered [2]. The rapid strep test works equally well for cutaneous and pharyngeal disease, as its sensitivity and specificity appear to be comparable. Prompt diagnosis and treatment of GABHS is important since acute glomerulonephritis has been associated with cutaneous GABHS infection. Recently, Lopez-Corominas et al. [3] reported an infant with GABHS intertrigo who developed bacteremia, supporting the need for early diagnosis. GABHS intertrigo should be treated with 10 days of penicillin [1]. While it is possible to have recurrent GABHS intertrigo, other less common dermatological conditions should also be considered for persistent or recurrent cases, such as psoriasis, seborrheic dermatitis and, rarely, acrodermatitis enteropathica and Langerhans cell histiocytosis [1]. Toxin-producing strains of GABHS and S. aureus cause a variety of cutaneous conditions characterized by redness, blistering and peeling of the skin. Circulating toxins are able to act directly on the skin to exfoliate it, causing blistering and peeling. Toxins may act as superantigens, which are capable of stimulating the immune system by bypassing antigen-presenting cells and binding directly to the major histocompatibility complex. This binding produces nonspecific T-cell activation with stimulation of up to 20–30% of the circulating T lymphocytes [4]. A recent study of S. aureus identified two distinct clinical patterns that can be useful to distinguish between an exfoliative toxin and a superantigen toxin [4]. Facial erythema, redness of the folds, spreading of the blister with pressure (Nikolski sign), early desquamation and the absence of mucosal involvement were due to exfoliative toxins found in superficial skin infections such as impetigo. Furuncles and abscess were associated with erythematous rashes with truncal involvement. Nikolski blistering was absent and no rash was seen on the face or folds. These deeper skin infections were due to organisms producing superantigen toxins. Both clinical patterns can be seen in young children as a generalized macular rash. These Volume 27 Number 2 April 2015
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cutaneous signs are seen early in the disease process and may allow prompt recognition and prevention of a serious superantigen-mediated disorder such as toxic shock syndrome. Treatment with a toxininhibiting antibiotic such as clindamycin or linezolid may be helpful to prevent full-blown toxic shock syndrome. Use of clindamycin or linezolid does not improve outcomes in patients with exfoliating strains of S. aureus, causing scalded skin syndrome [4]. Most widespread rashes with fever (exanthems) are due to either a drug or infection. Sixty-five percent of children with fever and widespread rash will have an underlying infection, and among these, viruses account for 75% of the rashes. Viral exanthems may be due to direct damage to the skin or due to an immune response generated by the infection [5–7]. The enteroviruses represent one of the most common viral infections encountered in clinical practice. The genus enterovirus is a member of the Picornaviridae family and is a nonenveloped icosahedral, single-stranded RNA virus [8]. There are five main enteroviral species: enterovirus (EV)-A (EV-71, Coxsackievirus group A), EV-B (coxsackievirus group B viruses, echoviruses), EV-C (polioviruses 1–3 and several CVA viruses), EV-D (EV-68 and EV-70) and the rhinoviruses [8]. Enteroviral infections are most common in children aged less than 10 years. In temperate climates, they are most common in the summer and fall, and in tropical climates, enterovirus infections occur year round. Enteroviral infections are transmitted via the fecal–oral route and by respiratory droplets. There are various clinical presentations, including the central nervous system disease, myocarditis, neonatal systemic infections, pleurodynia, pancreatitis, hepatitis, respiratory disease and HFMD [8]. HFMD is a clinical pattern showing superficial oval ulcerations involving the hands, feet, mouth and sometimes the buttocks [9 ]. Most children with HFMD are less than 5 years of age. The most commonly reported causes of HFMD are coxsackievirus (CV)-A16 and EV-71 [10], although various other outbreaks have also been studied, including coxsackievirus A6 infection in Edinburgh, United Kingdom [11], Taiwan [12], the United States [10], and EV-71 in China [13]. In the United States, investigators identified four EV-A6 clinical patterns: vesiculobullous and erosive eruption, eczema coxsackium, Gianotti–Crosti-like eruption, and petechial and purpuric rash [10]. These cutaneous findings in the setting of fever, oral erosions, mild gastrointestinal symptoms, oval vesicles on hands and feet and sick contacts are suggestive of HFMD. In this study, investigators noted delayed cutaneous findings, including onychomadesis (nail shedding), &&
