Introduction

In daily clinical practice, both paediatricians and paediatric dermatologists are frequently in charge of neonates, children and adolescents with cutaneous infections in the context of immunocompromise. Affected patients may either exhibit unusually severe or prolonged or extended skin infections with common pathogens, or infections with opportunistic organisms. Skin infections may be clinical ‘signs of impending doom’ allowing for an early detection and swift treatment of serious, sometimes life-threatening systemic infections in this vulnerable patient group [1]. Depending on the underlying condition, dysfunctional immune responses have been broadly classified into congenital (primary) and acquired (secondary) immunodeficiencies. Both categories predispose affected children to localized and disseminated infections potentially associated with cutaneous lesions [2,3].

References

1 Sillevis Smitt JH, Wulffraat NM, Kuijpers TW. The skin in primary immunodeficiency disorders, Eur J Dermatol 2005;15:425–32.

2 Chinen J, Shearer WT. Secondary immunodeficiencies, including HIV infection. J Allergy Clin Immunol 2010;125:S195–S203.

3 Notarangelo LD. Primary immunodeficiencies. J Allergy Clin Immunol 2010;125:S182–S194.

Skin infections in children with primary immunodeficiencies

Occurring in approximately 1:10,000 live births, primary immunodeficiencies (PIDs) represent a rare and phenotypically heterogeneous group of more than 150 mostly monogenic disorders affecting the development and/or function of the immune system [1]. As suggested by the International Union of Immunological Societies (IUIS), PIDs are currently subdivided into eight general categories, classified according to the primarily impaired immune component (see also Chapter 177) [2].

Clinically, PIDs are characterized by an increased susceptibility to potentially severe viral, fungal or bacterial infections, and frequently associated with an elevated risk for the development of autoimmune and lymphoproliferative disorders [3,4]. Besides the respiratory and gastrointestinal system, the skin has been found to be one of the organs most frequently involved in PID symptomatology, and characteristic cutaneous microorganisms may be a first clue to underlying primary immunodeficiency disorders (Table 64.1). Accordingly, recent retrospective cohort studies reported at least one cutaneous symptom in 41% to nearly 90% of included children suffering from various PIDs [5,6]. Cutaneous infections may be the exclusive presenting sign in 21% to 79% of PID patients [5,7].

Table 64.1 Cutaneous microorganisms as a clue to underlying primary immunodeficiency disorders

APECED, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy; BCG, bacille Calmette–Guérin; CGD, chronic granulomatous disease; CMC, chronic mucocutaneous candidiasis; CVID, common variable immunodeficiency; DGS, DiGeorge syndrome; EV, epidermodysplasia verruciformis; HIES, hyper-IgE syndrome; HSV, herpes simplex virus; SCID, severe combined immunodeficiency; VZV, varicella zoster virus; WAS, Wiskott–Aldrich syndrome; WHIM, warts, hypogammaglobulinaemia, infections, myelokathexis; XLA, X-linked agammaglobulinaemia.

Disclaimer: Microbiology results alone are insufficient to establish the diagnosis of a presumed immunodeficiency but should only be interpreted in the context of other evidence indicative of impaired immunity.

A complete review of skin infections in the large group of distinct genetic immunodeficiencies is beyond the scope of this chapter. We shall focus on selected major PIDs that are frequently associated with an increased susceptibility to cutaneous microbial pathogens. Further well-defined immunodeficiency syndromes with key dermatological features are more extensively reviewed in Chapter 177 of this textbook.

References

1 Notarangelo LD. Primary immunodeficiencies. J Allergy Clin Immunol 2010;125:S182–S194.

2 Notarangelo LD, Fischer A, Geha RS et al. Primary immunodeficiencies: 2009 update. J Allergy Clin Immunol 2009;124:1161–78.

3 Ballow M, Notarangelo L, Grimbacher B et al. Immunodeficiencies. Clin Exp Immunol 2009;158(Suppl. 1):14–22.

4 Gathmann B, Grimbacher B, Beaute J et al. The European internet-based patient and research database for primary immunodeficiencies: results 2006–2008. Clin Exp Immunol 2009;157(Suppl. 1):3–11.

5 Moin A, Farhoudi A, Moin M, Pourpak Z, Bazargan N. Cutaneous manifestations of primary immunodeficiency diseases in children. Iran J Allergy Asthma Immunol 2006;5:121–6.

