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Recognition of immunodeficiency in the first three months of life

Recognition of immunodeficiency in the first three months of life
Literature review current through: May 2024.
This topic last updated: Nov 30, 2023.

INTRODUCTION — This topic is an overview of the presentation and identification of the general types of immune defects in the newborn/neonate (infants within the first 28 days of life) and young infant (up to three months of age), including inborn errors of immunity (IEI; also called primary immunodeficiencies [PIDs]) and secondary immunodeficiencies. The diagnosis of an IEI in a premature neonate is difficult since classic complications of prematurity may in fact be manifestations of IEI (eg, severe lung disease in signal transducer and activator of transcription 3 [STAT3] gain-of-function [GOF] defect, necrotizing enterocolitis in severe combined immunodeficiency [SCID] immune dysregulation, polyendocrinopathy, enteropathy, X-linked [IPEX]). It also covers initial management of IEI and when to refer to a pediatric immunologist. The diagnosis of specific immunodeficiencies is discussed separately in topic reviews on the individual disorders, as is a detailed discussion of the laboratory evaluation of the immune system, including more advanced studies. The evaluation of the child with recurrent infections is also covered separately. (See "Laboratory evaluation of the immune system" and "Approach to the child with recurrent infections".)

OVERVIEW OF IMMUNITY OF THE FETUS AND NEWBORN — Fetal tissues (placenta, lung, thymus, spleen, gut, skin, mesenteric lymph nodes) have a microbiome. The fetal immune system is primed by maternally derived microbes before birth [1-3]. Fetal leukocytes (eg, dendritic cells, regulatory T cells) respond to maternal, dietary, and microbial antigens but are biased towards suppression of inflammation [4]. Reduced proinflammatory responses may facilitate the transition from the intrauterine environment to the outside world, including colonization with the commensal microbiome [5,6]. Other aspects of the immunology of the maternal-fetal interface are discussed in greater detail separately. (See "Immunology of the maternal-fetal interface".)

After birth, the newborn acutely faces an environment swarming with microbes. The normal newborn's immune system is anatomically intact, antigenically largely naïve, and demonstrates dynamic changes in multiple immune pathways during the first weeks of life [7]. Apart from anatomic characteristics (eg, thin mucosal barriers), impaired proinflammatory and T helper cell type 1 (Th1) cytokine production and diminished cell-mediated immunity render the newborn more vulnerable to infection. However, most infants survive this period without illness due to intact innate immunity, other adaptive defense mechanisms, and maternally transferred immunoglobulin G (IgG). The development of the adaptive immune system is discussed in detail separately. (See "Normal B and T lymphocyte development".)

Some newborns inherit a genetic immune defect that manifests at birth or early infancy, termed "inborn error of immunity" (IEI; also called "primary immunodeficiency" [PID]). IEI are collectively relatively common, occurring in up to approximately 1 to 5 in every 1000 persons [8-10]. Early detection of such IEI may save lives. The incidence of severe combined immunodeficiency (SCID) and other IEI are reviewed in detail separately in the appropriate topics. (See "Inborn errors of immunity (primary immunodeficiencies): Classification" and "Newborn screening for inborn errors of immunity" and "Severe combined immunodeficiency (SCID): An overview", section on 'Epidemiology'.)

RISK FACTORS FOR IMMUNODEFICIENCY AND INFECTION

Risk factors for immunodeficiency and immune dysregulation — Factors associated with an increased risk of IEI or secondary immunodeficiency in a newborn include (see "Approach to the child with recurrent infections", section on 'Clinical features suggestive of a primary immunodeficiency'):

Factors resulting in preterm delivery or a small for gestational age infant [11] (see 'Prematurity' below)

Maternal disease: infection (chronic, acute, perinatal), hypertension, autoimmune disease, immunodeficiency, immunosuppressive medications (eg, antimetabolites) (see 'Maternal factors' below)

Anatomic abnormalities

Genetic aberrations (eg, syndromic diseases)

Family history of confirmed or suspected IEI leading to early death or recurrent/chronic illness in one or more family members [12], consanguinity (higher incidence in certain geographic regions [eg, Middle East] or populations such as the Amish), and/or ethnicity associated with a high incidence of IEI due to founder mutations (eg, severe combined immunodeficiency [SCID] in Navajo people, ataxia-telangiectasia [AT] in the Amish, and Bloom syndrome in Ashkenazi Jews)

Viral infections in the perinatal period (eg, severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2], varicella zoster virus [VZV], respiratory syncytial virus [RSV], influenza A, human herpesvirus 6 [HHV-6], cytomegalovirus [CMV], parainfluenza) triggering immune dysregulation resulting in signs of inflammation (eg, exanthemas, bowel disease) and lymphoproliferation (eg, hepatosplenomegaly) [13-15]

Risk factors for infection (other than immunodeficiency) — Factors that increase the risk of infection in newborns and infants without necessarily directly affecting the function of the immune system should be sought including [16]:

Maternal factors (see 'Maternal factors' below)

Preterm birth

Difficult delivery with prolonged exposure to nonsterile secretions

Male sex (due to differences in the immune system that render them more vulnerable)

An underlying disease that endangers the infant's health (eg, severe cardiac or other anatomic defect, genetic disorder, metabolic disease)

Maternal factors — Maternal factors during pregnancy that may contribute to increased infection risk in the newborn include [17] (see "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates"):

Chronic or acute maternal infection, such as human immunodeficiency virus (HIV), symptomatic SARS-CoV-2 infection, or perinatal maternal colonization with group B streptococci that may predispose to neonatal sepsis, prematurity, and intrauterine growth retardation (IUGR)

Other maternal illnesses (eg, autoimmunity; endocrinopathies; cardiovascular, lung, or kidney disease)

Immunosuppressive medication taken during pregnancy that may cross the placenta

Nutritional status of the mother (eg, obesity, diabetes, malnutrition, mineral and vitamin deficiencies)

Maternal habits (tobacco use, alcoholism, or other substance abuse)

Inadequate maternal immunization that may place the newborn at risk for infections such as influenza, pertussis, RSV, or varicella [18]

Complications and procedures related to preterm birth — Pulmonary and cardiac abnormalities (eg, bronchopulmonary dysplasia, patent ductus arteriosus), necrotizing enterocolitis (due to increased intestinal permeability and/or decreased barrier), prolonged intubation, and prolonged intravascular access all lead to an increased risk of infection. (See "Overview of short-term complications in preterm infants".)

Nonimmunologic factors — Nonimmunologic factors associated with recurrent infections include neurologic abnormalities leading to aspiration, other genetic disorders that affect clearance of microorganisms from the respiratory tract, and cardiovascular abnormalities. (See "Approach to the child with recurrent infections", section on 'The child with chronic disease'.)