Beau’s lines (transverse grooves) and acral desquamation [10]. Hubiche et al. [9 ] conducted a prospective cross-sectional study from March 2010 to February 2012 in France to link enterovirus serotypes with clinical patterns of disease. The investigators included all patients with suspected HFMD during the 2-year study and collected swabs from the nasopharynx and vesicles. The samples were processed utilizing reverse transcription PCR and genotyping. Patients with a clinical pattern consistent with HFMD and positive enterovirus PCR results were included in the analysis. This study is unique in that several outbreaks over a period were prospectively studied. The authors found that HFMD most often presented with a diffuse vesicular rash; 37 (41.5%) developed lesions in at least five anatomical sites and were thought to have widespread exanthema. Twelve percent of the patients had lesions with minimal skin involvement with only two anatomical areas involved. Most of the patients in this study showed infections with CV-A6 (47.2%) and A16 (31.4%). The authors were not able to distinguish between infections with CV-A6 and CV-A16, and other serotypes based on clinical severity. Grouped vesicles were found in both CV-A6 and CV-A16. The authors did find a predominance of perioral lesions with CV-A6 infection. Recently, Sinclair et al. [11] described atypical HFMD associated with A6 infection from January to February 2014. Similar to the outbreak described in the United States, these authors noted more severe widespread rashes, simulating eczema herpeticum and varicella [11]. Chung et al. [12] studied A6 outbreaks from Taiwan in 2010 and 2012. These authors studied patients who had widespread blistering, resembling Stevens–Johnson syndrome (SJS). They postulated that the evolution of the nucleotide sequence of CV-A6 led to changes in the virus characteristics and clinical features. They conducted a phylogenetic analysis that showed a new CV-A6 variant from the blister fluid. Electron microscopy showed intact viral particles in the skin lesions and blister fluid. These blistering reactions they believe were mediated by cytotoxic T lymphocytes and natural killer cells expressing granulysin similar to that seen in SJS [11]. Enterovirus 71 is known to cause severe neurological disease and has a higher mortality rate. Gao et al. [13] conducted a correlation analysis of EV-71 in the Hunan Province of China from March 2010 to October 2012. These authors showed a positive correlation between EV-71 and disease severity [13]. The above disorders are prevalent and not all pediatricians will have access to specialty consultation, hence some will choose to diagnose and treat
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&&
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these common rashes. The development of a clinical approach such as the one summarized by the acronym ‘RASHES’ (listed below) will assist in identifying worrisome clinical signs (listed below), and is helpful in instilling parental confidence in the provider’s diagnostic capabilities. A referral to a dermatologist is recommended if the clinician would like to confirm a diagnosis and treatment plan, or if the rash is recurring or persistent. The acronym RASHES will assist in developing an organized approach to a child with a rash: (1) Rapport – establish a comforting rapport with patient and parent (2) Analyze – analyze location and distribution of the rash, consider diagnostic tests (3) Solicit records – obtain records from previous office visits (4) Hand holding – recognize and reassure parents and patients (5) Establish diagnosis – commit to a working diagnosis (6) Select treatment and set expectations
Adhesion proteins e.g. PI, P30
Mycoplasma pneumoniae
APC
APC Respiratory epithelium
Fever Skin tenderness Blisters Mucous membrane erosions Lymphadenopathy Bruising
Local cellular inflammation
APC IL-8
Peptide MHC I TCR
Neutrophil
MHC II
MHC II TCR
Naive cytotoxic T cell CD8+
*
IL-8 BCR
Naive T cell CD4+
B cell
MHC II
IL-2 INF-γ
TCR
IL-4 IL-5
T helper 2 IL-6 effector cell CD4+
T helper 1 effector cell CD4+
Signs of a worrisome rash: (1) (2) (3) (4) (5) (6)
TLR-2, paired with TLR-1/-6
Neutrophil
Effector cytotoxic T cell CD8+
Plasma cell
Antibody mediated inflammation
IgM IgG
AN UNCOMMON PEDIATRIC RASH Mycoplasma pneumoniae is a ubiquitous small organism that lacks a cell wall, and hence is resistant to many antibiotics. This organism is a common cause of community-acquired pneumonia and patients may present with low-grade fever, malaise, headache and cough. This organism has been associated with many cutaneous disorders [14–17] (listed below). These cutaneous disorders are secondary reaction patterns, although M. pneumoniae has been isolated from skin bullae, suggesting that primary skin disease is a possibility. Cutaneous manifestations of M. pneumoniae infection [16]: (1) (2) (3) (4) (5) (6) (7) 264
Exanthematous eruptions Erythema nodosum Urticaria SJS Pityriasis rosea Toxic epidermal necrolysis Kawasaki disease www.co-pediatrics.com
Oral 100%**
Ocula 97%
Uro-genital 78%
Skin 31%
FIGURE 1. Possible immune mechanisms induced by Mycoplasma pneumoniae in mycoplasma-induced mucositis. Reproduced with permission from [18 ]. Co-stimulatory molecules of the MHC-peptide complexes are not shown to simplify the figure. Percentages from the literature review. APC, antigen presenting cells (e.g. dendritic cells and macrophages); BCR, B cell receptor; IL, interleukins; MHC, major histocompatibility complex; TCR, T cell receptor; TLR, Toll-like receptor. Arrows: continuous, differentiation; dashed, activation. &&
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(8) (9) (10) (11) (12) (13)
prednisone, and intravenous immunoglobulin. Given the numerous differential diagnoses related to M. pneumoniae, a referral to a dermatologist is recommended to confirm or establish the diagnosis and treatment plan.