6 Benjasupattananan P, Simasathein T, Vichyanond P et al. Clinical characteristics and outcomes of primary immunodeficiencies in Thai children: an 18-year experience from a tertiary care center. J Clin Immunol 2009;29:357–64.

7 Berron-Ruiz A, Berron-Perez R, Ruiz-Maldonado R. Cutaneous markers of primary immunodeficiency diseases in children. Pediatr Dermatol 2000;17:91–6.

Combined immunodeficiencies

Combined immunodeficiencies (CIDs) comprise a multifaceted group of disorders of the adaptive immune response that are predominantly caused by disturbed T-cell differentiation and/or function. In addition, reduced B-cell/natural killer (NK) cell counts, hypogammaglobulinaemia, peripheral eosinophilia and elevated total serum IgE levels are frequently encountered [1,2]. In severe CIDs (SCIDs), functional peripheral T-cells are virtually absent and affected infants reveal early-onset failure to thrive, intractable diarrhoea and unusually severe, often life-threatening systemic infections. Besides hypoplasia or complete absence of lymphoid tissues (tonsils, lymph nodes), cutaneous findings in SCID patients often include neonatal or infantile erythroderma, alopecia and eczematous lesions, whereas autoimmune skin affections (vasculitis, panniculitis, vitiligo, non-infectious granuloma) are less frequently observed [3,4].

Mycobacterial Infections

Children suffering from SCIDs can develop localized cutaneous or systemic complications after receiving live attenuated vaccines. In particular, bacille Calmette–Guérin (BCG) immunization has been shown to cause cutaneous and extracutaneous sequelae in up to 45% of SCID patients; these sequelae were associated with mortality rates of more than 50% [4,5]. Skin manifestations caused by BCG vaccination in genetically immunodeficient infants include multiple erythematous to whitish papules with central umbilication [6], disseminated or localized subcutaneous nodules [7], Langerhans cell histiocytosis (LCH)-like rashes [8] and ulceration or abscess formation at the site of vaccination [9]. Although observed more rarely than in individuals with other primary immunodeficiencies (phagocytic disorders, defects in innate immunity) or secondary immunological impairment (particularly HIV infection), opportunistic infections with atypical mycobacteria can cause disseminated cutaneous infections in SCID patients too. This has been demonstrated for Mycobacterium marinum and, more recently, for M. avium-intracellulare in a patient with a hypomorphic RAG1 mutation [10,11]. To rule out possible differential diagnoses such as LCH, non-infectious granuloma or M. tuberculosis infection, skin biopsy and subsequent acid-fast bacilli stains as well as polymerase chain reaction (PCR) analyses and cultures including drug susceptibility testing are mandatory. BCG vaccination should be avoided in patients with known PIDs and in infants with an elevated genetic risk for such disorders (positive PID family history, parental consanguinity) [9]. Analogously to wild-type M. bovis infection, disseminated BCG disease in immunocompromised patients has successfully been treated with a combination of rifampicin, isoniazide and ethambutol or streptomycin. Yet, in some instances, pharmacological treatment will have to be performed for more than the usual 6-month period and a considerable proportion of patients may suffer from potentially fatal relapses, unless causative therapy is achieved by allogeneic bone marrow transplantation (BMT) or gene therapy [12].

Pyogenic Infections

Patients with SCID are also prone to recurrent pyogenic skin infections such as furunculosis, abscesses or cellulitis, which are mainly caused by Staphylococcus aureus and, less often, by Pseudomonas aeruginosa or other Gram-negative bacteria [13]. These infections can present atypically with uncommon clinical features such as ‘cold abscesses’ or unresponsiveness to conventional antibiotic treatment. Still, they seem to occur less frequently in SCIDs than in other PIDs, particularly than in phagocytic defects or certain well-defined immunodeficiency syndromes such as the hyper-IgE syndrome (HIES), Wiskott–Aldrich syndrome (WAS) or DiGeorge syndrome (DGS) [14,15].