CLINICAL FEATURES SUGGESTIVE OF IMMUNODEFICIENCY — The most common presenting clinical features of severe combined immunodeficiency (SCID) that is not identified by presymptomatic newborn screening include recurrent, severe and/or opportunistic infections; recurrent fevers; symptomatic infection from live vaccines (eg, rotavirus, Bacille Calmette-Guérin [BCG], oral polio); chronic diarrhea; and failure to thrive. (See "Severe combined immunodeficiency (SCID): An overview", section on 'Clinical features'.)

Additional signs (mostly by inspection) and symptoms suggestive of immunodeficiency in the first months of life, particularly if there are not other apparent causes, include:

Severe necrotizing skin infections in severe congenital neutropenia

Peculiar, severe rashes, erythroderma, pustular rash, extensive desquamation, severe eczema, pigmentation abnormalities, or palmar erythema indicating graft-versus-host disease (GVHD) caused by engraftment of maternal T cells in SCID [19]

Prolonged umbilical cord separation (>42 days; typical time to separation 10 to 14 days) or omphalitis (infection of umbilical cord and/or surrounding tissue) in leucocyte adhesion deficiencies [20,21]

Extensive mucosal abnormalities such as severe thrush, mouth sores, and ulcerations

Congenital asplenia [22]

Skeletal or cutaneous abnormalities that suggest a syndrome associated with an immunodeficiency (eg, DiGeorge syndrome, cartilage-hair hypoplasia, Kabuki syndrome, short-limbed dwarfism, CHARGE [coloboma of the eye, heart anomalies, choanal atresia, retardation, genital and ear anomalies] association) [23-25]

The presence of any of the features listed above should lead to the suspicion of an IEI or secondary immunodeficiency. Prompt measures should be taken to prevent further exposures/infections when one or more of these features are present. Further history taking and prompt laboratory evaluation are needed to establish a definitive diagnosis. (See 'Laboratory evaluation' below and 'Specific disorders' below and "Approach to the child with recurrent infections" and "Laboratory evaluation of the immune system" and 'Initial management prior to definitive diagnosis' below.)

INITIAL MANAGEMENT PRIOR TO DEFINITIVE DIAGNOSIS — Several precautions are commonly undertaken prior to exact diagnosis or therapy if there is clinical or laboratory suspicion of a severe immunodeficiency. These measures, which are all discussed in greater detail separately, include:

Protective isolation to limit exposure to infection. (See "Inborn errors of immunity (primary immunodeficiencies): Overview of management", section on 'Isolation measures'.)

Avoidance of live vaccines (eg, rotavirus, Bacille Calmette-Guérin [BCG], oral polio). (See "Immunizations in patients with inborn errors of immunity", section on 'Live vaccines'.)

Avoidance of blood transfusions, if possible, with use of irradiated, leukoreduced, cytomegalovirus (CMV) negative blood products if transfusion is needed. (See "Red blood cell transfusion in infants and children: Selection of blood products", section on 'Red blood cell products' and "Inborn errors of immunity (primary immunodeficiencies): Overview of management", section on 'Caution with blood products'.)

Feeding precautions. Breast milk is preferable, when possible, given its multiple benefits. However, sterile formula (ready-to-feed and 2x concentrated) should be used instead of breast milk if there is confirmed maternal human immunodeficiency virus (HIV) infection or if the mother is CMV seropositive. (See "Intrapartum and postpartum management of pregnant women with HIV and infant prophylaxis in resource-rich settings", section on 'Breastfeeding' and "Severe combined immunodeficiency (SCID): An overview", section on 'Measures to prevent initial infections'.)

Antibody replacement with immune globulin, if needed. Immunoglobulin levels should be measured prior to immune globulin replacement therapy, as well as antibody titers to vaccines unless hypogammaglobulinemia is profound (IgG <100 mg/dL), the infant is suspected to have a severe combined immunodeficiency (SCID) disorder in which specific antibody production cannot occur, or the infant has not been immunized. (See "Immune globulin therapy in inborn errors of immunity".)

Prophylaxis against infection, including antimicrobial prophylaxis and respiratory syncytial virus (RSV) immunoprophylaxis. (See "Inborn errors of immunity (primary immunodeficiencies): Overview of management", section on 'Prophylactic antimicrobial therapy' and "Severe combined immunodeficiency (SCID): An overview", section on 'Measures to prevent initial infections' and "Respiratory syncytial virus infection: Prevention in infants and children".)

If infections are suspected, appropriate microbiologic studies should be obtained and empiric treatment initiated promptly while awaiting culture results. (See 'Laboratory evaluation' below.)

The management of hyperinflammation in neonates depends on the underlying disease causing the immune dysregulation. If there is hyperinflammation and suspicion of an underlying inborn error of immunity (IEI), it may be necessary to use nonspecific immunosuppressive treatment, as in the case of life-threatening hemophagocytic lymphohistiocytosis (HLH)/macrophage activation syndrome (MAS) or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neonatal multisystem inflammatory syndrome (MIS-N). In addition, supportive care maintains critical organ function and eliminates triggers for immune dysregulation. Management of these disorders is discussed in greater detail separately (See "Treatment and prognosis of hemophagocytic lymphohistiocytosis" and "COVID-19: Multisystem inflammatory syndrome in children (MIS-C) management and outcome" and "The autoinflammatory diseases: An overview" and 'Infection' below.)

REFERRAL — Awareness of potential immunodeficiency is key. Many immunodeficiencies that present in early infancy are potentially life threatening. Early consultation with a pediatric immunologist and/or an infectious disease specialist is recommended whenever possible when an immunodeficiency is suspected in a newborn or young infant.

The diagnosis and management of inborn errors of immunity (IEI) is increasingly complex due to the wide range of defects, heterogeneity of their clinical presentations, and expanding options available for evaluation (eg, whole genome sequencing [WGS]) and treatment (eg, immunomodulatory modalities). Thus, consultation with pediatric immunology as well as multiple additional specialties, including genetics, pediatric infectious disease, pediatric rheumatology, pediatric oncology, and others, may be optimal.

LABORATORY EVALUATION — Genetic testing by gene panel, exome sequencing, or genome sequencing is increasingly used early. Initial evaluation of the newborn or young infant with suspected immunodeficiency and several intermediate studies of immune function are reviewed here. A more extensive discussion of laboratory studies available to evaluate the immune system, including advanced studies, is covered in detail separately. (See "Next-generation DNA sequencing (NGS): Principles and clinical applications" and "Laboratory evaluation of the immune system" and "Approach to the child with recurrent infections", section on 'Laboratory evaluation'.)

