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 primary and secondary immunodeficiencies. It also covers initial management and when to refer to an immunology specialist. 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 NEWBORN — The placenta has a microbiome, and the fetal immune system may already be exposed to some microbes before birth [1,2]. Fetal immune cells (eg, dendritic cells) respond to maternal, dietary, and microbial antigens but are biased towards suppression of inflammation [3]. 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 [4]. Reduced proinflammatory responses may facilitate the transition from the intrauterine environment to the outside world, including colonization with the commensal microbiome [5,6]. 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 primary immunodeficiency (PID). PIDs are collectively relatively common, occurring in up to approximately 1 in every 1200 individuals [7,8]. The incidence of severe combined immunodeficiency (SCID) and other PIDs are reviewed in detail separately in the appropriate topics. (See "Newborn screening for primary immunodeficiencies" and "Severe combined immunodeficiency (SCID): An overview", section on 'Epidemiology'.)
RISK FACTORS FOR IMMUNODEFICIENCY AND INFECTION — Factors that increase the likelihood of giving birth to an infant with an immunodeficiency include genetic factors leading to primary immunodeficiencies (PIDs) and multiple other factors that can lead to secondary immunodeficiency (eg, immaturity, infection, maternal illness, medications, anatomic abnormalities).
Factors that increase risk of immunodeficiency in a newborn include:
●Family history of immunodeficiency or early death, consanguinity, ethnicity with a high incidence of PID (eg, severe combined immunodeficiency [SCID] in Navajos, ataxia-telangiectasia [AT] in Amish, and Bloom syndrome in Ashkenazi Jews)
●Maternal infection (chronic, acute, perinatal), hypertension, autoimmune disease, immunodeficiency, immunosuppressive medications (eg, antimetabolites)
●Other factors resulting in preterm delivery or a small for gestational age infant [9]
●Genetic aberrations (eg, syndromic diseases)
The most predictive factor for a PID is a family history of immunodeficiency, either confirmed or suspected, leading to early death or recurrent/chronic illness in one or more family members [10]. Certain ethnic groups with founder mutations (eg, Navajo American Indians) or countries or populations where there is a high incidence of consanguinity (Amish, many Arab countries) have a higher incidence of immunodeficiency. (See "Approach to the child with recurrent infections", section on 'Clinical features suggestive of a primary immunodeficiency'.)
Maternal factors relevant to an increased risk of immunodeficiency in the infant and prematurity are discussed in greater detail below. (See 'Maternal factors' below and 'Prematurity' below.)
In addition to determining the presence of features suggestive of 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. These factors include [11]:
●Maternal illness or infection
●Maternal immunosuppressive medication taken during pregnancy
●Inadequate prenatal care
●Preterm birth
●Difficult delivery with prolonged exposure to nonsterile secretions
●Male sex
●A nonimmunologic problem that endangers the infant's health (severe cardiac or other anatomic defect, genetic disorder, metabolic disease)
Maternal factors during pregnancy that may contribute to increased infection risk in the newborn include nutritional status of the mother (eg, obesity, malnutrition, mineral and vitamin deficiencies); chronic or acute maternal infection, such as human immunodeficiency virus (HIV) infection; other maternal illnesses (eg, autoimmunity; endocrinopathies; cardiovascular, lung, or kidney disease) and their treatment (including immunosuppressive medications that may cross the placenta); maternal habits (tobacco use, alcoholism, or other substance abuse); and inadequate prenatal care [12]. Perinatal maternal colonization with group B streptococci, for example, may predispose to neonatal sepsis or prematurity. Inadequate maternal immunization may place the newborn at risk for infections such as influenza, pertussis, or varicella [13]. (See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates".)
Complications and procedures related to preterm birth that are associated with an increased risk of infection include 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. (See "Short-term complications of the preterm infant".)
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 — In addition to the risk factors detailed above, a neonate at birth or in the first months of life may exhibit signs and symptoms suggestive of immunodeficiency. These include:
●Infection at any site
●Failure to thrive
●Chronic diarrhea
●Symptomatic infection due to live vaccines (eg, rotavirus, Bacille Calmette-Guérin [BCG], oral polio)
●Heart or lung disease (low oxygen saturation suggests one of these problems)
●Congenital asplenia [14]
●Mucosal abnormalities such as thrush, mouth sores, and ulcerations
●Cutaneous rashes, pigmentary abnormalities
●Certain facial or craniofacial anomalies [15,16]
●Petechiae, melena, bleeding
●Lymphadenopathy and/or hepatosplenomegaly
●Syndromic appearance (abnormal facies or habitus)
●Abdominal distension
●Autoimmunity
●Neonatal surgery
●Delayed umbilical cord separation
The presence of any of the features listed above should lead to the suspicion of a primary or secondary immunodeficiency. Measures should be taken to prevent further exposures/infections when one or more of these features are present. Further history taking and 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".)