Leukocytoclastic vasculitis Subcorneal pustular dermatosis Thrombotic thrombocytopenic purpura Henoch-Schonlein purpura Urticaria vasculitis Raynaud’s phenomenon
SJS is a severe cutaneous reaction that has been firmly associated with M. pneumoniae. The definition of SJS generally has been accepted to be a combination of blisters involving less than 10% of the total body surface area with more than one mucous membrane erosion. This disorder is most commonly triggered by medications; however, infections such as herpes simplex virus and M. pneumoniae have been shown to cause SJS. M. pneumoniae may cause classic SJS as well as a cutaneous eruption limited to the mucous membranes. Some authors propose that mucous membrane-limited disease should be classified as a separate entity [16], whereas others believe that mucous membrane limited disease lies on a continuum of SJS (Fig. 1) [18 ]. Recently, Milner and Gomez Mendez [19] describe an adolescent male with erosions and ulcers of the mouth and genitalia, and no cutaneous involvement caused by Chlamydophila pneumoniae. This case suggests that other organisms apart from M. pneumoniae are capable of producing mucous membrane–only disease. Nevertheless, since M. pneumoniae infection is quite common, pediatricians should be aware that M. pneumoniae is capable of causing severe mucous membrane disease. M. pneumoniae may be diagnosed with serologic tests, including acute and convalescent titers and PCRbased tests. Treatment options include antibiotics, &&
A RARE PEDIATRIC RASH Recurrent toxin-mediated erythema is a clinical disorder characterized by repeated episodes of the sudden appearance of asymptomatic erythema and rapid desquamation involving the perineum. Certain patients may also develop redness of the hands and feet and a ‘strawberry’ tongue. Patients may have streptococcal pharyngitis, facial impetigo, or perianal streptococcal dermatitis [20,21]. This disorder is thought to be produced by both streptococcal and staphylococcal toxins. Manders et al. [22] reported two patients whose recurrent perineal erythema was due to Streptococcal pyrogenic exotoxins A and B and toxic shock toxin 1. There is considerable overlap between Kawasaki disease and recurrent toxin-mediated erythema (RTPE; Table 1). Children with RTPE tend to be well appearing, which suggests a mild disease. Nevertheless, appropriate culture from involved skin sites, throat, and perineum, as well as complete blood count, comprehensive metabolic panel, urinalysis, and C-reactive protein should be obtained. Echocardiogram and blood cultures should be ordered if clinically appropriate [23]. Given the rarity and complexity of recurrent toxin-mediated erythema, referral to a dermatologist is recommended to help diagnose and treat children with this condition.
Table 1. Differences between Kawasaki syndrome and recurrent toxin-mediated perineal erythema Variable
Kawasaki syndrome
RTPE (our patients)
Age
5-day duration)
Present
Absent
Polymorphous exanthem
Present
Absent
Perineal erythema
Frequent
Always present
Conjunctival injection
Present
Rare
Strawberry tongue and oral mucosal changes
Present
Present
Cervical acute macrolymphadenopathy
Present
Absent
Extremity changes (palmoplantar erythema with desquamation)
Present
Present
Recurrences
Rare
Frequently present
Alterations of instrumental and laboratory tests (electrocardiography, two-dimensional echocardiography, coronary angiography, and platelet count)
Frequent
Rare
Streptococcal or staphylococcal pathogenesis
Undetermined
Yes
RTPE, recurrent toxin-mediated erythema. Reproduced with permission from [22].
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CONCLUSION The number of rashes acquired in childhood is vast, requiring the pediatrician to be able to identify worrisome rashes from those with a more benign course. There is no substitute for clinical experience when diagnosing childhood rashes. The described approach should serve as a rudimentary framework to build on clinical experience. Acknowledgements The author would like to thank Paulette Dinulos for her editorial contributions. Financial support and sponsorship None. Conflicts of interest None.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Honig PJ, Frieden IJ, Kim HJ, Yan AC. Streptococcal intertrigo: an underrecognized condition in children. Pediatrics 2003; 112 (6 Pt 1):1427–1429. 2. Silverman RA, Schwartz RH. Streptococcal intertrigo of the cervical folds in a five-month-old infant. Pediatr Infect Dis J 2012; 31:872–873. 3. Lopez-Corominas V, Yague F, Knopfel N, et al. Streptococcus pyogenes cervical intertrigo with secondary bacteremia. Pediatr Dermatol 2014; 31:e71–72. 4. Courjon J, Hubiche T, Phan A, et al. Skin findings of Staphylococcus aureus toxin-mediated infection in relation to toxin encoding genes. Pediatr Infect Dis J 2013; 32:727–730. 5. Folster-Holst R, Kreth HW. Viral exanthems in childhood: infectious (direct) exanthems. Part 1: classic exanthems. J German Soc Dermatol 2009; 7:309– 316.