Inborn errors of immunity (IEI) may be identified on newborn screening. This screening and subsequent evaluation are discussed in greater detail separately. (See 'Newborn screening' below and "Newborn screening for inborn errors of immunity".)

Initial evaluation — Basic immune laboratory studies should be conducted by the neonatologist if one or more of the risk factors for immunodeficiency are present. Initial evaluation in the newborn/young infant includes a complete blood count (CBC) with differential and immunoglobulin levels. (See 'Risk factors for immunodeficiency and infection' above and 'Secondary immunodeficiency' below.)

CBC with differential – Findings on the CBC with differential may include:

Leukopenia or leukocytosis – Leukopenia is defined as a white blood cell (WBC) count <4000 cells/microL. Leukocytosis (WBC >12,000 cells/microL) is sometimes noted: Either leukopenia or leukocytosis may suggest the presence of infection.

Lymphopenia – Lymphopenia is defined as an absolute lymphocyte count <2500 cells/microL in infants and suggests a primary T and/or B cell defect or a defect secondary to medication and/or viral infection (human immunodeficiency virus [HIV], cytomegalovirus [CMV]) or sepsis/tuberculosis (TB). The total lymphocyte count as measured on a CBC with differential normally exceeds 5000 cells/microL at birth. If it is repeatedly low, further testing with lymphocyte subsets should be performed.

Neutropenia – Mild neutropenia is defined as a neutrophil count 1000 to 1500 cells/microL, moderate neutropenia 500 to 1000 cells/microL, and severe neutropenia <500 cells/microL. Neutropenia <100 cells/microL is life threatening. Neutropenia (and/or lymphopenia) in the newborn can be caused by sepsis, maternal autoimmune disorders, or medications [26]. Benign neutropenia unassociated with infection or other illness is common in the newborn period (eg, neonatal isoimmune neutropenia). This neutropenia usually resolves within days. (See "Congenital neutropenia".)

Eosinophilia – Eosinophilia may suggest allergy or immune dysregulation.

Thrombocytopenia or thrombocytosis – Thrombocytopenia may be directly due to an IEI (eg, in Wiskott-Aldrich syndrome [WAS]) or associated with infection (eg, fungal or CMV infection). Thrombocytosis suggests chronic inflammation.

Age-adjusted reference ranges should be used when evaluating the results of a CBC with differential. The presence of anemia, thrombocytopenia (platelets <100,000 cells/microL), or an abnormal differential count warrants further investigation. (See "Approach to the child with recurrent infections", section on 'Laboratory evaluation' and "Laboratory evaluation of the immune system", section on 'Initial screening laboratory tests' and "Severe combined immunodeficiency (SCID): An overview", section on 'Laboratory abnormalities'.)

Immunoglobulin levels and vaccine titers – Measuring quantitative immunoglobulin levels (IgG, IgA, IgM, and IgE) is less informative in newborn/young infants than in older infants and children because young infants produce only small amounts of immunoglobulins and much of the IgG present in early infancy is IgG transferred from the mother (figure 1). Thus, a low IgG level may be due to factors other than low production by the infant (eg, gastrointestinal loss of immunoglobulins or consumption in severe infections). Similarly, antibody titers to vaccines are typically not obtained in infants under seven months of age, since the presence of maternal antibody makes the results difficult to interpret.

Additional screening tests – Biomarkers of systemic inflammation, such as C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and interleukin (IL) 6, may give some clues as to active infections; however, CRP and IL-6 levels are physiologically increased in the first hours of life and are also increased in autoinflammatory or immune dysregulation diseases. Additional screening tests conducted to exclude systemic disease (eg, metabolic disorders, kidney disease, malnutrition, protein loss) and infection based upon the clinical presentation may include:

Cultures, antibody titers, and/or polymerase chain reaction (PCR) studies to evaluate for infection in the infant and/or mother

Urinalysis

Electrolytes, glucose, blood urea nitrogen (BUN), creatinine, liver function tests (LFTs), and albumin (noting hypoalbuminemia, elevated LFTs, hypocalcemia); immunoglobulins (for low IgG or elevated IgM)

Radiologic imaging of the site(s) of suspected infection or pathology (eg, absent thymic shadow on chest radiograph in a lymphopenic patient suggests severe combined immunodeficiency [SCID])

This additional evaluation is discussed in greater detail separately. (See "Approach to the child with recurrent infections", section on 'Laboratory evaluation'.)

Intermediate and advanced studies — Abnormalities in one or more of the basic immunologic studies should prompt additional evaluation. Lymphocyte-subset analysis (lymphocyte enumeration by flow cytometry) and review of the T cell receptor excision circle (TREC) laboratory reports from newborn screening (if this newborn screening was done) as well as other intermediate studies will usually exclude or suggest a diagnosis of newborn immunodeficiency or determine which group of disorders should be explored for a definitive diagnosis. Advanced immunologic tests are best conducted in a graded fashion, and referral to an immunology specialist should be sought early in the process. (See "Laboratory evaluation of the immune system" and "Approach to the child with recurrent infections", section on 'Laboratory evaluation'.)

Intermediate immunologic studies include:

T, B, and NK cell subsets – T, B, and natural killer (NK) cell enumeration by flow cytometry is indicated if lymphopenia is detected on a CBC with differential or if SCID is suspected even in the setting of a normal lymphocyte count. This procedure enumerates CD3+ cells (total T lymphocytes), CD3+CD4+ cells (T helper cells), CD3+CD8+ cells (T cytotoxic cells), CD19+ or CD20+ cells (total B lymphocytes), and CD3-CD16/56+ cells (NK cells). This test will identify most infants with SCID or complete DiGeorge syndrome and may characterize the nature of the T cell defect. CD45 and its isoforms are additional markers indicating the proportion of naïve, newly formed T cells, which express the isoform CD45RA. Oligoclonal expansion of a small T cell pool, as is seen in certain T cell defects and some cases of SCID or maternally engrafted T cells, should be suspected when the majority of T cells have the memory-associated isoform CD45RO. (See 'Cellular immunodeficiencies' below and "Severe combined immunodeficiency (SCID): An overview", section on 'Detection of maternal T cell engraftment'.)

Lymphocyte proliferation assay – If a T cell defect is suspected, the initial test for T cell function is a lymphocyte proliferation assay. Newborns show lymphoproliferation to nonspecific stimuli, such as the mitogen phytohemagglutinin or anti-CD3, but not to most antigens, because of lack of exposure. Thus, the lymphoproliferative response to mitogens is the primary test for evaluating T cell function in newborns. (See "Laboratory evaluation of the immune system", section on 'Response to mitogens'.)