LABORATORY EVALUATION — Multiple blood tests are available to pinpoint or exclude an immunodeficiency. Initial screening 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 "Laboratory evaluation of the immune system" and "Approach to the child with recurrent infections", section on 'Laboratory evaluation'.)
Primary immunodeficiencies (PIDs) may also be identified on newborn screening. This screening and subsequent evaluation are discussed in greater detail separately. (See 'Newborn screening' below and "Newborn screening for primary immunodeficiencies".)
Initial evaluation — Screening laboratory studies should be conducted by the neonatologist if one or more of the risk factors for immunodeficiency are present. Initial screening in the newborn/young infant includes a complete blood count (CBC) with differential and immunoglobulin levels. Biomarkers of systemic inflammation, such as C-reactive protein (CRP) and interleukin (IL) 6, may give clues as to active infections; however, CRP and IL-6 levels are physiologically increased in the first hours of life. Measuring quantitative immunoglobulin levels (IgG, IgA, IgM, and IgE) is less informative in newborn/young infants 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. 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. (See 'Risk factors for immunodeficiency and infection' above and 'Secondary immunodeficiency' below.)
On the CBC with differential:
●Leukopenia is defined as a white blood cell (WBC) count <4000 cells/microL. Leukocytosis (WBC >12,000 cells/microL) is sometimes noted: Both leukopenia and leukocytosis suggest the presence of infection.
●Lymphopenia is defined as an absolute lymphocyte count <2500 cells/microL in infants and suggests a T and/or B cell defect. The total lymphocyte count, as measured on a CBC with differential, normally exceeds 5000 cells/microL at birth.
●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 in the newborn can be caused by sepsis, necrotizing enterocolitis, maternal autoimmune disorders or medications, or primary phagocyte disorders [17]. However, benign neutropenia unassociated with infection or other illness is common in the newborn period (eg, neonatal isoimmune neutropenia) (see "Congenital neutropenia"). This neutropenia usually resolves within days.
●Eosinophilia may suggest allergy or immune dysregulation.
●Thrombocytopenia may be directly due to PID (eg, in Wiskott-Aldrich syndrome [WAS]) or associated with infection (eg, fungal or cytomegalovirus [CMV] infection). Thrombocytosis suggests chronic inflammation.
Age-adjusted reference ranges are necessary 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'.)
Additional screening tests conducted to exclude systemic disease (eg, metabolic disorders, renal disease, malnutrition, protein loss) and evaluate for 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)
●CRP
●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 screening is discussed in greater detail separately. (See "Approach to the child with recurrent infections", section on 'Laboratory evaluation'.)
Intermediate studies — Abnormalities in one or more of the immunologic screening studies should prompt additional evaluation. Lymphocyte-subset analysis (lymphocyte enumeration by flow cytometry) and 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'.)
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 provide guidance as to the nature of the T cell defect. CD45 and its isoforms are additional markers that can be used to indicate 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'.)
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'.)
Flow cytometry is also used to evaluate for specific defects in T cell, B cell, and phagocyte function. These tests are reviewed in greater detail separately. (See "Flow cytometry for the diagnosis of primary immunodeficiencies".)
Whole-blood assays to evaluate innate Toll-like receptor (TLR) function by measurement of cytokine production [18] 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 (IL-1 receptor associated kinase 4 [IRAK-4], myeloid differentiation primary response protein 88 [MyD88] deficiency). (See 'Other defects in the innate immune system' below.)
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 [19-21]. Circulating T cells in the infant's blood (including newborn heel stick blood) can be estimated by measuring T cell receptor excision circles (TRECs), a byproduct of thymic production of newly formed T cells [22,23]. A few severe PIDs are not identified by newborn screening (eg, bare lymphocyte syndrome) [24]. (See "Newborn screening for primary immunodeficiencies", 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. This provides additional diagnostic information for some forms of SCID [25]. TREC and KREC tests may be particularly useful in locales where flow cytometry is not available.
