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Recognition of immunodeficiency in the newborn period

Authors: E Richard Stiehm, MD, Tim Niehues, MD, Ofer Levy, MD, PhD
Section Editor: Jennifer M Puck, MD
Deputy Editor: Elizabeth TePas, MD, MS

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jun 2018. | This topic last updated: Sep 27, 2017.

INTRODUCTION — 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) already 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 somewhat reduced function of several immune pathways.
Reduced proinflammatory responses may facilitate the transition from the intrauterine environment to the outside
world, including colonization with the commensal microbiome [4,5]. 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).

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 [6,7]. 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'.)

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".)

The development of the adaptive immune system and normal newborn immunity are discussed in detail
separately. (See "Normal B and T lymphocyte development" and "Immunity of the newborn".)

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

● Other factors resulting in preterm delivery or a small for gestational age infant (eg, antimetabolites)

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 [8]. Certain ethnic groups with
founder mutations (eg, Navajo Native Americans) 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 [9]:

● Maternal illness or infection

● Inadequate prenatal care

● Preterm birth

● Difficult delivery with prolonged exposure to nonsterile secretions

● Male gender

● 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; maternal habits
(tobacco use, alcoholism, or other substance abuse); and inadequate prenatal care [10]. 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 [11]. (See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm infants".)

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 micro-organisms 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

● Heart or lung disease (low oxygen saturation suggests one of these problems)

● Mucosal abnormalities such as thrush, mouth sores, and ulcerations

● Cutaneous rashes, pigmentary abnormalities, or alopecia

● Petechiae, melena, bleeding

● Lymphadenopathy and/or hepatosplenomegaly

● Syndromic appearance (abnormal facies or habitus)

● Abdominal distension

● Autoimmunity

● Neonatal surgery

● Delayed umbilical cord separation

● Infection due to live vaccines (eg, rotavirus, Bacille Calmette-Guérin [BCG], oral polio)

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 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 (Ig) 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 Ig levels (IgG, IgA, IgM, and IgE) is less
informative in newborn/young infants because young infants produce only small amounts of Igs 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.

● Typically, the total lymphocyte count, as measured on a CBC with differential, exceeds 5000 cells/microL at
birth. Lymphopenia is defined as an absolute lymphocyte count <2500 cells/microliter in infants and
suggests a T and/or B cell defect.

● 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 [12]. 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 'Initial tests' 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 (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 'Initial tests'.)

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. (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. In addition, delayed-type hypersensitivity (DTH) reactions are
decreased to absent in the first year of life. 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' and "Immunity of the newborn", section on 'Delayed-type hypersensitivity'.)

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
[13] are commercially available at specialty labs and 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 [14-16]. 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 [17,18]. A few severe PIDs are not identified by newborn screening (eg, bare
lymphocyte syndrome) [19]. (See "Newborn screening for primary immunodeficiencies", section on 'Screening for
SCID and other T 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 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. However, CMV-
positive breast milk may transmit CMV infection, which can cause significant disease in infants with severe T cell
deficiency such as SCID. (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 (immunoglobulin G [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 — Early consultation with a pediatric immunologist is highly 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 [20,21].

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 [5].The development of the adaptive immune system and newborn immunity are
reviewed in greater detail separately. (See "Normal B and T lymphocyte development" and "Immunity of the
newborn".)

The antibody response to polysaccharide vaccines is poor, although response to protein antigens is intact.
Maternal immunoglobulin G (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, 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. A
more detailed discussion of the causes of secondary immunodeficiency, particularly in older children and adults,
is presented separately. (See "Secondary immunodeficiency due to underlying disease states, environmental
exposures, and miscellaneous causes" and "Secondary immunodeficiency induced by biologic therapies".)

Prematurity — Premature infants have immune defects in proportion to their degree of immaturity [22-28].
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 [24,25]. 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 [22,25,26]. 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
"Immunity of the newborn" and '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 [29-33]. Peripheral edema and marked hypoalbuminemia
are the usual presenting features. Gastrointestinal loss is most common, secondary to intestinal
lymphangiectasia, prolonged diarrhea, exudative enteropathy, allergic gastroenteropathy, protein-calorie
malnutrition, or cardiac surgery, particularly the Fontan procedure for single ventricle repair [29]. 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 – Untreated maternal hypogammaglobulinemia, notably common variable

immunodeficiency, will result in profound neonatal hypogammaglobulinemia due to lack of transplacental
transfer of maternal IgG [34]. 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 [35-38]. Hypogammaglobulinemia that results from maternal medications is rarely
severe. (See "Safety of antiinflammatory and immunosuppressive drugs in rheumatic diseases during
pregnancy and lactation" and "Drug-induced neutropenia and agranulocytosis", section on 'Drug-induced
neutropenia/agranulocytosis' 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 [10]. (See "Infants with fetal (intrauterine) growth restriction", section on 'Impaired immune function'
and "Fetal growth restriction: Evaluation and management".)