Viral Infections

Likewise, CIDs and SCIDs generally predispose to cutaneous viral infections, especially to those caused by human papillomavirus (HPV), herpes simplex virus (HSV), varicella zoster virus (VZV) and molluscum contagiosum virus. In particular, patients with idiopathic CD4+ lymphopenia have been described to develop heterogeneous HPV-associated mucocutaneous lesions such as disfiguring generalized verrucosis [16], epidermodysplasia verruciformis-like eruptions [17], juvenile laryngeal papillomatosis [18], disseminated flat warts [19], extragenital bowenoid papulosis [20], vulvar intraepithelial neoplasia [21] and anogenital warts [22]. Furthermore, CID due to homozygous and compound heterozygous mutations in the gene encoding for the dedicator of cytokinesis 8 (DOCK8) protein has only recently been identified as a cause of severe viral, fungal and bacterial skin infections. Intriguingly, affected children and adults revealed extensive, frequently co-existing cutaneous viral diseases such as ulcerating anogenital or orolabial HSV infection, recalcitrant periungual and acral verrucae vulgares, recurrent herpes zoster and disfiguring mollusca contagiosa [23]. Disseminated giant mollusca contagiosa have also occurred in other cases of CID and have been successfully treated with topical imiquimod [24] or subcutaneous alpha-interferon [25,26] in individual cases.

Fungal Infections

In contrast to the comparatively low incidence of bacterial and viral skin infections, mucocutaneous Candida infection, predominantly due to C. albicans, is encountered in up to 50% of paediatric CID patients [27,28]. In fact, recalcitrant oral candidiasis in neonates or young infants with failure to thrive and chronic diarrhoea is highly suspicious of (S)CIDs such as Omenn syndrome, idiopathic CD4+ lymphocytopenia or X-linked severe combined immunodeficiency [29,30]. Furthermore, the molecular basis of another phenotypic presentation of complex primary immunodeficiency, chronic mucocutaneous candidiasis (CMC), has just recently been further unravelled. In a series of highly interesting investigations, T-helper 17 (Th17) lymphocytes have been shown to be at the centre of genetic susceptibility to candidiasis and, to a lesser extent, other fungal infections [31]. It has been elegantly demonstrated that hereditary defects in antifungal immune defence can be attributed to polymorphisms or mutations within genes encoding for caspase recruitment domain-containing protein 9 (CARD9) and Dectin-1, which are crucial for sensing of Candida cell wall components, intracellular signalling of myeloid cells and consecutive differentiation of Th17 cells [32,33]. However, it has to be noted that protracted mucocutaneous candidiasis is a clinical hallmark of other primary immunodeficiency syndromes that should be considered as important differential diagnoses: autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), hyper-IgE syndrome (HIES), DiGeorge syndrome (DGS), mucocutaneous candidiasis with thymoma (Good syndrome) or PID due to DOCK8 mutations. As in other primary and secondary disorders linked to protracted mucocutaneous candidiasis, systemic application of ketoconazole, fluconazole, itraconazole or amphotericin B and topical therapy with clotrimazole, miconazole or nystatin preparations have been described as effective antifungal treatment options [34].

References

1 Notarangelo LD, Fischer A, Geha RS et al. Primary immunodeficiencies: 2009 update. J Allergy Clin Immunol 2009;124:1161–78.

2 Ballow M, Notarangelo L, Grimbacher B et al. Immunodeficiencies. Clin Exp Immunol 2009;158(Suppl. 1):14–22.

3 Yee A, De Ravin SS, Elliott E, Ziegler JB. Severe combined immunodeficiency: a national surveillance study. Pediatr Allergy Immunol 2008;19:298–302.

4 Yeganeh M, Heidarzade M, Pourpak Z et al. Severe combined immunodeficiency: a cohort of 40 patients. Pediatr Allergy Immunol 2008;19:303–6.

5 Bernatowska EA, Wolska-Kusnierz B, Pac M et al. Disseminated bacillus Calmette-Guerin infection and immunodeficiency. Emerg Infect Dis 2007;13:799–801.

6 Antaya RJ, Gardner ES, Bettencourt MS et al. Cutaneous complications of BCG vaccination in infants with immune disorders: two cases and a review of the literature. Pediatr Dermatol 2001;18:205–9.

7 Huang LH, Shyur SD, Weng JD, Shin C, Huang FY, Tzen CY. Disseminated cutaneous bacille Calmette-Guerin infection identified by polymerase chain reaction in a patient with X-linked severe combined immunodeficiency. Pediatr Dermatol 2006;23:560–3.

8 Culic S, Kuzmic I, Culic V et al. Disseminated BCG infection resembling langerhans cell histiocytosis in an infant with severe combined immunodeficiency: a case report. Pediatr Hematol Oncol 2004;21:563–72.

9 Bellet JS, Prose NS. Skin complications of Bacillus Calmette-Guerin immunization. Curr Opin Infect Dis 2005;18:97–100.

10 Avila EM, Uzel G, Hsu A et al. Highly variable clinical phenotypes of hypomorphic RAG1 mutations. Pediatrics 2010;126:e1248–e1252.

