Review article Prevention of infection in children and adolescents with primary immunodeficiency disorders Efimia Papadopoulou-Alataki, 1 Amel Hassan 2 and E. Graham Davies 2 Summary diseases if recurrent infections exceed three per year, if severe infections occur despite adequate Background: Primary Immunodeficiency diseases immunoglobulin replacement and in (PIDs) are a heterogenous group of inherited hypogammaglobulinaemic patients who have disorders that may involve one or multiple bronchiectasis. Certain immunisations are effective components of the immune system. PIDs are in antibody deficiencies, T cell deficiencies, uncommon, chronic and severe disorders, in complement deficiencies and phagocytic disorders. which patients cannot mount a sufficiently protective immune response, leading to an Conclusion: There are remarkably few published increased susceptibility to infections. This review data relating to clinical management aimed at addresses the current practices for the prevention of preventing infectious complications in children infection in children and adolescents with PIDs, and adolescents with PIDs. The cornerstones of in particular covering immunisations and the prevention of infection in most PID patients antimicrobial prophylaxis. are: antimicrobial prophylaxis, appropriate vaccination, immunoglobulin replacement, for Results: Over recent years, there have been the more severe cases, and regular ongoing major advances in molecular and cellular follow-up. (Asian Pac J Allergy Immunol understanding in the field of PIDs. Many 2012;30:249-58) different disorders are recognised with variable spectra of infection susceptibility depending on Key words: adolescents, antimicrobial prophylaxis, the particular aspects of the immune response bronchiectasis, children, immunizations, primary that are affected. Immunoglobulin prophylaxis is immunodeficiencies the mainstay of treatment for PIDs and provides passive protection. Prophylactic antimicrobials Introduction are efficacious in children and adolescents with Primary immunodeficiency diseases (PIDs) are a predominant defects in primary T cell heterogenous group of inherited disorders that may immunodeficiency diseases and phagocytic involve one or multiple components of the immune disorders, and also with predominant defects in system. PIDs are classified according to the antibody production. Prophylactic antibiotics are compartment of the immune system that is primarily suggested for patients with antibody deficiency involved 1,2 (Table 1). Tremendous progress has been made in the identification and characterisation of genes responsible for PIDs in the past 15 years. Around 200 clinical entities have been described, From 1. Fourth Department of Pediatrics more than 100 of which now have a known genetic Aristotle University of Thessaloniki, General Regional aetiology. 3-5 PIDs are uncommon, chronic and Hospital Papageorgiou, Ring Road 56403 Thessaloniki, severe disorders in which patients cannot mount a Greece sufficiently protective immune response, leading to 2. Department of Immunology, Great Ormond Street an increased susceptibility to infections. 6 Hospital for Children, NHS Trust, London, UK. Given the major role of infection in determining Corresponding author: Efimia Papadopoulou-Alataki the outcome for patients with PID, clearly defined E-mail: [email protected] practices for prophylaxis are important and, where Submitted date: 14/9/2011 possible, should have a sound evidence base. Accepted date: 26/6/2012 249 Asian Pac J Allergy Immunol 2012;30:249-58 Table 1. Classification of primary immunodeficiencies General measures against infections in primary immunodeficiencies Defects of Predominantly XLA Measures of hygiene are advised to prevent Adaptive Major CVID infections in highly sensitive patients with PIDs. Immunity Antibody IgA deficiency Deficiencies Isolated IgG subclass Hand and dental hygiene, good nutrition, avoidance deficiency of exposure to people who are ill with an infection, THI and withdrawal from school during periods of Combined T- cell T - B+ SCID chickenpox and measles outbreaks are several useful and B- cell ADA deficiency precautions for immunodeficient children. immunodeficiencies T - B- SCID ADA deficiency In particular, children with severe combined Omenn syndrome immune deficiencies need strict isolation and CD8 +deficiency filtered air and should be cared for by staff immune ZAP-70 deficiency to varicella and influenza. Prophylaxis against MHC class I, II deficiency cryptosporidium infection is needed for some PNP deficiency patients with Hyper IgM syndrome type 1 associated HIGM-CD40 Ligand with combined immunodeficiency (X-linked Hyper deficiency IgM). Measures reducing the risk of Defects of Phagocytic CGD Innate