● 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) [39]. (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 [40].

● Other maternal illnesses – Maternal hypertension may result in neonatal neutropenia that is usually mild.
Maternal diabetes and alcohol abuse are associated with DiGeorge syndrome [10,41,42].

● Maternal malnutrition – Malnutrition in the mother, as well as subsequently in the infant, can lead to a
spectrum of immune defects. The impact of malnutrition on the immune system is discussed in detail
separately. (See "Secondary immunodeficiency due to underlying disease states, environmental exposures,
and miscellaneous causes", section on 'Malnutrition'.)

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" and "The 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. The most common cause 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 [43]. 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 (SCIDs) — 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-virus vaccines. 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 primary immunodeficiency".)

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 stem 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 [44]. (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
patients have been identified on newborn screening for T cell defects, despite the presence of some T cells.
This disorder 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 phagocytic 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 [45]. 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 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) [46]. (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 Bacille Calmette-Guérin (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: 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 'Introduction' above and "Immunity of the newborn".)

● 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.)

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Berlin 2008. p.235.

Topic 16608 Version 5.0

GRAPHICS

Immunoglobulin (IgG, IgM, IgA) levels in the fetus and infant in the first year
of life

The IgG of the fetus and newborn infant is solely of maternal origin. Maternal IgG disappears by nine months
of age, by which time endogenous synthesis of IgG is well established. IgM and IgA in the neonate are
entirely endogenously synthesized because maternal IgM and IgA do not cross the placenta.

IgG: immunoglobulin G; IgM: immunoglobulin M; IgA: immunoglobulin A.

Modified with permission from: Schneider LC, TePas EC, Umetsu DT. Allergy and Immunology. In: Pediatrics for
Medical Students, 3rd ed, Bernstein D, Shelov SP (Eds), Lippincott Williams & Wilkins, Philadelphia 2012. Copyright
© 2012 Lippincott Williams & Wilkins. www.lww.com.

Graphic 99496 Version 6.0

Most common causes of immunodeficiency presenting at birth or in early infancy

Humoral (antibody) deficiencies (IgG <400 mg/dL, severe <200 mg/dL)

Cause Features

Prematurity Severe infection in infants less than 1500 g

Physiologic hypogammaglobulinemia of infancy Usually asymptomatic

Maternal hypogammaglobulinemia Mother has untreated hypogammaglobulinemia or on

immunosuppression causing low B cells

Immunoglobulin loss Surgery, blood drawing, diarrhea, exudative skin lesions

Congenital agammaglobulinemias Usually asymptomatic, IgG low after several months

Combined immunodeficiencies Severe infection, IgG low after several months

Cellular (T cell) immunodeficiencies (CD3 T cells <500 cells/microL, severe <200

cells/microL)

Cause Features

Severe combined immunodeficiencies Thrush, diarrhea, failure to thrive, Pneumocystis jirovecii

pneumonia

DiGeorge syndrome Outflow cardiac defects, typical facies, hypocalcemia,

absent thymic shadow

Wiskott-Aldrich syndrome Boys with thrombocytopenia, bleeding, eczema,

respiratory infections

Hyperimmunoglobulin M syndromes Respiratory infection (eg, P. jirovecii pneumonia),

neutropenia, elevated IgM hemolytic anemia

Mucocutaneous candidiasis Early onset of thrush, esophagitis, skin infections,

endocrinopathies

Neutropenia (Granulocytes <500 cells/microL, severe <200 cells/L)

Cause Features

Neutropenia due to maternal hypertension mild Asymptomatic

Drug-induced neutropenia Various drugs, usually reversible, asymptomatic

Benign neutropenia Moderate, asymptomatic, normalizes with infection

Severe congenital neutropenia Early onset of refractory infection

Cyclic neutropenia Moderate or severe infections, often asymptomatic

Autoimmune or isoimmune neutropenia Maternal neutropenia, neutrophil antibodies, familial

Neutropenia of infection Develops during severe infection of the newborn, poor

prognostic sign

Other phagocytic immunodeficiencies (T and B cell function normal, no neutropenia)

Cause Features

Chronic granulomatous disease Deep-seated infections, abscesses, pneumonia, moderate

leukocytosis

Leukocyte adhesion deficiency Marked leukocytosis, poor wound healing, delayed

umbilical cord separation (>30 days)

