Immunodeficiency Disorders

Immunodeficiencies are no longer considered rare conditions. Although susceptibility to infections has become well-recognized as a sign of most primary immunodeficiencies, some children will present with noninfectious manifestations that remain underappreciated and warrant evaluation by an immunologic specialist. Providers must also consider common secondary causes of immunodeficiency in children.After completing this article, readers should be able to:Immunodeficiency disorders represent defects in the immune system that result in weakened or dysregulated immune defense. These deficiencies may occur as primary diseases or secondary conditions. This article reviews primary and secondary immunodeficiencies, with particular emphasis on the evaluation and management of children with primary immunodeficiencies (PIDs).PIDs constitute inherent defects in immunity, most of which arise from inborn deviations in the genetic code. More than 300 PIDs have been identified. These conditions have been placed into 9 categories corresponding with their clinical and immunologic phenotypes by an international group of experts who evaluate these diseases every 2 years (Table 1). (1) Although PIDs were previously believed to represent rare conditions, they are now known to affect 1 of every 1,200 to 2,000 individuals, with growing prevalence due to increased recognition. (2)(3) The magnitude of this disease frequency, therefore, mandates that all health-care providers recognize the associated clinical infectious and noninfectious characteristics, testing options, and management recommendations for children with PIDs. And because so many PIDs present in childhood, and several are now captured by newborn screening, their understanding by pediatricians remains especially important.Infections serve as the key hallmark warning signs for the presence of PID. (4) In general, children with PIDs develop infections more frequently, more severely, and more atypically. Although noninfectious characteristics of PIDs can result from inappropriate immune function and are discussed in the next section, the link between PID and infection remains essential and must be regarded as a prompt to consider PID in pediatric practice. Each of the 9 PID categories conveys a different risk for certain infectious susceptibilities in accordance with the molecular mechanism for the impaired immunity. Offending organisms encompass the entire spectrum of pathogens, including bacteria, viruses, fungi, and parasites. Thus, awareness of infections associated with defective humoral immunity, T-cell function, phagocytic capacity, complement activity, and other innate immunity becomes essential.Defects in humoral immunity that cause PID result in impaired antibody production. Infants receive maternal immunoglobulin (Ig) G transplacentally. Because the half-life of IgG is approximately 21 days in the circulation, children have protection from these maternal antibodies until approximately 3 to 4 months of life. At that time, characteristic infections tend to ensue, although some antibody deficiencies are known to present at older ages. Because antibodies serve as critical elements for protection of the sinopulmonary tract, affected individuals typically develop recurrent otitis media, sinusitis, and pneumonia. Infections are by no means limited to these sites, however, and can result in sepsis, meningitis, osteomyelitis, or chronic diarrhea. For example, X-linked agammaglobulinemia is characterized by a lack of B cells due to mutations in BTK located at Xq22.1. Absence of B cells results in failure to produce IgG, IgA, IgM, and IgE. In affected boys, disappearance of maternal antibodies is associated with the appearance of recurrent sinopulmonary tract infections, classically by polysaccharide-encapsulated bacteria, such as Streptococcus pneumoniae and Haemophilus influenzae. (5) The lack of antibodies also results in susceptibility to infections by mycoplasmal and pseudomonal organisms, Salmonella species, Campylobacter jejuni, rotavirus, and Giardia lamblia.T-cell deficiency produces combined humoral and cellular immune defects. Because of this extensive effect on immune function, affected individuals demonstrate susceptibility to opportunistic fungal, viral, mycobacterial, and parasitic infections in addition to the infections observed in antibody deficiencies. Classic pathogens include candidal species, Pneumocystis jirovecii, Mycobacteria species (including bacille Calmette-Guérin), and Cryptosporidium parvum. Viral infections surpass the ordinary and are notably severe, disseminated, or persistent. Severe combined immunodeficiency disease (SCID) serves as a classic example of primary T-cell deficiency. The diagnosis is established by either 1) the absence or a very low number of T cells (<300 CD3+ T cells/mm3) with no or very low T-cell function (<10% of the lower limit of normal) as determined by response to phytohemagglutinin or 2) the presence of T cells of maternal origin. (6) Mutations in at least 16 genes lead to SCID, and most forms are caused by disrupted T-cell development secondary to abrogated T-cell receptor formation or cytokine signaling (Table 2). (1) The most common type of SCID in the United States results from mutations in IL2RG at Xq13.1 and is, thus, found in boys. SCID represents a true pediatric emergency, and mortality from infections is certain if affected infants are not treated appropriately. (7) Life-threatening infections are caused by respiratory syncytial virus, rhinovirus, parainfluenza virus, adenovirus, cytomegalovirus, and even attenuated vaccine strains of measles virus, varicella virus, rotavirus, and oral poliovirus. Invasive bacterial and fungal infections also occur, the former mostly resulting from impaired humoral immunity secondary to the defects in T-cell immunity.Because neutrophils play a significant role in the clearance of bacterial and fungal pathogens, PIDs due to defective phagocytic capacity are marked by infections caused by these organisms. Phagocytic