The approach to evaluating an infant with an abnormal (low) TREC test on newborn screening is discussed in detail separately. (See "Newborn screening for primary immunodeficiencies", section on 'Interpreting TREC results' and "Newborn screening for primary immunodeficiencies", section on 'Follow-up testing'.)
INITIAL MANAGEMENT PRIOR TO DEFINITIVE DIAGNOSIS — Neonates and young infants suspected of having a severe immunodeficiency should be kept in protective isolation if they are in the hospital or away from other children or adults who are not their primary caregivers if they are at home. In most such patients (including those with severe combined immunodeficiency [SCID] but not necessarily those with severe neutropenia), live vaccines (eg, oral rotavirus, oral poliovirus, Bacille Calmette-Guérin [BCG], intranasal influenza) should be avoided in the patient and their close contacts. If blood products are needed, they should be irradiated, leukodepleted, and cytomegalovirus (CMV) negative. Formulae should be sterile. Breast milk (either via nursing or expressed and bottle fed) is probably safe and is preferable given its multiple benefits, with the notable exception of suspected or confirmed maternal human immunodeficiency virus (HIV) infection. CMV-positive breast milk may transmit CMV infection, which can cause significant disease in infants with severe T cell deficiency such as SCID and should be avoided. (See "Severe combined immunodeficiency (SCID): An overview", section on 'Protective measures'.)
If infections are suspected, appropriate cultures should be obtained and early preemptive treatment initiated even before culture results are available. Prophylactic antibiotics to prevent Pneumocystis infection are recommended if the lymphocyte count is <1500/microL. A permanent line may be placed if multiple blood tests and intravenous antibiotics are needed. (See 'Laboratory evaluation' above.)
Immunoglobulin levels and antibody titers should be measured prior to intravenous immune globulin (IVIG) replacement therapy. However, measurement of antibody titers is not indicated if hypogammaglobulinemia is profound (IgG <100 mg/dL) or if the infant has not been immunized. IVIG is given if there is symptomatic hypogammaglobulinemia with an IgG level <400 mg/dL. Palivizumab is recommended during respiratory syncytial virus (RSV) season, even if the infant is on immune globulin replacement therapy.
REFERRAL — Awareness of potential immunodeficiency is key. Early consultation with a pediatric immunologist is recommended, whenever possible, when an immunodeficiency is suspected in a newborn or young infant. Many immunodeficiencies that present in early infancy are potentially life threatening. The diagnosis and management of primary immunodeficiencies (PIDs) is increasingly complex due to the wide range of defects and heterogeneity of their clinical presentations, the increasing sophistication of their potential evaluation (including whole-exome sequencing), and an increasing number of immunomodulatory modalities.
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 a primary immunodeficiency (PID) 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 [26].
Distinct immunity of the normal newborn — The immune system changes with the age of an individual (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.
Secondary immunodeficiency — Various secondary factors can enhance the immunodeficiency of infancy. In the newborn, a secondary (acquired) immunodeficiency is usually less severe than a PID, and the defect(s) correct(s) over time. However, similar to a PID, 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 [27-33]. Thus, it can be difficult to distinguish a premature infant with PID from an infant who is just premature, unless there is a positive family history. Indications for an immune evaluation for PID 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 [29,30]. 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 [27,30,31,34,35]. 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 go on to develop 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 [36-40]. Peripheral edema and marked hypoalbuminemia are the usual presenting features. 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 [36]. Associated features are anemia, hypoalbuminemia, and lymphopenia. (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 – In mothers with antibody deficiency, immune globulin therapy should be administered in the early stages of pregnancy as it takes months to achieve the protective IgG levels in the mother and infant [41]. Untreated maternal hypogammaglobulinemia, notably common variable immunodeficiency, will result in profound neonatal hypogammaglobulinemia due to lack of transplacental transfer of maternal IgG [42]. 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.
●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 that results in detection of kappa-deleting recombination excision circles (KRECs)/T cell receptor excision circles (TRECs) on newborn screening [43-46]. Tumor necrosis factor (TNF) blocking agents may dangerously affect immunity to mycobacteria and are associated with neutropenia in the neonate [47]. 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".)
●Factors that predispose to preterm birth – Maternal factors that predispose to the birth of a preterm infant include extremes of maternal age, lack of prenatal care, maternal lifestyle (eg, substance abuse and diet), cervical uterine and placental factors, multiple gestation, and heredity (family history of preterm birth). The effects of preterm birth on immune function are discussed above. (See 'Prematurity' above.)