Immunoregulatory disorders

Cause Features

Mendelian susceptibility to mycobacterial diseases Chronic Bacillus Calmette-Guérin (BCG) infection,

 environmental nontuberculous mycobacteria

Hemophagocytic lymphohistiocytosis (HLH) Fever, vomiting, hepatosplenomegaly, seizures, liver

failure

Immunodysregulation, polyendocrinopathy, enteropathy, Boys with enteropathy/colitis, diabetes, dermatitis

X-linked (IPEX) syndrome

Innate immune defects

Cause Features

NF-kappa-B essential modulator (NEMO) defects Severe infections, sparse hair

Toll-like receptor (TLR) defects Severe bacterial infections (especially Staphylococcus and
pneumococcus) with little or no fever or elevation of
inflammatory markers

Congenital asplenia Overwhelming sepsis, other abnormalities

Natural killer cell deficiencies Severe herpes infections

Complement deficiencies

Cause Features

Prematurity with opsonic defects Neonatal sepsis in infants <1500 g

Regulatory protein deficiencies Hemolytic-uremic syndrome, renal failure,

thrombocytopenia

IgG: immunoglobulin G; IgM: immunoglobulin M.

Graphic 100552 Version 4.0

Clinical characteristics of primary immunodeficiencies

B cell defects
Recurrent pyogenic infections with extracellular encapsulated organisms, such as Streptococcus pneumoniae,
Haemophilus influenzae type b, and group A Streptococcus.

Otitis, sinusitis, recurrent pneumonia, bronchiectasis, and conjunctivitis.

Few problems with fungal or viral infections (except enterovirus and poliomyelitis).

Diarrhea common, especially secondary to infection with Giardia lamblia.

Minimal growth retardation.

Compatible with survival to adulthood or for several years after onset unless complications occur.

Complement defects
Recurrent bacterial infections with extracellular encapsulated organisms, such as S. pneumoniae and H. influenzae.

Susceptibility to recurrent infections with Neisseria meningitides.

Increased incidence of autoimmune disease.

Severe or recurrent skin and respiratory tract infection.

T cell defects
Recurrent infections with less virulent or opportunistic organisms, such as fungi, Candida sp mycobacteria, viruses,
and protozoa as well as bacteria.

Growth retardation, malabsorption, diarrhea, and failure to thrive common.

Anergy.

Susceptible to graft-versus-host disease from nonirradiated blood or from maternal engraftment.

Fatal reactions may occur from live virus or Bacille Calmette-Guérin vaccination.

High incidence of malignancy.

Poor survival beyond infancy or early childhood.

Neutrophil defects
Recurrent dermatologic infections with bacteria such as Staphylococcus spp, Pseudomonas spp, and Escherichia coli,
and fungi such as Aspergillus.

Subcutaneous, lymph node, lung, and liver abscesses.

Pulmonary infections common, including abscess and pneumatocele formation, contributing to chronic disease.

Bone and joint infection common.

Delayed separation of umbilical cord.

Absence of pus at site(s) of infection.

Poor wound healing.

Innate TLR signaling defects (eg, MyD88 and IRAK4 deficiencies)

Early life infection with Staphylococcus spp, Streptococcus spp, and Pseudomonas aeruginosa.

Impaired/delayed systemic response (fever, acute phase response [increased CRP]) to infection.

Affects newborns, infants, and young children; lack of invasive infections after the teenage years.

TLR: Toll-like receptor; MyD88: myeloid differentiation primary response protein 88; IRAK4: interleukin-1 receptor associated
kinase 4; CRP: C-reactive protein.

Original figure modified for this publication. TePas EC, Umetsu DT. Immunology and Allergy. In: Nelson Essentials of
Pediatrics, 4th ed, Behrman RE, Kliegman RM, WB Saunders Company, Philadelphia, 2002. Table used with the permission of
Elsevier Inc. All rights reserved.

Graphic 99498 Version 2.0

Contributor Disclosures
E Richard Stiehm, MD Consultant/Advisory Boards: ADMA Biologics [Infections of respiratory syncytial virus in
organ transplants (Respiratory syncytial virus immune globulin)]. Tim Niehues, MD Nothing to disclose Ofer
Levy, MD, PhD Grant/Research/Clinical Trial Support: Crucell (Johnson & Johnson) [Vaccines (Meningococcal
and pertussis vaccines)]; Shire [Antimicrobial proteins]. Patent Holder: Use of antimicrobial protein rBPI31 for
radiation mitigation. Jennifer M Puck, MD Consultant/Advisory Boards (spouse): Pfizer [Rare diseases].
Employment (spouse): Invitae [Gene sequencing]. Equity Ownership/Stock Options (spouse): Invitae [Gene
sequencing]. Elizabeth TePas, MD, MS Nothing to disclose

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
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