Advanced studies include:

Additional flow cytometry studies – Flow cytometry is also used to evaluate for specific defects in T cell, B cell, and phagocyte function, as well as for evaluation of T and NK cell cytotoxicity. These tests are reviewed in greater detail separately. (See "Flow cytometry for the diagnosis of inborn errors of immunity".)

Assays of TLR function – Whole-blood assays to evaluate innate Toll-like receptor (TLR) function by measurement of cytokine production [27] are useful in children who lack innate responses (eg, lack of CRP elevation despite severe infection) and are commercially available at specialty labs. They can detect infants with TLR pathway defects (eg, IL-1 receptor associated kinase 4 [IRAK-4] or myeloid differentiation primary response protein 88 [MyD88] deficiency). (See 'Other defects in the innate immune system' below.)

Chromosomal testing – Testing for increased chromosomal breakage, cell-cycle, or telomere length analysis. (See "Dyskeratosis congenita and other telomere biology disorders", section on 'Laboratory testing and bone marrow' and "Nijmegen breakage syndrome", section on 'Diagnosis' and "Laboratory evaluation of the immune system", section on 'Chromosomal instability assays for radiation-sensitive patients'.)

Newborn screening — T cells are released from the neonatal thymus gland in large quantities, thus accounting for the high numbers of circulating lymphocytes in newborn and infant blood. T cells make up almost 50 percent of the lymphocytes in the first year of life [28-30]. Circulating T cells in the infant's blood (including newborn heel stick blood) can be estimated by measuring TRECs, a byproduct of thymic production of newly formed T cells [31,32]. Premature or low-birthweight newborns may have low TRECs that normalize with repeat testing. Not all severe IEI are identified by newborn screening (eg, bare lymphocyte syndrome; hemophagocytic lymphohistiocytosis [HLH]; immune dysregulation, polyendocrinopathy, enteropathy, X-linked [IPEX]) [33]. (See "Newborn screening for inborn errors of immunity", section on 'Screening for SCID and other T cell defects'.)

In addition to TREC screening, some countries and municipalities perform kappa-deleting recombination excision circle (KREC) screening on heel stick blood to estimate B cells, enhancing diagnosis of some forms of SCID [34]. TREC and KREC tests may be particularly useful in locales where flow cytometry is not available. (See "Newborn screening for inborn errors of immunity", section on 'Screening for B cell defects'.)

The approach to evaluating an infant with an abnormal (low) TREC test on newborn screening is discussed in detail separately. (See "Newborn screening for inborn errors of immunity", section on 'Interpreting TREC results' and "Newborn screening for inborn errors of immunity", section on 'Follow-up testing'.)

SPECIFIC DISORDERS — Once an immunodeficiency is suspected, the next step is to determine whether the immunodeficiency is likely to be the normal physiologic susceptibility of a newborn/young infant enhanced by additional factors (eg, prematurity, blood loss due to phlebotomy or surgery) that cause a secondary (acquired) immunodeficiency, or an inborn error of immunity (IEI) due to an underlying genetic defect that alters the function of the immune system. The clinical features of each type of immunodeficiency are reviewed below, and examples of the most common causes of immunodeficiency in this age group are shown in the table (table 1). Algorithms have been published for the diagnosis of less common immunodeficiencies [35].

Distinct immunity of the normal newborn — The immune system changes with the age of a person (ie, immune ontogeny). Many parts of the immune system in the healthy newborn are distinct because it is designed to mediate the transition from intrauterine to outside life. These differences lead to a higher risk of infection during the newborn period [6]. The development of the adaptive immune system is reviewed in greater detail separately. (See "Normal B and T lymphocyte development".)

The antibody response to polysaccharide vaccines is poor, although response to protein antigens is intact. Maternal IgG is present at birth and wanes over several months (IgG half-life is approximately 30 days), with a gradual maturation of B cells to plasma cells capable of synthesizing immunoglobulins in the infant (figure 1). This leads to physiologic hypogammaglobulinemia of infancy, with IgG levels <400 mg/dL from approximately three to six months of age. Infant IgM and IgA are also low by adult standards, although breastfed infants receive local secretory IgA from breast milk. Transient hypogammaglobulinemia of infancy is reviewed in greater detail separately. (See "Transient hypogammaglobulinemia of infancy".)

Secondary immunodeficiency — Various secondary factors can enhance the immunodeficiency of infancy. In the newborn, a secondary (acquired) immunodeficiency is usually less severe than an IEI, and the defect(s) correct(s) over time. However, similar to an IEI, it may be accompanied by infection, growth failure, cytopenias, or organ dysfunction. Examples of factors that can cause secondary immunodeficiency include prematurity, hydrops fetalis, blood loss (with resultant hypogammaglobulinemia) due to surgery or frequent phlebotomy, maternal factors/in utero exposures, use of immunosuppressive agents, biochemical abnormalities, environmental exposures, infections, and miscellaneous disorders. The factors most pertinent in newborns and young infants are mentioned here.

Prematurity — Premature infants have immune defects in proportion to their degree of immaturity [36-42]. Thus, it can be difficult to distinguish a premature infant with IEI from an infant who is only premature, unless there is a positive family history. Indications for an immune evaluation for IEI in a premature infant include infection with unusual pathogens or failure to respond to conventional therapies for infection. (See 'Referral' above.)

Compared with the term infant, the preterm infant demonstrates fragile skin prone to breakage and severely decreased mucosal barriers (particularly in the gut), moderate-to-severe hypogammaglobulinemia, lower lymphocyte counts, weaker proinflammatory/T helper cell type 1 (Th1) polarizing cytokine responses, and lower plasma complement and antimicrobial protein/peptide levels, rendering the preterm infant particularly susceptible to infection. Very small premature newborns may have profound lymphopenia that is identified during newborn screening. In addition, the premature infant's antibody response to antigenic challenge, such as polysaccharide antigen-based vaccines, is blunted compared with the term infant [38,39]. Distinct innate immune function of the preterm gut, including a hyperinflammatory response to endotoxin in the gut, may contribute to the risk of necrotizing enterocolitis.

Physiologic hypogammaglobulinemia appears earlier, is more profound, and lasts longer in the premature infant due to a reduced level of transplacental transfer of maternal IgG at birth and delayed acquisition of endogenous IgG synthetic capacity: At 28 weeks of gestation, fetal IgG is less than 50 percent of the maternal concentration [36,39,40,43,44]. Hypogammaglobulinemia in the preterm infant may be aggravated by illness with accelerated IgG catabolism (eg, protein-losing enteropathy, exudative skin disorders, nephrotic syndrome) or blood loss from frequent blood draws or surgery. Infants with neonatal hypogammaglobulinemia, particularly premature infants, may be diagnosed with transient hypogammaglobulinemia of infancy after age six months. (See 'Immunoglobulin loss' below and "Transient hypogammaglobulinemia of infancy".)