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6. Folster-Holst R, Kreth HW. Viral exanthems in childhood. Part 3: parainfectious exanthems and those associated with virus-drug interactions. J German Soc Dermatol 2009; 7:506–510. 7. Folster-Holst R, Kreth HW. Viral exanthems in childhood: infectious (direct) exanthems. Part 2: other viral exanthems. J German Soc Dermatol 2009; 7:414–419. 8. Muehlenbachs A, Bhatnagar J, Zaki SR. Tissue tropism, pathology and pathogenesis of enterovirus infection. J Pathol 2015; 235:217–228. 9. Hubiche T, Schuffenecker I, Boralevi F, et al. Dermatological spectrum of && hand, foot and mouth disease from classical to generalized exanthema. Pediatr Infect Dis J 2014; 33:e92–e98. This is an excellent prospective article describing the clinical patterns of HFMD with enterovirus subtypes. 10. Mathes EF, Oza V, Frieden IJ, et al. ‘‘Eczema coxsackium’’ and unusual cutaneous findings in an enterovirus outbreak. Pediatrics 2013; 132:e149–157. 11. Sinclair C, Gaunt E, Simmonds P, et al. Atypical hand, foot, and mouth disease associated with coxsackievirus A6 infection, Edinburgh, United Kingdom, January to February 2014. Eur Commun Dis Bull 2014; 19:20745. 12. Chung WH, Shih SR, Chang CF, et al. Clinicopathologic analysis of coxsackievirus A6 new variant induced widespread mucocutaneous bullous reactions mimicking severe cutaneous adverse reactions. J Infect Dis 2013; 208:1968–1978. 13. Gao LD, Hu SX, Zhang H, et al. Correlation analysis of EV71 detection and case severity in hand, foot, and mouth disease in the Hunan Province of China. PloS One 2014; 9:e100003. 14. Schalock PC, Dinulos JG, Pace N, et al. Erythema multiforme due to Mycoplasma pneumoniae infection in two children. Pediatr Dermatol 2006; 23:546–555. 15. Schalock PC, Dinulos JG. Mycoplasma pneumoniae-induced cutaneous disease. Int J Dermatol 2009; 48:673–680. [quiz 680–671] 16. Schalock PC, Dinulos JG. Mycoplasma pneumoniae-induced Stevens–Johnson syndrome without skin lesions: fact or fiction? J Am Acad Dermatol 2005; 52:312–315. 17. Schalock PC, Brennick JB, Dinulos JG. Mycoplasma pneumoniae infection associated with bullous erythema multiforme. J Am Acad Dermatol 2005; 52:705–706. 18. Meyer Sauteur PM, Goetschel P, Lautenschlager S. Mycoplasma pneumo&& niae and mucositis: part of the Stevens–Johnson syndrome spectrum. J German Soc Dermatol 2012; 10:740–746. This author thoroughly reviews Mycoplasma pneumoniae and mucositis. 19. Milner TL, Gomez Mendez LM. Stevens–Johnson syndrome, mucositis, or something else? Hosp Pediatr 2014; 4:54–57. 20. Patrizi A, Raone B, Savoia F, et al. Recurrent toxin-mediated perineal erythema: eleven pediatric cases. Arch Dermatol 2008; 144:239–243. 21. El Bouch R, Reubsaet P, Koop K, Jansen J. A case of recurrent toxin-mediated perineal erythema. Arch Dis Child 2013; 98:776. 22. Manders SM, Heymann WR, Atillasoy E, et al. Recurrent toxin-mediated perineal erythema. Arch Dermatol 1996; 132:57–60. 23. Levy ML. Recurrent toxin-mediated perineal erythema in children: is that all there is? Arch Dermatol 2008; 144:245.
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What’s new with common, uncommon and rare rashes in childhood James G. Dinulos a,b
Purpose of review Children with rashes account for many of the outpatient visits to a general pediatrician. As such, pediatricians are often the first to identify and treat these rashes. Establishing an approach to common, uncommon and rare pediatric rashes assists in accurate assessment. This review highlights newly identified clinical patterns and disease severity. Recent findings Group A b-hemolytic streptococci (GABHS) have been shown to be an important cause of intertrigo and to cause more widespread disease in some instances. Superficial skin infections with GABHS have been associated with strains secreting exfoliating toxins, whereas deeper infections have been associated with superantigen toxins. Hand-foot-and-mouth disease (HFMD) outbreaks have occurred with more virulent strains, causing more widespread disease that may be confused with eczema herpeticum or varicella. Mycoplasma pneumoniae has been shown to be an important cause of common disorders such as urticaria, and less common disorders such as Stevens–Johnson syndrome and Mycoplasma-associated mucositis. Recurrent toxin-mediated erythema is a recently described entity that must be differentiated from Kawasaki disease. Summary The number of rashes acquired in childhood is vast, requiring the pediatrician to be able to identify worrisome rashes from those with a more benign course. Key clinical signs may assist in clinical diagnosis and treatment. Keywords enterovirus, hand-foot-and-mouth disease, Mycoplasma-induced mucositis, recurrent toxin-mediated erythema, streptococcal intertrigo
INTRODUCTION Children with rashes account for many of the outpatient visits to a general pediatric practice. As such, pediatricians are on the front lines, requiring a firm understanding of the various causes and treatments for common, uncommon and even rare rashes (listed below). Examples of common pediatric rashes:
(10) (11) (12) (13) (14) (15) (16)
Molluscum contagiosum Scabies Folliculitis Intertrigo Insect bite reactions Fungal/bacterial/viral infections Acne
Examples of uncommon pediatric rashes: (1) Drug-induced exanthems (morbilliform, urticaria, petechial) (2) Classic exanthems (measles, scarlet fever, erythema infectiosum, exanthem subitum) (3) Other viral exanthems (varicella, hand-footand-mouth disease (HFMD), herpes simplex) (4) Pityriasis rosea (5) Atopic dermatitis (6) Contact dermatitis (7) Seborrheic dermatitis (8) Psoriasis (9) Urticaria
(1) Gianotti–Crosti syndrome (2) Pityriasis lichenoides (3) Henoch–Schonlein purpura a
Geisel School of Medicine at Dartmouth, Hanover, New Hampshire and University of Connecticut, Farmington, Connecticut, USA
b
Correspondence to James G. Dinulos, MD, Seacoast Dermatology, 330 Borthwick Avenue, Suite 303, Portsmouth, NH 03801, USA. Tel: +1 603 431 5205; fax: +1 603 436 4257; e-mail: [email protected] Curr Opin Pediatr 2015, 27:261–266 DOI:10.1097/MOP.0000000000000197
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KEY POINTS Consider GABHS intertrigo in infants when standard therapies fail or when the rash is well demarcated, foul-smelling and lacks satellite pustules. Deep furuncles and abscesses due to Staphylococcus aureus and GABHS have been associated with superantigen-mediated disease, placing children at risk for toxic shock syndrome. HFMD caused by EV-A6 has been associated with widespread rash mimicking eczema herpeticum or varicella. Mycoplasma pneumoniae may be associated with mucositis in the absence of cutaneous skin findings. Recurrent erythema of the perineum has been associated with toxin-producing strains of GABHS and Staphylococcus aureus.