Immunity Disorders Severe Congenital cryptosporidium infection are: boiling of all Neutropenia drinking water and/or installation of a professionally Kostmann syndrome fitted filter with <1 micron pore size, avoidance of Cyclic neutropenia swimming in ponds and lakes, use of swimming LAD syndrome type I, pool only when aged >5 years, avoidance of contact II, III Myeloperoxidase with farm animals (lambs and calves) and with 7 deficiency kittens and puppies. Complement Complement Deficiencies Components 1-9 Prophylactic antimicrobials in children and deficiencies adolescents with primary immunodeficiencies Mannose-binding lectin A recent large survey conducted by the American disorder Academy of Allergy, Asthma and Immunology Properdin deficiency Defects of IL12/INF-γ signal ling pathway concluded that the use of prophylactic antibiotics in 8 Defects of Toll-Like Receptor Signalling PIDs is widespread and perceived to be efficacious. X-linked ectodermal dysplasia However, a sound evidence base for many practices Immune Chediack Higashi syndrome is not available for PIDs. Practice is often based on Dysregulation Griscelli syndrome Disorders XLP syndrome extrapolation from studies in other immuno- ALPS suppressed states (e.g. Human Immunodeficiency IPEX Virus or chemotherapy-induced immuno-suppression) APECED or based on expert opinion. The choice of anti- Other well defined WAS micriobials is based on the particular type of PID immunodeficiency A-T syndromes DiGeorge syndrome and the expected microbial susceptibility. Hyper IgE syndromes Predominantly defects in antibody production They are characterised by chronic or recurrent ADA, Adenosine Diaminase; ALPS, autoimmune lymphoproliferative sino-pulmonary infections with encapsulated bacteria syndrome; APECED, autoimmune polyendocrinopathy candidiasis such as Streptococcus pneumoniae and Haemophilus ectodermal dystrophy; A-T, Ataxia Telangiectasia; CGD, Chronic 3 Granulomatous Disease; CVID, Common Variable Immunodeficiency; influenzae . Among patients with antibody HIGM, Hyper IGM; IPEX, immunedysregulation polyendocrinopathy deficiencies, those with severe illness should be on enteropathy X-linked; LAD, leukocyte adhesion deficiency; MHC, immunoglobulin (Ig) which is the most important Major Histocompatibility Complex; PNP, purine nucleoside phosphorylase; SCID, Severe Combined Immunodeficiency; THI, treatment. It has been suggested that prophylactic Transient Hypogammaglobulinaemia of infancy; WAS, Wiskott Aldrich antibiotics should be used if recurrent infections syndrome; XLA, X-Linked Agammaglobulinaemia; XLP, X-linked lymphoproliferative; ZAP-70 deficiency, zeta chain associated protein exceed three per year or if any very severe infection 9 70 deficiency. occurs despite adequate Ig replacement. Antimicrobial long-term prophylaxis with Trimethoprim- 250 Prevention in primary immunodeficiencies sulphamethoxazole (TMP-SMX), amoxicillin or X-Linked Agammaglobulinaemia (XLA) is a macrolides may then be required. 10 humoral immunodeficiency characterised by Common Variable Immunodeficiency (CVID) is respiratory infections, mainly due to encapsulated the most common symptomatic PID with recurrent bacteria. It may be associated with neutropenia and infections of the respiratory tract including those it may also predispose to staphylococcal or caused by Streptococcus pneumoniae, Moxarella pseudomonas infections. Giardia, mycoplasma and catarrhalis, Haemophilus influenzae. 11 Early diagnosis ureoplasma infections can also occur. 10 Severe viral in childhood and close follow-up are required to infections are rare, but patients with XLA have a prevent bronchiectasis. Repeated high resolution unique susceptibility to meningoencephalitis caused computed tomography of the thorax should be by enteroviruse s. 4 To prevent enteroviral and considered every 3-5 years, or more frequently if enterococcal infections, particular attention should recurrent clinical infections or change in pulmonary be given to hand hygiene of healthcare tests suggest deterioration in pulmonary function. 9 professionals, especially after diaper changing. 12 Antibiotic prophylaxis should depend on the XLA patients with infections despite adequate Ig patient’s pathogens. Macrolides and TMP-SMX are replacement may benefit from antibiotic useful agents for this purpose; they are well prophylaxis, although evidence is lacking and tolerated and cover the most relevant pathogens. In variations in practice are observed. Some some circumstances, quinolones can be used (Table practitioners add continuous antibiotic prophylaxis 2). However, the development of antimicrobial (TMP-SMX) 13 (Table 2). In a series of XLA resistance needs to be taken into account. 10 children, prophylactic antibiotics were given to Table