Immunoglobulin loss — Neonatal hypogammaglobulinemia can be caused by immunoglobulin loss into the gastrointestinal tract, urine, thorax, peritoneum, or skin [45-49]. Peripheral edema and marked hypoalbuminemia are the usual presenting features. Associated features are anemia, hypoalbuminemia, and lymphopenia. Gastrointestinal loss is most common, secondary to intestinal lymphangiectasia. Other causes include injury to lymphatic vessels during cardiac surgery, particularly the Fontan procedure for single ventricle repair; prolonged diarrhea; exudative enteropathy; allergic gastroenteropathy; or protein-calorie malnutrition [45]. (See "Protein-losing gastroenteropathy".)

Blood loss as a result of surgery or frequent blood draws can also result in hypogammaglobulinemia, especially in the premature infant. (See 'Prematurity' above.)

Maternal factors — Maternal factors that can affect immune function during the neonatal period and early infancy include maternal hypogammaglobulinemia, immunosuppressive medications used in the mother during pregnancy, and perinatal complications such as preeclampsia, eclampsia, hypertension, placenta praevia, or placental abruption. These factors can lead to lower levels of IgG transferred to the newborn or placental transfer of residual drug levels that can affect the neonate.

Maternal immunodeficiency – Untreated maternal hypogammaglobulinemia, notably common variable immunodeficiency, will result in profound neonatal hypogammaglobulinemia due to lack of transplacental transfer of maternal IgG [50]. Most of these infants are not ill and develop normal immunoglobulin levels by six months of age, but they are susceptible to early-onset tetanus, pertussis, Haemophilus influenzae, and pneumococcal illness. Thus, immune globulin therapy should be administered during pregnancy in mothers with antibody deficiency, as it takes months to achieve the protective IgG levels in the mother and infant [51].

Maternal autoimmune disease – Maternal autoimmune neutropenia can result in neonatal neutropenia due to passage of maternal autoantibodies across the placenta. This type of neutropenia is usually mild.

Isoimmune neutropenia of infancy is not uncommon and, analogous to Rh sensitization, occurs when the mother develops an antibody to one or more of her unborn infant's leukocyte antigens inherited from the father that she does not share. Isoimmune neutropenia is usually moderate to severe. These types of neutropenia typically resolve in 12 to 15 weeks. (See "Immune neutropenia", section on 'Neonatal isoimmune (alloimmune) neutropenia' and "Immune neutropenia", section on 'Autoimmune neutropenia'.)

Immunosuppressive drugs in the mother – In utero exposure to immunosuppressive medications given to the mother, such as glucocorticoids, purine antagonists such azathioprine, and rituximab (monoclonal antibody against CD20 on B cells), can affect perinatal immunity and may lead to lymphopenia resulting in detection on newborn screening due to a low number of kappa-deleting recombination excision circles (KRECs) and/or T cell receptor excision circles (TRECs) [52-55]. Tumor necrosis factor (TNF) blocking agents may reduce immunity to mycobacteria and are associated with neutropenia in the neonate [56]. Hypogammaglobulinemia that results from maternal medications is rarely severe. (See "Safety of rheumatic disease medication use during pregnancy and lactation" and "Drug-induced neutropenia and agranulocytosis", section on 'Drug-induced neutropenia' and "Secondary immunodeficiency induced by biologic therapies".)

Maternal disorders leading to fetal growth restriction – Fetal growth restriction, which can be caused by various maternal factors such as severe hypertension, hematologic or autoimmune disorders, pulmonary disease, diabetes, malnutrition, smoking, or substance abuse, is associated with impaired immune function. Newborns with severe intrauterine growth retardation (IUGR) have low T cell numbers at birth and a higher subsequent risk of infection [17]. (See "Fetal growth restriction (FGR) and small for gestational age (SGA) newborns", section on 'Impaired immune function' and "Fetal growth restriction: Evaluation".)

Maternal infection with transmission to the fetus or newborn – Infection during pregnancy can result in intrauterine infection (eg, TORCH [toxoplasmosis, syphilis, rubella, cytomegalovirus (CMV), herpes simplex], varicella, and human immunodeficiency virus [HIV] infections) or tuberculosis (TB) that causes mild-to-severe immunodeficiency. Intrauterine infection with CMV can result in an illness resembling severe combined immunodeficiency (SCID), and rubella infection can resemble hyperimmunoglobulin M syndrome (HIGM) [57]. (See "Overview of TORCH infections" and "Tuberculosis disease (active tuberculosis) in pregnancy" and "Tuberculosis infection (latent tuberculosis) in pregnancy".)

Perinatal maternal infection, including HIV, herpes simplex virus (HSV), group B Streptococcus, TB, or varicella, can be transmitted to the newborn infant at birth, resulting in a variable secondary immunodeficiency, including neutropenia and cellular immunodeficiency [58].

Other maternal illnesses – Maternal hypertension may result in neonatal neutropenia that is usually mild. Maternal diabetes and alcohol use disorder are associated with DiGeorge syndrome [17,59,60].

Maternal malnutrition – Malnutrition in the mother, as well as subsequently in the infant, can lead to a spectrum of immune defects [61,62].

Infection — Infections may cause secondary immunodeficiency or immune dysregulation in the neonate:

CMV, varicella-zoster virus (VZV), HIV – These viral infections are discussed in greater detail separately. (See "Congenital cytomegalovirus infection: Clinical features and diagnosis" and "Varicella-zoster infection in the newborn" and "Pediatric HIV infection: Classification, clinical manifestations, and outcome".)

SARS-CoV-2:

Coronavirus disease 2019 (COVID-19) – COVID-19 due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is rare in neonates (0.5 to 2 percent), mostly transmitted through family members (vertical transmission only in 2 to 6 percent of maternal COVID-19 [63]), and presents clinically with fever but is often asymptomatic or less commonly oligosymptomatic (only respiratory distress, tachypnea, rhinorrhea, feeding difficulties, or diarrhea). It does not cause immunodeficiency but, in rare cases, is associated with immune dysregulation (multisystem inflammatory syndrome in neonates [MIS-N]; see below) and a severe/critical course [64-66]. (See "COVID-19: Clinical manifestations and diagnosis in children".)