impairment can result from inadequate neutrophil quantity or function. Classic infections in children with neutrophil deficiency include skin or solid organ abscesses, cellulitis, pneumonia, sepsis, and severe gingivitis or periodontitis. Other signs of a phagocytic defect include omphalitis, poor wound healing, and aphthous stomatitis. Affected individuals have an increased risk of life-threatening infections from Staphylococcus aureus and Pseudomonas aeruginosa. As a key illustration, chronic granulomatous disease (CGD) serves as an example of PID caused by impaired neutrophil function. This condition arises from defects in components of nicotinamide adenine dinucleotide phosphate oxidase, which produces the oxidative burst needed for neutrophils to kill phagocytized organisms. (8) The most common form of CGD results from mutations in CYBB, which is located at Xp21.1-p11.4. Thus, most children with CGD are boys. CGD can be recognized by susceptibility to catalase-positive organisms, such as S aureus, Serratia marcescens, Klebsiella species, Burkholderia cepacia, Aspergillus species, and Nocardia species (8)(9) Infections caused by unusual pathogens, especially methylotrophic microorganisms capable of using single-carbon compounds as their sole source of energy, should also raise concern for the presence of CGD. (10) In children with CGD who have received bacille Calmette-Guérin immunization, infection by the bacterium itself should be considered. Characteristic sites of various infections in CGD include the skin, lungs, lymph nodes, liver, spleen, central nervous system, and bones.Children with defects in primary complement deficiencies can be recognized by infections caused by encapsulated bacteria. (11) Complement deficiency, whether of the early or terminal classical complement pathway components, should be considered in children who have invasive meningococcal disease, such as sepsis or meningitis from Neisseria meningitidis. Individuals who have primary early classical complement pathway protein (C1, C4, C2, and C3) deficiencies further demonstrate susceptibility to other encapsulated bacteria, such as S pneumoniae and H influenzae.Finally, children with PIDs due to other defects in innate immunity exhibit susceptibility to a variety of pathogens, depending on the critical defense mechanism affected. For example, natural killer cell deficiency should be suspected in individuals with recurrent, unusual, or severe herpesviral infections. (12)(13) Children with defects in the interferon-γ–interleukin-12 signaling pathway, on the other hand, develop atypical mycobacterial infections. (14) Perturbation of other key innate immune signaling pathways leads to chronic mucocutaneous candidiasis, which should be suspected in children with thrush that is unusually recurrent or unresponsive to nystatin. (15) Finally, defects in toll-like receptor (TLR) signaling pathways offer an excellent example of the diversity of infectious susceptibilities affected by various innate immunity disorders. Humans express 10 TLRs, each of which performs an inherent danger-sensing function by recognizing specific intracellular or extracellular bacterial, fungal, or viral components. TLR3 deficiency leads to susceptibility to herpes simplex virus encephalitis. (16) IRAK-4 and MyD88, however, serve as adaptor molecules that mediate signaling downstream from all the other TLRs (except partly TLR4). Deficiencies of either of these proteins result instead in vulnerability to invasive infections (sepsis, meningitis, arthritis, and osteomyelitis, among others) that are caused by pyogenic bacteria, such as S aureus, S pneumoniae, and H influenzae, rather than by viruses or fungi. (17)Improved understanding of PIDs and enhanced diagnostic capabilities, especially genetic testing, (18) have provided greater awareness of the need to appreciate noninfectious manifestations, as discussed in the following paragraphs, that can serve as early or initial warning signs for the presence of underlying PID. The pediatrician should keep in mind that inherently defective immunity not only results in an inability to defend against the external environment (ie, infections) but also produces impaired ability to navigate the internal environment, leading to autoimmune and autoinflammatory conditions. In some children, these conditions will appear before infections ensue and can engage nearly any organ system. Affected children may, therefore, first come to the attention of other specialist providers. Presence of any of these features in a pediatric patient, especially with early or very early onset, should prompt consideration of additional evaluation for underlying PID. These noninfectious manifestations of PIDs are reviewed in the following accompanying tables and figures. Of importance, the lists of defective PID genes provided in the tables and figures are by no means comprehensive. Instead, they are intended to underscore the degree to which concern for PID is deserved.Gastrointestinal disorders can reveal the presence of underlying PID (Table 3). (19) Autoimmune enteropathy can be observed when children lack regulatory T cells. The autoimmune disease in other PIDs, on the other hand, leads to In several PIDs, dysregulated rather than results in Finally, the presence of with is nearly associated with deficiency. Thus, children with chronic disease, or should all be considered for evaluation for underlying variety of conditions, many of which to underlying dysregulated immunity in the skin, can the of PID 1). is a of several PIDs, most notably and or can be observed in autoinflammatory on the other hand, can PID due to a defect in of B cells signaling or have been associated with and in addition to several other PIDs. can also serve as a sign of PID. is observed in and and or is present in and due to is for the absence of should concern for or deficiency. autoinflammatory is marked by a of characterized by a and response to an placed on the and is caused by mutations in or different form of that produces a but significant