(4) Kawasaki syndrome (5) Mycoplasma-induced mucositis Examples of rare pediatric rashes: (1) Drug rash with eosinophilia and systemic symptoms (DRESS) (2) Syphilis (3) Leukemia cutis (4) Netherton syndrome (5) Neonatal lupus (6) Zinc deficiency dermatitis (7) Langerhans cell histiocytosis (8) Recurrent toxin-mediated erythema Rashes can engender extreme anxiety on the part of parents and caregivers, especially if the rashes are itchy, painful or widespread. This article will focus on four distinct clinical entities with recent findings in the literature. The two common rashes to be discussed are group A b-hemolytic streptococci (GABHS) intertrigo and HFMO. The uncommon rash to be covered is Mycoplasma pneumoniae-associated mucositis (MPAM) and the rare rash discussed is recurrent toxin-mediated erythema (RTME). Special emphasis will be placed on differential diagnosis and when to recommend specialty care.
COMMON PEDIATRIC RASHES Intertrigo occurs when two cutaneous surfaces touch each other in the setting of increased friction and moisture. Neonates and infants are particularly susceptible because of the deep folds on the neck, extremity and inguinal areas. Intertriginous skin 262
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commonly becomes secondarily infected with Candida albicans. Bacterial pathogens such as GABHS, Staphylococcus aureus, Pseudomonas aeruginosa, Proteus vulgaris and Proteus mirabilis may cause intertrigo as a single agent or in combination [1]. Satellite pustules – pustules immediately adjacent to bright red weepy plaques – are suggestive of candidal intertrigo, although rarely GABHS may also produce satellite pustules. A bright red, foul-smelling, well demarcated intertriginous rash favors the diagnosis of GABHS intertrigo [1,2]. Infants may become fussy with a low-grade fever. Diagnosis should be confirmed with surface swabs for bacterial and yeast culture. A streptococcal rapid antigen test should also be considered [2]. The rapid strep test works equally well for cutaneous and pharyngeal disease, as its sensitivity and specificity appear to be comparable. Prompt diagnosis and treatment of GABHS is important since acute glomerulonephritis has been associated with cutaneous GABHS infection. Recently, Lopez-Corominas et al. [3] reported an infant with GABHS intertrigo who developed bacteremia, supporting the need for early diagnosis. GABHS intertrigo should be treated with 10 days of penicillin [1]. While it is possible to have recurrent GABHS intertrigo, other less common dermatological conditions should also be considered for persistent or recurrent cases, such as psoriasis, seborrheic dermatitis and, rarely, acrodermatitis enteropathica and Langerhans cell histiocytosis [1]. Toxin-producing strains of GABHS and S. aureus cause a variety of cutaneous conditions characterized by redness, blistering and peeling of the skin. Circulating toxins are able to act directly on the skin to exfoliate it, causing blistering and peeling. Toxins may act as superantigens, which are capable of stimulating the immune system by bypassing antigen-presenting cells and binding directly to the major histocompatibility complex. This binding produces nonspecific T-cell activation with stimulation of up to 20–30% of the circulating T lymphocytes [4]. A recent study of S. aureus identified two distinct clinical patterns that can be useful to distinguish between an exfoliative toxin and a superantigen toxin [4]. Facial erythema, redness of the folds, spreading of the blister with pressure (Nikolski sign), early desquamation and the absence of mucosal involvement were due to exfoliative toxins found in superficial skin infections such as impetigo. Furuncles and abscess were associated with erythematous rashes with truncal involvement. Nikolski blistering was absent and no rash was seen on the face or folds. These deeper skin infections were due to organisms producing superantigen toxins. Both clinical patterns can be seen in young children as a generalized macular rash. These Volume 27 Number 2 April 2015
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cutaneous signs are seen early in the disease process and may allow prompt recognition and prevention of a serious superantigen-mediated disorder such as toxic shock syndrome. Treatment with a toxininhibiting antibiotic such as clindamycin or linezolid may be helpful to prevent full-blown toxic shock syndrome. Use of clindamycin or linezolid does not improve outcomes in patients with exfoliating strains of S. aureus, causing scalded skin syndrome [4]. Most widespread rashes with fever (exanthems) are due to either a drug or infection. Sixty-five percent of children with fever and widespread rash will have an underlying infection, and among these, viruses account for 75% of the rashes. Viral exanthems may be due to direct damage to the skin or due to an immune response generated by the infection [5–7]. The enteroviruses represent one of the most common viral infections encountered in clinical practice. The genus enterovirus is a member of the Picornaviridae family and is a nonenveloped icosahedral, single-stranded RNA virus [8]. There are five main enteroviral species: enterovirus (EV)-A (EV-71, Coxsackievirus group A), EV-B (coxsackievirus group B viruses, echoviruses), EV-C (polioviruses 1–3 and several CVA viruses), EV-D (EV-68 and EV-70) and the rhinoviruses [8]. Enteroviral infections are most common in children aged