COVID-19-induced multisystem inflammatory syndrome in neonates (MIS-N) – MIS-N makes up <3 percent of reported cases of MIS in children (MIS-C) [67]. It is probably caused by exposure to maternal antibodies and cytokines rather than primary viral infection in the neonate. In one review of case reports and case series, neonates with MIS presented with coronary dilatation, ventricular dysfunction, anasarca, coagulopathy, hepatic dysfunction, oliguria, gastrointestinal and pulmonary bleeding, pulmonary hypertension, encephalopathy, and seizures [68,69]. Laboratory findings included elevated inflammatory markers, D-dimer, brain natriuretic peptide (BNP), and troponin; thrombocytopenia; and lymphopenia. (See "COVID-19: Multisystem inflammatory syndrome in children (MIS-C) clinical features, evaluation, and diagnosis".)

MIS-N diagnostic criteria are controversial and evolving [70]. The Centers for Disease Control and Prevention (CDC) case definition for MIS-C cannot be applied to neonates/preterm newborns, as they may not manifest fever or a prior history of infection. SARS-CoV-2 IgG titers are probably maternal and may not indicate active maternal infection (eg, in vaccinated mothers).

Inborn errors of immunity — IEI are categorized by the compartment(s) of the immune system that is affected [10]. Host defense in humans consists of the adaptive immune system, which includes T cells (cellular immunity) and B cells/antibodies (humoral immunity), and the innate immune system, which consists of physical barriers, serum proteins (eg, complement), immune cells (eg, phagocytes and natural killer [NK] cells), and several other components. The types and sites of infections, as well as associated features, vary depending upon which of these compartments are involved (table 2) and the specific genetic defect. (See "Inborn errors of immunity (primary immunodeficiencies): Classification" and "The adaptive cellular immune response: T cells and cytokines" and "The adaptive humoral immune response" and "An overview of the innate immune system".)

Antibody deficiencies — Antibody deficiencies (table 3) typically do not present in the first three months of life, even in the case of congenital agammaglobulinemia, because of the presence of transplacental maternal IgG. However, the diagnosis can be made prenatally in families with a history of agammaglobulinemia by genetic testing or assaying B cells on a fetal blood sample. They characteristically lead to recurrent, often severe, upper and lower respiratory tract infections (eg, otitis media, sinusitis, and pneumonia) with encapsulated bacteria (eg, Streptococcus pneumoniae, H. influenzae) (table 2). Common associated findings in infants include poor growth/failure to thrive, recurrent fevers, and chronic diarrhea. (See "Primary humoral immunodeficiencies: An overview", section on 'Presentation of humoral immunodeficiency' and "Agammaglobulinemia".)

Cellular immunodeficiencies — Infants with cellular immunodeficiency have deficiencies of both T cell immunity and antibody immunity (combined immunodeficiency [CID]). They typically present in early infancy due to the defect in cellular immunity, particularly those with a severe defect. However, the antibody deficiency is initially masked by transplacental IgG, and the infant does not become hypogammaglobulinemic until after the third month of life, unless there is immunoglobulin loss through the gastrointestinal tract or through the skin or lower levels due to prematurity (see 'Immunoglobulin loss' above and 'Prematurity' above). Many different genetic defects can result in CID, which are divided into severe and less severe groups [10].

Severe combined immunodeficiencies — Patients with profound, life-threatening defects are labeled as having a "severe combined immunodeficiency" (SCID) (table 4). All of the distinct genetic forms of SCID are characterized by severe cellular and antibody deficiency. Most affected infants appear normal at birth but, if untreated, develop severe infections with organisms that include viruses, bacteria, and fungi within the first few months of life (table 2). Severe complications can follow immunization with routine live-attenuated vaccines, especially Bacille Calmette-Guérin (BCG) and rotavirus vaccine as these are given within the first weeks of life. Associated findings include chronic diarrhea and failure to thrive. A few infants manifest graft-versus-host disease (GVHD) as a result of transplacental passage of alloreactive maternal T cells or inadvertent receipt of viable lymphocytes from a blood transfusion. Manifestations of acute GVHD include maculopapular rash, vomiting, and diarrhea. Other reasons to suspect SCID are a low lymphocyte count on a routine blood count or a chest radiograph showing no thymic shadow. SCID is reviewed in greater detail separately. (See "Severe combined immunodeficiency (SCID): An overview" and "Severe combined immunodeficiency (SCID): Specific defects" and "Clinical manifestations, diagnosis, and grading of acute graft-versus-host disease".)

Inheritance of SCID can be X linked or autosomal recessive. A family history of the disease is often negative because new mutations are common. Early diagnosis can be established by prenatal tests of fetal blood, by neonatal TREC screening, or by recognition of early manifestations and confirmation by immunologic and genetic testing. Characteristic laboratory features on initial screening studies include profound lymphopenia (total lymphocyte count <1500 cells/microL) with low T cells and absent antibody responses to vaccine antigens if the infant has been immunized. Immunoglobulin synthesis is absent or minimal, but hypogammaglobulinemia is sometimes masked by the presence of transplacental maternal IgG, particularly in the first month of life. Evaluation that includes immune cell enumeration by flow cytometry and additional advanced studies is usually performed by, or in consultation with, an immunology specialist. The more advanced laboratory studies and diagnostic evaluation of SCID are reviewed in detail separately. (See 'Referral' above and "Severe combined immunodeficiency (SCID): An overview" and "Approach to the child with recurrent infections" and "Laboratory evaluation of the immune system".)

Referral to a tertiary care center for genetic diagnosis, tissue typing, and consideration of hematopoietic cell transplantation (HCT) is necessary when the diagnosis of SCID is suspected. Treatment, both before and after confirmation of diagnosis, is discussed in detail separately. (See 'Initial management prior to definitive diagnosis' above and "Severe combined immunodeficiency (SCID): An overview", section on 'Measures to prevent initial infections' and "Hematopoietic cell transplantation for severe combined immunodeficiencies".)

Combined immunodeficiencies — Patients with less severe forms are labeled as having a "combined immunodeficiency" (CID) with or without syndromic or other associated features (table 4 and table 5). CIDs may affect those patients with significant but less severe T cell defects than in the SCID syndromes presented above. Most have delayed onset of severe infections, even far beyond infancy, and their antibody deficiencies are masked by transplacental maternal antibody for the first three months of life, unless there is immunoglobulin loss through the gastrointestinal tract or through the skin. However, many of these infants have characteristic clinical and laboratory features that allow a clinical diagnosis in the first months of life. (See "Combined immunodeficiencies: An overview" and "Wiskott-Aldrich syndrome" and "Ataxia-telangiectasia" and "Syndromic immunodeficiencies".)