to in antibody deficiency and immune Finally, skin can be found in several PIDs, including and or or PIDs are caused by and dysregulated immunity, as that some affected individuals will present with autoimmune disease as the or even sole 2). arthritis, including arthritis, may be a sign of a PID Autoimmune are classically associated with impaired immunologic whether defective of T cells in the or regulatory T-cell of T cells. can also present in individuals with autoimmune serves as a of many of the and several complement deficiencies. In of the known associated features underscore the need to consider further evaluation in a who of arthritis, or and any other signs of of these result from of which are protein critical for and can be treated with disease is also known to occur in several PIDs. Thus, that PIDs will to be as causes of in Finally, evaluation for PIDs should be considered for children who present with or is known to be associated with deficiencies of all components of the classical complement pathway (except Individuals with CGD and can also present with remains to that of the disease known as can present with an known as This condition must be recognized because is treated more than other conditions that the for PIDs should be considered in children with 3). of these disorders are resulting from the disrupted inherent to the associated PIDs. Severe or type 1 can regulatory T-cell is an of and deficiencies. is observed in deficiency and In the between and remains must that the absence of not the diagnosis of as nearly of affected individuals may not have the characteristic Children who present with any features or disease, or or characteristic of therefore, be for deficiency represents a classic characteristic of deficiency but is known to occur in with deficiency and Finally, disease underappreciated as a of PID but can a to the of underlying conditions should raise concern for underlying PIDs (Table The PID that lead to these 2 disorders include impaired of immunologic and dysregulated of immune cells. disease an inherent defect in immune function. For example, in of immune cells due to defective several other PIDs are characterized by disease associated with virus is observed in pediatric who develop should be for PIDs if they not have defects in any of the PIDs associated with include and and a variety of other conditions that affect T-cell or natural killer cell PIDs are characterized by signs These occur most typically due to that the genes serve of the immune system. the mechanism for and remains in many conditions and is not to the defective immune function in the associated PID. is a of and among on the other hand, is a of H and other PIDs. is associated with a variety of PIDs, but providers to evaluate for defective immunity due to the attention to the This the critical between development and and immune function, especially in of of to play an essential role in and children with PIDs caused by a defect in this mechanism present with As example, is observed in which is caused by and Other of and PID caused by inappropriate of include and deficiencies. from defects in is also known to play a role in immunologic and As a a variety of disorders of represent PIDs that as should be considered in a with or various disorders. Thus, should be of these and consider immunologic evaluation rare noninfectious conditions can the presence of underlying PIDs (Table disease has been in several PIDs. is most associated with deficiency but can also be observed in with other PIDs. and should raise concern for Finally, represents a key of disease, and caused by should be of 2 additional noninfectious manifestations of PIDs (Table which are severe or can serve as the of several PIDs. In many of these conditions, the is by serves as a classic of with immune and but can the presence of other PIDs as of when to for or a for evaluation of a suspected PID may be affected by several a of recurrent, severe, or unusual infections or any of the noninfectious discussed previously immunologic The of recurrent remains may not be unusual for a to have 3 or more of otitis media, and of the children will have at least 3 of otitis by 3 years of that children than 3 years may have respiratory tract infections and children 3 to years may have respiratory tract infections Thus, clinical remains As a of is the clinical of the to pediatricians to consider PID in their who from the the of infections. a pediatric of will have to 10 of PID therefore, be of who as from an infectious so that they will be to PID their the may immunologic PID should be considered if have recurrent or unusual infections, especially maternal or other Other elements of the include and early mortality from infections or for PID may be in children with with any of the noninfectious Children with failure to should also raise for underlying PID. a who or should be for an underlying infants with newborn for SCID must receive immunologic As of the of all but 2 and have SCID newborn The is to or low of T-cell receptor in from Thus, an newborn may the presence of T-cell are for initial evaluation for suspected PID. because defects in humoral immunity of immunoglobulin and of specific antibody excellent for PID. antibody function should be by antibody These represent the most most and humoral immune As a more diagnostic children older than 2 years can be for humoral to the in the these are by antibody the and the approximately 3 for 4 to and months for the a cell with a can be to for T-cell deficiency the In a an than that T cells have not and that they may even be in or in a PID is essential for pediatricians to on and the in cell should be by a T-cell by to the presence and of the different Absence of a on in an should also raise concern for the absence of T cells. For of T in testing by the of T-cell such as and can be in the but the of to an specialist for in The of the from the that is and with a complement can be to deficiency of any of the components of the classic complement This is to and true deficiency is only if the