less than 10 years. In temperate climates, they are most common in the summer and fall, and in tropical climates, enterovirus infections occur year round. Enteroviral infections are transmitted via the fecal–oral route and by respiratory droplets. There are various clinical presentations, including the central nervous system disease, myocarditis, neonatal systemic infections, pleurodynia, pancreatitis, hepatitis, respiratory disease and HFMD [8]. HFMD is a clinical pattern showing superficial oval ulcerations involving the hands, feet, mouth and sometimes the buttocks [9 ]. Most children with HFMD are less than 5 years of age. The most commonly reported causes of HFMD are coxsackievirus (CV)-A16 and EV-71 [10], although various other outbreaks have also been studied, including coxsackievirus A6 infection in Edinburgh, United Kingdom [11], Taiwan [12], the United States [10], and EV-71 in China [13]. In the United States, investigators identified four EV-A6 clinical patterns: vesiculobullous and erosive eruption, eczema coxsackium, Gianotti–Crosti-like eruption, and petechial and purpuric rash [10]. These cutaneous findings in the setting of fever, oral erosions, mild gastrointestinal symptoms, oval vesicles on hands and feet and sick contacts are suggestive of HFMD. In this study, investigators noted delayed cutaneous findings, including onychomadesis (nail shedding), &&
Beau’s lines (transverse grooves) and acral desquamation [10]. Hubiche et al. [9 ] conducted a prospective cross-sectional study from March 2010 to February 2012 in France to link enterovirus serotypes with clinical patterns of disease. The investigators included all patients with suspected HFMD during the 2-year study and collected swabs from the nasopharynx and vesicles. The samples were processed utilizing reverse transcription PCR and genotyping. Patients with a clinical pattern consistent with HFMD and positive enterovirus PCR results were included in the analysis. This study is unique in that several outbreaks over a period were prospectively studied. The authors found that HFMD most often presented with a diffuse vesicular rash; 37 (41.5%) developed lesions in at least five anatomical sites and were thought to have widespread exanthema. Twelve percent of the patients had lesions with minimal skin involvement with only two anatomical areas involved. Most of the patients in this study showed infections with CV-A6 (47.2%) and A16 (31.4%). The authors were not able to distinguish between infections with CV-A6 and CV-A16, and other serotypes based on clinical severity. Grouped vesicles were found in both CV-A6 and CV-A16. The authors did find a predominance of perioral lesions with CV-A6 infection. Recently, Sinclair et al. [11] described atypical HFMD associated with A6 infection from January to February 2014. Similar to the outbreak described in the United States, these authors noted more severe widespread rashes, simulating eczema herpeticum and varicella [11]. Chung et al. [12] studied A6 outbreaks from Taiwan in 2010 and 2012. These authors studied patients who had widespread blistering, resembling Stevens–Johnson syndrome (SJS). They postulated that the evolution of the nucleotide sequence of CV-A6 led to changes in the virus characteristics and clinical features. They conducted a phylogenetic analysis that showed a new CV-A6 variant from the blister fluid. Electron microscopy showed intact viral particles in the skin lesions and blister fluid. These blistering reactions they believe were mediated by cytotoxic T lymphocytes and natural killer cells expressing granulysin similar to that seen in SJS [11]. Enterovirus 71 is known to cause severe neurological disease and has a higher mortality rate. Gao et al. [13] conducted a correlation analysis of EV-71 in the Hunan Province of China from March 2010 to October 2012. These authors showed a positive correlation between EV-71 and disease severity [13]. The above disorders are prevalent and not all pediatricians will have access to specialty consultation, hence some will choose to diagnose and treat
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these common rashes. The development of a clinical approach such as the one summarized by the acronym ‘RASHES’ (listed below) will assist in identifying worrisome clinical signs (listed below), and is helpful in instilling parental confidence in the provider’s diagnostic capabilities. A referral to a dermatologist is recommended if the clinician would like to confirm a diagnosis and treatment plan, or if the rash is recurring or persistent. The acronym RASHES will assist in developing an organized approach to a child with a rash: (1) Rapport – establish a comforting rapport with patient and parent (2) Analyze – analyze location and distribution of the rash, consider diagnostic tests (3) Solicit records – obtain records from previous office visits (4) Hand holding – recognize and reassure parents and patients (5) Establish diagnosis – commit to a working diagnosis (6) Select treatment and set expectations
Adhesion proteins e.g. PI, P30
Mycoplasma pneumoniae
APC
APC Respiratory epithelium
Fever Skin tenderness Blisters Mucous membrane erosions Lymphadenopathy Bruising
Local cellular inflammation
APC IL-8
Peptide MHC I TCR
Neutrophil
MHC II
MHC II TCR
Naive cytotoxic T cell CD8+
*
IL-8 BCR
Naive T cell CD4+
B cell
MHC II
IL-2 INF-γ
TCR
IL-4 IL-5
T helper 2 IL-6 effector cell CD4+
T helper 1 effector cell CD4+