The most common CIDs that present in the newborn period, or are identified by newborn screening, and their identifying features are as follows (table 1):

DiGeorge syndrome – The immunodeficiency in these patients can range from recurrent sinopulmonary infections to a SCID phenotype (complete DiGeorge). Associated features that can be identified in the newborn period include conotruncal cardiac anomalies, hypocalcemia, hypoplastic thymus, and craniofacial abnormalities. (See "DiGeorge (22q11.2 deletion) syndrome: Clinical features and diagnosis".)

Wiskott-Aldrich syndrome (WAS) – WAS is an X-linked disorder characterized by thrombocytopenia, small platelets, early onset of eczema, and a CID. Infants with WAS may present with petechiae, melena, intracranial bleeding, soft tissue bruising, and/or bleeding after circumcision. The T cell deficiency may result in Pneumocystis infection, meningitis, viral infections, or thrush. (See "Wiskott-Aldrich syndrome".)

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) – IPEX is a monogenic autoimmune disease caused by forkhead box P3 (FOXP3) gene mutations leading to T regulatory cell dysfunction and thus multiple autoimmune manifestations. HCT is considered the only curative option. Approximately half of patients with IPEX are diagnosed in the neonatal period with the classical triad of enteropathy, type 1 diabetes mellitus, and eczema. Later, failure to thrive is a hallmark of the disease. Other manifestations include nephropathy (autoimmune or secondary to malnutrition and medications), hemolytic anemia, autoimmune thyroiditis, and hepatitis [71]. (See "IPEX: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked".)

Phagocyte defects — Susceptibility to infection from phagocytic dysfunction (table 6) ranges from mild, recurrent skin infections to overwhelming, fatal, systemic infection (table 2). Affected patients are more susceptible to bacterial (eg, Staphylococcus aureus, Pseudomonas aeruginosa, Nocardia asteroides, Salmonella typhi) and fungal (eg, Candida and Aspergillus species) infections but have a normal resistance to viral infections. Response to nontuberculous mycobacteria (NTM) may also be abnormal, particularly in patients with chronic granulomatous disease (CGD). The most common sites of infection are the respiratory tract and skin. Tissue and organ abscesses also occur. Other frequent manifestations include abnormal wound healing, dermatitis/eczema, and stomatitis. Many patients have growth failure. Most patients are diagnosed in infancy due to the severity of the infection or the unusual presentation of the organism. (See "Primary disorders of phagocyte number and/or function: An overview".)

The following are the most common phagocytic defects that present during the newborn period (table 1):

Chronic granulomatous disease – CGD is a genetically heterogeneous disease characterized by life-threatening infection with specific bacteria and fungi leading to the formation of granulomata throughout the body. Clinical manifestations include neonatal-onset fever, growth failure, pneumonia, abnormal wound healing, diarrhea, and pustular rash. The X-linked form can present in infancy [72]. In one cohort (n = 35), disease onset was in infancy in 23 percent and in the neonatal period in 8.5 percent, with three neonates presenting with an hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS) like picture [73]. Infectious manifestations included pulmonary aspergillosis, hepatic abscesses, and other infections of the lung, bone, and skin. Autosomal (non-X-linked) variants of CGD exist. Thus, females can be affected. (See "Chronic granulomatous disease: Pathogenesis, clinical manifestations, and diagnosis".)

Congenital neutropenia – The congenital neutropenias start at or around birth and are due to many genetic defects that cause increased neutrophil apoptosis or primary bone marrow failure. They include severe congenital neutropenia (absolute neutrophil count <200 cells/microL; Kostmann syndrome and Jagunal homolog 1 [JAGN1] deficiency are two subtypes [74,75]), cyclic neutropenia, and Shwachman-Diamond syndrome. Patients present with oropharyngeal problems, otitis media, respiratory infections, cellulitis, and skin infections, most often due to staphylococci and streptococci. Sepsis can occur. Some patients have dysmorphic features or other associated physical findings that suggest a specific diagnosis. (See "Congenital neutropenia".)

Toll-like receptor (TLR) pathway defects – Interleukin (IL) 1 receptor associated kinase 4 (IRAK-4) deficiency and myeloid differentiation primary response protein 88 (MyD88) deficiency are due to defects in innate TLR pathway immune signaling. These disorders are associated with impaired microbe-induced cytokine induction and present as recurrent and/or severe pyogenic infections. The first bacterial infection occurred during the neonatal period in approximately 30 percent of patients with IRAK-4 deficiency [76]. Infections with S. pneumoniae, Staphylococcus spp, and P. aeruginosa are most frequent in these patients. Clinical and laboratory signs of inflammation develop slowly in these patients, even in cases of severe infection. Weak inflammatory responses, including modest or absent CRP production and low-grade fever despite severe infection, provide a further clue to these defects. (See "Toll-like receptors: Roles in disease and therapy", section on 'MyD88/IRAK4/IRAK1 deficiency'.)

Leukocyte-adhesion deficiency (LAD) – The LADs are a group of rare disorders characterized by recurrent bacterial infections and poor wound healing due to defects in neutrophil adhesion and movement. A characteristic feature is delayed separation of the umbilical cord. Other features include severe infections of the skin, respiratory tract, bowel, and perirectal area, with lack of pus formation at the site of infection. (See "Leukocyte-adhesion deficiency".)

Complement factor deficiencies — New inherited disorders of complement components (table 7) are rarely identified in neonates without a family history of a complement deficiency (table 1). Testing for a complement defect is indicated in neonates with a positive family history and severe infections due to encapsulated bacteria such as streptococci, meningococci, or H. influenzae type B (table 2) [77]. (See "Overview and clinical assessment of the complement system" and "Inherited disorders of the complement system".)

Other defects in the innate immune system — Additional defects in the innate immune system (table 8) include NK cell deficiency syndromes and defects in cytokines and inflammatory mediators released by innate immune cells (table 1). Examples include:

NK cell and cytotoxic T cell deficiency syndromes – Disorders due to NK cell or cytotoxic T cell deficiency are rare and are characterized primarily by severe, recurrent, or atypical infections with herpes viruses and papilloma viruses. Some cause familial hemophagocytic lymphohistiocytosis (FHL) or HLH. They are classified as either classical NK cell deficiency, lacking NK cells, or functional NK cell deficiency, with normal numbers of NK cells but absent or severely decreased NK cell function. (See "NK cell deficiency syndromes: Clinical manifestations and diagnosis".)