11 Parent LJ, Salam MM, Appelbaum PC, Dossett JH. Disseminated Mycobacterium marinum infection and bacteremia in a child with severe combined immunodeficiency. Clin Infect Dis 1995;21:1325–7.

12 Reichenbach J, Rosenzweig S, Doffinger R, Dupuis S, Holland SM, Casanova JL. Mycobacterial diseases in primary immunodeficiencies. Curr Opin Allergy Clin Immunol 2001;1:503–11.

13 Sillevis Smitt JH, Wulffraat NM, Kuijpers TW. The skin in primary immunodeficiency disorders. Eur J Dermatol 2005;15:425–32.

14 Torchia D, Connelly EA. Skin manifestations of immunodeficiencies in children. G Ital Dermatol Venereol 2010;145:269–87.

15 Chang SH, Yang YH, Chiang BL. Infectious pathogens in pediatric patients with primary immunodeficiencies. J Microbiol Immunol Infect 2006;39:503–15.

16 Alisjahbana B, Dinata R, Sutedja E et al. Disfiguring generalized verrucosis in an Indonesian man with idiopathic CD4 lymphopenia. Arch Dermatol 2010;146:69–73.

17 Tobin E, Rohwedder A, Holland SM, Philips B, Carlson JA. Recurrent ‘sterile’ verrucous cyst abscesses and epidermodysplasia verruciformis-like eruption associated with idiopathic CD4 lymphopenia. Br. J Dermatol 2003;149:627–33.

18 Pasic S, Minic P, Dzudovic S, Minic A, Slavkovic B. Idiopathic CD4+ lymphocytopenia and juvenile laryngeal papillomatosis. Pediatr Pulmonol 2005;39:281–3.

19 Gubinelli E, Posteraro P, Girolomoni G. Idiopathic CD4+ T lymphocytopenia associated with disseminated flat warts and alopecia areata. J Dermatol 2002;29:653–6.

20 Purnell D, Ilchyshyn A, Jenkins D, Salim A, Seth R, Snead D. Isolated human papillomavirus 18-positive extragenital bowenoid papulosis and idiopathic CD4+ lymphocytopenia. Br J Dermatol 2001;144:619–21.

21 Stetson CL, Rapini RP, Tyring SK, Kimbrough RC. CD4+ T lymphocytopenia with disseminated HPV. J Cutan Pathol 2002;29:502–5.

22 Manchado LP, Ruiz de Morales JM, Ruiz G, Rodriguez Prieto MA. Cutaneous infections by papillomavirus, herpes zoster and Candida albicans as the only manifestation of idiopathic CD4+ T lymphocytopenia. Int J Dermatol 1999;38:119–21.

23 Zhang Q, Davis JC, Lamborn IT et al. Combined immunodeficiency associated with DOCK8 mutations. N Engl J Med 2009;361:2046–55.

24 Yazdani S, Stiehm ER. Topical imiquimod for molluscum contagiosum in T cell immunodeficiency. Pediatr Infect Dis J 2003;22:575–6.

25 Bohm M, Luger TA, Bonsmann G. Disseminated giant molluscum contagiosum in a patient with idiopathic CD4+ lymphocytopenia. Successful eradication with systemic interferon. Dermatology 2008;217:196–8.

26 Hourihane J, Hodges E, Smith J, Keefe M, Jones A, Connett G. Interferon alpha treatment of molluscum contagiosum in immunodeficiency. Arch Dis Child 1999;80:77–9.

27 Hague RA, Rassam S, Morgan G, Cant AJ. Early diagnosis of severe combined immunodeficiency syndrome. Arch Dis Child 1994;70:260–3.

28 Antachopoulos C, Walsh TJ, Roilides E. Fungal infections in primary immunodeficiencies. Eur J Pediatr 2007;166:1099–117.

29 Messner AH, Mitchell DP, Roifman CM. Mucosal lesions in severe combined immunodeficiency syndrome. J Otolaryngol 1996;25:200–2.

Related posts:

12 Collodion Baby 104 Disorders of Pigmentation 96 Knuckle Pads 140 Skin Gene and Cell Therapy 58 Bartonella Infections: Bacillary Angiomatosis, Cat Scratch Disease and Bartonellosis 168 Kawasaki Disease

Stay updated, free articles. Join our Telegram channel

Join