Signs of a worrisome rash: (1) (2) (3) (4) (5) (6)
TLR-2, paired with TLR-1/-6
Neutrophil
Effector cytotoxic T cell CD8+
Plasma cell
Antibody mediated inflammation
IgM IgG
AN UNCOMMON PEDIATRIC RASH Mycoplasma pneumoniae is a ubiquitous small organism that lacks a cell wall, and hence is resistant to many antibiotics. This organism is a common cause of community-acquired pneumonia and patients may present with low-grade fever, malaise, headache and cough. This organism has been associated with many cutaneous disorders [14–17] (listed below). These cutaneous disorders are secondary reaction patterns, although M. pneumoniae has been isolated from skin bullae, suggesting that primary skin disease is a possibility. Cutaneous manifestations of M. pneumoniae infection [16]: (1) (2) (3) (4) (5) (6) (7) 264
Exanthematous eruptions Erythema nodosum Urticaria SJS Pityriasis rosea Toxic epidermal necrolysis Kawasaki disease www.co-pediatrics.com
Oral 100%**
Ocula 97%
Uro-genital 78%
Skin 31%
FIGURE 1. Possible immune mechanisms induced by Mycoplasma pneumoniae in mycoplasma-induced mucositis. Reproduced with permission from [18 ]. Co-stimulatory molecules of the MHC-peptide complexes are not shown to simplify the figure. Percentages from the literature review. APC, antigen presenting cells (e.g. dendritic cells and macrophages); BCR, B cell receptor; IL, interleukins; MHC, major histocompatibility complex; TCR, T cell receptor; TLR, Toll-like receptor. Arrows: continuous, differentiation; dashed, activation. &&
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Rashes in childho od Dinulos
(8) (9) (10) (11) (12) (13)
prednisone, and intravenous immunoglobulin. Given the numerous differential diagnoses related to M. pneumoniae, a referral to a dermatologist is recommended to confirm or establish the diagnosis and treatment plan.
Leukocytoclastic vasculitis Subcorneal pustular dermatosis Thrombotic thrombocytopenic purpura Henoch-Schonlein purpura Urticaria vasculitis Raynaud’s phenomenon
SJS is a severe cutaneous reaction that has been firmly associated with M. pneumoniae. The definition of SJS generally has been accepted to be a combination of blisters involving less than 10% of the total body surface area with more than one mucous membrane erosion. This disorder is most commonly triggered by medications; however, infections such as herpes simplex virus and M. pneumoniae have been shown to cause SJS. M. pneumoniae may cause classic SJS as well as a cutaneous eruption limited to the mucous membranes. Some authors propose that mucous membrane-limited disease should be classified as a separate entity [16], whereas others believe that mucous membrane limited disease lies on a continuum of SJS (Fig. 1) [18 ]. Recently, Milner and Gomez Mendez [19] describe an adolescent male with erosions and ulcers of the mouth and genitalia, and no cutaneous involvement caused by Chlamydophila pneumoniae. This case suggests that other organisms apart from M. pneumoniae are capable of producing mucous membrane–only disease. Nevertheless, since M. pneumoniae infection is quite common, pediatricians should be aware that M. pneumoniae is capable of causing severe mucous membrane disease. M. pneumoniae may be diagnosed with serologic tests, including acute and convalescent titers and PCRbased tests. Treatment options include antibiotics, &&
A RARE PEDIATRIC RASH Recurrent toxin-mediated erythema is a clinical disorder characterized by repeated episodes of the sudden appearance of asymptomatic erythema and rapid desquamation involving the perineum. Certain patients may also develop redness of the hands and feet and a ‘strawberry’ tongue. Patients may have streptococcal pharyngitis, facial impetigo, or perianal streptococcal dermatitis [20,21]. This disorder is thought to be produced by both streptococcal and staphylococcal toxins. Manders et al. [22] reported two patients whose recurrent perineal erythema was due to Streptococcal pyrogenic exotoxins A and B and toxic shock toxin 1. There is considerable overlap between Kawasaki disease and recurrent toxin-mediated erythema (RTPE; Table 1). Children with RTPE tend to be well appearing, which suggests a mild disease. Nevertheless, appropriate culture from involved skin sites, throat, and perineum, as well as complete blood count, comprehensive metabolic panel, urinalysis, and C-reactive protein should be obtained. Echocardiogram and blood cultures should be ordered if clinically appropriate [23]. Given the rarity and complexity of recurrent toxin-mediated erythema, referral to a dermatologist is recommended to help diagnose and treat children with this condition.
Table 1. Differences between Kawasaki syndrome and recurrent toxin-mediated perineal erythema Variable
Kawasaki syndrome
RTPE (our patients)
Age
5-day duration)
Present
Absent
Polymorphous exanthem
Present
Absent
Perineal erythema
Frequent
Always present
Conjunctival injection
Present
Rare
Strawberry tongue and oral mucosal changes
Present
Present
Cervical acute macrolymphadenopathy
Present
Absent
Extremity changes (palmoplantar erythema with desquamation)
Present
Present
Recurrences
Rare
Frequently present
Alterations of instrumental and laboratory tests (electrocardiography, two-dimensional echocardiography, coronary angiography, and platelet count)
Frequent
Rare
Streptococcal or staphylococcal pathogenesis
Undetermined
Yes
RTPE, recurrent toxin-mediated erythema. Reproduced with permission from [22].