Autoinflammatory disease – Some autoinflammatory diseases are caused by excess IL-1 (due to dysregulation of inflammasomes) or type I interferon (IFN). Neonatal-onset persistent fever and exanthemas in the absence of infection are characteristic and a pseudo-TORCH presentation (interferonopathies) with basal ganglia calcifications. Targeted treatment with monoclonal antibodies (IL-1 blocking) or Janus kinase (JAK) inhibitors is available [13]. (See "The autoinflammatory diseases: An overview".)

Deficiencies in type 1 IFN signaling – Susceptibility to life-threatening infections with viruses, including influenza virus, HSV-1, SARS-CoV-2, and live-viral vaccines (variants in TLR3, UNC93B1, TICAM1, TBK1, IRF3, IRF7, IFNAR1, and IFNAR2). (See "Inborn errors of immunity (primary immunodeficiencies): Overview of management".)

Mendelian susceptibility to mycobacteria disease (MSMD) – MSMD is caused by defects in the IFN-gamma-IL-12 pathway and/or supporting accessory pathways. The hallmark of MSMD is the early onset of potentially overwhelming infection with BCG, other environmental NTM, other intracellular pathogens (nontyphoid Salmonella), or viral infection. Neonates and infants may present with impressive generalized cutaneous lesions, abdominal tenderness, and hepatosplenomegaly. BCG infections will present within weeks or months of BCG immunization. Disease severity is variable. (See "Mendelian susceptibility to mycobacterial diseases: An overview" and "Mendelian susceptibility to mycobacterial diseases: Specific defects".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inborn errors of immunity (previously called primary immunodeficiencies)".)

SUMMARY AND RECOMMENDATIONS

Immunity of the fetus and the newborn – The normal newborn's immune system is anatomically intact but antigenically naïve and functionally distinct, with lower inflammatory and T helper cell type 1 (Th1) responses compared with older persons, potentially leaving the infant more vulnerable to infection. However, most persons survive the newborn period without illness due to intact innate immunity, adaptive defense mechanisms, and maternal immunoglobulin G (IgG) transferred through the placenta. (See 'Overview of immunity of the fetus and newborn' above.)

Risk factors for immunodeficiency and infection – Factors that increase the likelihood of giving birth to an infant with an immunodeficiency include genetic factors and consanguinity leading to inborn errors of immunity (IEI; also called primary immunodeficiencies [PIDs]) and multiple other factors that can lead to secondary immunodeficiency (eg, immaturity, malnutrition, infection, maternal illness, medications). Infections may trigger immune dysregulation. (See 'Risk factors for immunodeficiency and infection' above and 'Infection' above.)

Categories of IEI – Categories of IEI that may present at birth or during the first three months of life include defects in innate immunity such as neutropenic disorders, phagocyte defects, complement deficiencies, and pattern recognition receptor (eg, Toll-like receptor [TLR] pathway) defects, as well as antibody deficiencies, cellular (T cell) deficiencies, and immunoregulatory disorders (table 2). (See 'Inborn errors of immunity' above and "Inborn errors of immunity (primary immunodeficiencies): Classification".)

Initial evaluation – Initial evaluation in the newborn/young infant includes a complete blood count (CBC) with differential and immunoglobulin levels. Laboratory features suggestive of immunodeficiency include abnormal newborn severe combined immunodeficiency (SCID) screening tests using dried blood spots (low T cell receptor excision circles [TRECs] indicating severe lymphopenia), abnormal CBC (lymphopenia, neutropenia, thrombocytopenia), abnormal liver function tests (LFTs), hypoalbuminemia, and low immunoglobulin levels. Interpretation of studies requires age-adjusted reference/normal ranges and must take into account certain limitations of these studies that are unique to newborns and young infants due the developmental stage of their immune systems. (See 'Laboratory evaluation' above and "Newborn screening for inborn errors of immunity" and "Laboratory evaluation of the immune system".)

Clinical features suggestive of immunodeficiency – Features suggestive of immunodeficiency include family history of immunodeficiency; postnatal infection that is unusual with regard to infectious agent, duration, complications, and response to treatment; heart or lung disease; hepatosplenomegaly; desquamating rash; chronic diarrhea; failure to thrive; syndromic appearance; and/or abdominal distention. (See 'Clinical features suggestive of immunodeficiency' above.)

Initial management prior to definitive diagnosis – Several precautions are commonly undertaken prior to exact diagnosis or therapy if there is clinical or laboratory suspicion of a severe immunodeficiency. These measures, which are all discussed in greater detail separately, include:

Protective isolation to limit exposure to infection. (See "Inborn errors of immunity (primary immunodeficiencies): Overview of management", section on 'Isolation measures'.)

Avoidance of live vaccines. (See "Immunizations in patients with inborn errors of immunity", section on 'Live vaccines'.)

Avoidance of blood transfusions, if possible, with use of irradiated, leukoreduced, cytomegalovirus (CMV) negative blood products if transfusion is needed. (See "Red blood cell transfusion in infants and children: Selection of blood products", section on 'Red blood cell products' and "Inborn errors of immunity (primary immunodeficiencies): Overview of management", section on 'Caution with blood products'.)

Use of sterile formula (eg, ready-to-feed or 2x concentrated) instead of breast milk if there is confirmed maternal human immunodeficiency virus (HIV) infection or if the mother is CMV seropositive. (See "Intrapartum and postpartum management of pregnant women with HIV and infant prophylaxis in resource-rich settings", section on 'Breastfeeding' and "Severe combined immunodeficiency (SCID): An overview", section on 'Measures to prevent initial infections'.)

Antibody replacement with immune globulin, if needed. (See "Immune globulin therapy in inborn errors of immunity".)

Prophylaxis against infection, including antimicrobial prophylaxis and respiratory syncytial virus (RSV) immunoprophylaxis. (See "Inborn errors of immunity (primary immunodeficiencies): Overview of management", section on 'Prophylactic antimicrobial therapy' and "Severe combined immunodeficiency (SCID): An overview", section on 'Measures to prevent initial infections' and "Respiratory syncytial virus infection: Prevention in infants and children".)

If infections are suspected, appropriate microbiologic studies should be obtained and empiric treatment initiated promptly while awaiting culture results. (See 'Laboratory evaluation' above.)

When to refer – Referral to a tertiary care center is recommended for advanced diagnosis and treatment, including hematopoietic cell transplantation (HCT). (See 'Referral' above.)

Identifying the specific etiology – Once an immunodeficiency is suspected, the next step is to determine whether the immunodeficiency is the normal physiologic susceptibility of a newborn/young infant enhanced by additional factors (eg, prematurity, blood loss due to phlebotomy or surgery) that cause a secondary (acquired) immunodeficiency or an IEI due to an underlying genetic defect that alters the function of the immune system. (See 'Specific disorders' above.)

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Topic 16608 Version 12.0

References

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