complement is or a diagnosis of CGD should be using a is no longer due to and lack of should be that individuals with and deficiencies can have Children clinical may should be by cell with This 2 to 3 for to Finally, for is suspected should be with a which is typically in affected with suspected PIDs should be to a clinical for further evaluation because many different immune are that in the further of the different PIDs. additional testing may be and genetic testing may be considered in some (18) are a environment in which genetic testing as may of a PID in an This has the to in some but the and with the of whether certain genetic represent an for the clinical and immunologic this the of this but the is to several excellent is essential for the pediatrician to that several different to for of SCID newborn and can all known genes with Although genetic are and can be they not and immune which are needed to the of a should be as as and should be by the susceptibilities associated with the immunologic mechanism that is These are especially because any infection in an with PID has the to become severe, and infections in particular can the risk of and is for the of Pneumocystis and is also for against and infections in CGD. Children with susceptibility to atypical mycobacterial infections should be placed on and is as a in individuals who are to invasive herpes simplex virus infections. can be for against candidal infections, although some with chronic mucocutaneous will for In children with is typically for against Aspergillus and other fungal infections. is especially in these as Aspergillus infection represents the most significant cause of Children who are to Cryptosporidium infections, such as with X-linked should and attenuated should not be to individuals with certain PIDs and therefore, be by an specialist before attenuated should be to and however, to For all children, such as should be not need to be in a but should be from with individuals who have infections and from for pathogens, such as Children with severe T-cell deficiencies in and become for these individuals, they should receive only In all children with PIDs, a low of should be for infections. should be and is also to that many of these become in who have immune such as cell or more should be with from an in PIDs. For example, IgG is as a for PIDs that humoral deficiency as a and should be to such with PID a of IgG and to as the defective for impaired immunity for various PIDs, are and to more immune function in these the for for most children with PIDs will come in cell and in as by an causes of immunodeficiency should be in children with suspected PIDs. of these causes of immunodeficiency must be considered. as causes of deficiency and include such as and deficiency has also been to of Other associated with include compounds and for in the or for of such as and can cause and secondary T-cell deficiencies. also T-cell function and wound healing, and they have been to if for are in a variety of disease conditions, such as autoimmune or diseases and solid organ and they have been to cause secondary The primary mechanism of of the immunologic defense that are the clinical For example, individuals who are for disease are to have increased risk for infection or and receptor T are to cause of B cells and result in Finally, to the can cause and T-cell deficiency of into the of immunoglobulin and must be as for include or from of or can also represent a significant cause of secondary of IgG, and can be observed in children with Other of include disease and chronic diarrhea. can even lead to IgG deficiency in some be as a secondary cause of and is to represent the most common cause of an immune deficiency. Severe results in of by and lower of B cells. T and T-cell and T-cell to and becomes The absence of specific can affect immunity in a variety of For example, lack of protein results in and innate immune function. deficiency, on the other hand, results in impaired neutrophil and natural killer cell and T-cell deficiency has been to cause T-cell function, and deficiency is associated with antibody and lower T-cell to deficiency is known to result in susceptibility to infections, especially pneumonia, and poor wound impaired neutrophil and the of the can neutrophil activity, and T-cell Thus, must be and can also cause secondary For example, have been to have impaired neutrophil and of S As a example, of immune function. In can affect children, whether at at or in other For children with can have neutrophil and S the have the effect of on immune function in children, but may be from in which is associated with secondary antibody and to among other immunologic immunodeficiency virus infection remains the most cause of secondary a remains the of this infection should be by and combined with For only testing should be due to of maternal These should be at to 21 1 to 2 and 4 to should be as secondary causes of such as and can lead to recurrent infections. can produce that results in recurrent otitis or can also to which may be as recurrent or can which can recurrent infections. In of and chronic are known to produce secondary but these not occur in have been to the prevalence of secondary immunodeficiency in pediatric Other disease conditions, such as and are known to the appearance of recurrent infections. has been associated with deficiency, but remains whether the is some effect on immune function is as 1 of the for diagnosis or Infections can immunity. example is provided by measles which can produce impairment of and T-cell function. Finally, infants are with an of maternal antibodies the but the T cells can be at to 16 of but diversity is not until to of and remains resulting in low T-cell receptor and newborn for must a of for immunodeficiency disorders in pediatric of and the that PIDs are rare to and Instead, of these conditions by testing and to an specialist remains for essential to and for these As early or present a critical of which a diagnosis can be established or even to and of the that this article, the at