●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, malnutrition, smoking, or substance abuse, is associated with impaired immune function. Newborns with severe intrauterine growth retardation have low T cell numbers at birth and a higher subsequent risk of infection [12]. (See "Infants with fetal (intrauterine) growth restriction", 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) 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) [48]. (See "Overview of TORCH infections".)
Perinatal maternal infection with HIV, herpes simplex virus (HSV), group B Streptococcus, and varicella can be transmitted to the newborn infant at birth, resulting in variable immunodeficiencies, including neutropenia and cellular immunodeficiency [49].
●Other maternal illnesses – Maternal hypertension may result in neonatal neutropenia that is usually mild. Maternal diabetes and alcohol abuse are associated with DiGeorge syndrome [12,50,51].
●Maternal malnutrition – Malnutrition in the mother, as well as subsequently in the infant, can lead to a spectrum of immune defects [52,53].
Primary immunodeficiencies — PIDs are categorized by the compartment(s) of the immune system that is affected. Host defense in humans consists of the adaptive immune system that includes T cells (cellular immunity) and B cells/antibodies (humoral immunity) and the innate immune system that 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 "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 deficiency characteristically leads to recurrent, often severe, upper and lower respiratory tract infections with encapsulated bacteria (eg, Streptococcus pneumoniae, H. influenzae) (table 2). Children usually present with recurrent otitis media, sinusitis, and pneumonia. Common associated findings in children include poor growth/failure to thrive, recurrent fevers, and chronic diarrhea. (See "Primary humoral immunodeficiencies: An overview", section on 'Presentation of humoral immunodeficiency' and "Laboratory evaluation of the immune system", section on 'Initial screening laboratory tests'.)
A newborn infant with hypogammaglobulinemia (serum IgG <400 mg/dL, severe <200 mg/dL) is unusual, even in the face of low or absent B cells, due to the active maternofetal transfer of immunoglobulins, particularly in the last trimester. The most common cause of hypogammaglobulinemia is prematurity with exaggerated physiologic hypogammaglobulinemia. An alternative explanation may be a low maternal IgG level with diminished transplacental IgG passage. In this setting, the infant's immunoglobulin level should be repeated and a maternal IgG level obtained. (See 'Prematurity' above and 'Maternal factors' above.)
Infants with congenital agammaglobulinemias usually have low B cells and absent or very low IgM and IgA and do not become hypogammaglobulinemic until after the third month of life, 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. The presence of a female fetus on ultrasound or chromosome analysis on prenatal blood makes X-linked agammaglobulinemia very unlikely. Routine KRECs testing at the time of birth is a proposed screening procedure. (See "Agammaglobulinemia" and "Newborn screening for primary immunodeficiencies", section on 'Screening for B cell defects'.)
Agammaglobulinemia can be confirmed by the absence of B cells on flow cytometry or identification of a mutated Bruton tyrosine kinase (BTK) gene in X-linked agammaglobulinemia, the most common form of agammaglobulinemia. This evaluation is typically performed by, or in consultation with, an immunology specialist. If the infant is a girl or the BTK gene is normal, a form of autosomal-recessive agammaglobulinemia should be suspected. Prenatal and/or early diagnosis of these disorders can allow cord blood banking (for future gene therapy), early treatment, and genetic counseling. (See "Flow cytometry for the diagnosis of primary immunodeficiencies" and "Agammaglobulinemia".)
Other predominantly antibody deficiencies, such as transient hypogammaglobulinemia of infancy, selective IgA deficiency, IgG subclass deficiency, or common variable immunodeficiency, cannot be identified before birth or in the perinatal period, since B cells are present and the onset of illness is delayed [54]. These patients are generally asymptomatic for the first several months because of transplacental maternal antibody and an intact cellular immune system. These disorders are discussed in greater detail separately. (See "Transient hypogammaglobulinemia of infancy" and "Selective IgA deficiency: Clinical manifestations, pathophysiology, and diagnosis" and "IgG subclass deficiency" and "Common variable immunodeficiency in children".)
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.
CIDs can be the result of many different genetic defects and can be divided into severe and less severe groups:
●Patients with profound, life-threatening defects are labeled as having a "severe combined immunodeficiency" (SCID). (See "Severe combined immunodeficiency (SCID): An overview" and "Severe combined immunodeficiency (SCID): Specific defects".)