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CONCLUSION The number of rashes acquired in childhood is vast, requiring the pediatrician to be able to identify worrisome rashes from those with a more benign course. There is no substitute for clinical experience when diagnosing childhood rashes. The described approach should serve as a rudimentary framework to build on clinical experience. Acknowledgements The author would like to thank Paulette Dinulos for her editorial contributions. Financial support and sponsorship None. Conflicts of interest None.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Honig PJ, Frieden IJ, Kim HJ, Yan AC. Streptococcal intertrigo: an underrecognized condition in children. Pediatrics 2003; 112 (6 Pt 1):1427–1429. 2. Silverman RA, Schwartz RH. Streptococcal intertrigo of the cervical folds in a five-month-old infant. Pediatr Infect Dis J 2012; 31:872–873. 3. Lopez-Corominas V, Yague F, Knopfel N, et al. Streptococcus pyogenes cervical intertrigo with secondary bacteremia. Pediatr Dermatol 2014; 31:e71–72. 4. Courjon J, Hubiche T, Phan A, et al. Skin findings of Staphylococcus aureus toxin-mediated infection in relation to toxin encoding genes. Pediatr Infect Dis J 2013; 32:727–730. 5. Folster-Holst R, Kreth HW. Viral exanthems in childhood: infectious (direct) exanthems. Part 1: classic exanthems. J German Soc Dermatol 2009; 7:309– 316.
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6. Folster-Holst R, Kreth HW. Viral exanthems in childhood. Part 3: parainfectious exanthems and those associated with virus-drug interactions. J German Soc Dermatol 2009; 7:506–510. 7. Folster-Holst R, Kreth HW. Viral exanthems in childhood: infectious (direct) exanthems. Part 2: other viral exanthems. J German Soc Dermatol 2009; 7:414–419. 8. Muehlenbachs A, Bhatnagar J, Zaki SR. Tissue tropism, pathology and pathogenesis of enterovirus infection. J Pathol 2015; 235:217–228. 9. Hubiche T, Schuffenecker I, Boralevi F, et al. Dermatological spectrum of && hand, foot and mouth disease from classical to generalized exanthema. Pediatr Infect Dis J 2014; 33:e92–e98. This is an excellent prospective article describing the clinical patterns of HFMD with enterovirus subtypes. 10. Mathes EF, Oza V, Frieden IJ, et al. ‘‘Eczema coxsackium’’ and unusual cutaneous findings in an enterovirus outbreak. Pediatrics 2013; 132:e149–157. 11. Sinclair C, Gaunt E, Simmonds P, et al. Atypical hand, foot, and mouth disease associated with coxsackievirus A6 infection, Edinburgh, United Kingdom, January to February 2014. Eur Commun Dis Bull 2014; 19:20745. 12. Chung WH, Shih SR, Chang CF, et al. Clinicopathologic analysis of coxsackievirus A6 new variant induced widespread mucocutaneous bullous reactions mimicking severe cutaneous adverse reactions. J Infect Dis 2013; 208:1968–1978. 13. Gao LD, Hu SX, Zhang H, et al. Correlation analysis of EV71 detection and case severity in hand, foot, and mouth disease in the Hunan Province of China. PloS One 2014; 9:e100003. 14. Schalock PC, Dinulos JG, Pace N, et al. Erythema multiforme due to Mycoplasma pneumoniae infection in two children. Pediatr Dermatol 2006; 23:546–555. 15. Schalock PC, Dinulos JG. Mycoplasma pneumoniae-induced cutaneous disease. Int J Dermatol 2009; 48:673–680. [quiz 680–671] 16. Schalock PC, Dinulos JG. Mycoplasma pneumoniae-induced Stevens–Johnson syndrome without skin lesions: fact or fiction? J Am Acad Dermatol 2005; 52:312–315. 17. Schalock PC, Brennick JB, Dinulos JG. Mycoplasma pneumoniae infection associated with bullous erythema multiforme. J Am Acad Dermatol 2005; 52:705–706. 18. Meyer Sauteur PM, Goetschel P, Lautenschlager S. Mycoplasma pneumo&& niae and mucositis: part of the Stevens–Johnson syndrome spectrum. J German Soc Dermatol 2012; 10:740–746. This author thoroughly reviews Mycoplasma pneumoniae and mucositis. 19. Milner TL, Gomez Mendez LM. Stevens–Johnson syndrome, mucositis, or something else? Hosp Pediatr 2014; 4:54–57. 20. Patrizi A, Raone B, Savoia F, et al. Recurrent toxin-mediated perineal erythema: eleven pediatric cases. Arch Dermatol 2008; 144:239–243. 21. El Bouch R, Reubsaet P, Koop K, Jansen J. A case of recurrent toxin-mediated perineal erythema. Arch Dis Child 2013; 98:776. 22. Manders SM, Heymann WR, Atillasoy E, et al. Recurrent toxin-mediated perineal erythema. Arch Dermatol 1996; 132:57–60. 23. Levy ML. Recurrent toxin-mediated perineal erythema in children: is that all there is? Arch Dermatol 2008; 144:245.
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