●The less severe forms are designated as "combined immunodeficiencies" (CIDs). The latter group includes Wiskott-Aldrich syndrome (WAS), ataxia-telangiectasia (AT), and many of the other syndromic PIDs. (See "Combined immunodeficiencies" and "Wiskott-Aldrich syndrome" and "Ataxia-telangiectasia" and "Syndromic immunodeficiencies".)
Severe combined immunodeficiencies — All forms of SCID are characterized by severe cellular and antibody deficiency. Most affected infants appear normal at birth but go on to 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 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 'Protective measures' and "Hematopoietic cell transplantation for severe combined immunodeficiencies".)
Combined immunodeficiencies — 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 several months after birth. 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".)
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, soft tissue bruising, or bleeding after circumcision. The T cell deficiency may result in Pneumocystis infection, meningitis, viral infections, or thrush. (See "Wiskott-Aldrich syndrome".)
●X-linked hyperimmunoglobulin M syndrome (HIGM) – X-linked HIGM often presents in the first few months of life with increased susceptibility to recurrent sinopulmonary infections and opportunistic infections. Patients may also have chronic diarrhea and failure to thrive. (See "Hyperimmunoglobulin M syndromes".)
●Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) – IPEX is a monogenic autoimmune disease caused by FOXP3 gene mutations leading to T regulatory cell dysfunction and thus multiple autoimmune manifestations. Hematopoietic cell transplantation (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 [55]. (See "IPEX: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked".)
●Ataxia-telangiectasia (AT) – Most patients with AT are asymptomatic for the first several years, but a few neonates have been identified on newborn screening for T cell defects, despite the presence of some T cells. These infants may later have a SCID-like presentation. AT is characterized by an ataxic gait, recurrent sinopulmonary infections, and sensitivity to radiation with genomic instability. Early recognition is imperative to avoid radiation exposure. (See "Ataxia-telangiectasia".)
Phagocyte defects — Susceptibility to infection from phagocytic dysfunction 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) – 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. Other clinical manifestations include growth failure, abnormal wound healing, diarrhea, and infected dermatitis. The X-linked form can present in infancy. 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 different genetic defects that cause primary bone marrow failure. They include severe congenital neutropenia (absolute neutrophil count <200 cells/microL; Kostmann syndrome is one subtype), 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 – 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 [56]. Infections with S. pneumoniae, staphylococcal 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 C-reactive protein (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 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) [57]. (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 include NK cell deficiency syndromes and defects in cytokines and inflammatory mediators released by innate immune cells (table 1). Examples include:
●NK cell deficiency syndromes – Disorders due to NK cell deficiency are rare and are characterized primarily by severe, recurrent, or atypical infections with herpes viruses and papilloma viruses. 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".)
●Mendelian susceptibility to mycobacteria disease (MSMD) – MSMD is caused by defects in the interferon (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
●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 individuals, potentially leaving the infant more vulnerable to infection. However, most individuals survive the newborn period without illness due to innate immunity, other adaptive defense mechanisms, and maternal immunoglobulin G (IgG) transferred through the placenta. (See 'Overview of immunity of the newborn' above.)
●Factors that increase the likelihood of giving birth to an infant with an immunodeficiency include genetic factors and consanguinity leading to primary immunodeficiencies (PIDs) and multiple other factors that can lead to secondary immunodeficiency (eg, immaturity, malnutrition, infection, maternal illness, medications). (See 'Risk factors for immunodeficiency and infection' above.)
●Features suggestive of immunodeficiency include family history of immunodeficiency; postnatal infection that is unusual with regard to infectious agent, duration, complications, 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 screening 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. (See 'Laboratory evaluation' above and "Newborn screening for primary immunodeficiencies".)
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.
●Categories of PID disorders 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 'Primary immunodeficiencies' above.)
●It is prudent to place infants who are suspected of having a severe immunodeficiency under special precautions to limit exposure to infection. In most instances, live vaccines and blood transfusions should be avoided (if needed, blood products should be from a cytomegalovirus [CMV] negative donor, leukodepleted, and irradiated). Prophylactic antibiotics and intravenous immune globulin (IVIG) replacement therapy may also be indicated. Referral to a tertiary center is recommended for advanced diagnosis and treatment, including hematopoietic cell transplantation. (See 'Initial management prior to definitive diagnosis' above.)
●Many immunodeficiencies that present in early infancy are potentially life threatening. The range of PIDs is growing, and the diagnosis and management of these disorders continues to increase in complexity. Early consultation with a pediatric immunologist is highly recommended. (See 'Referral' above.)
