Immunodeficiency typically manifests as recurrent infections. However, recurrent infections are more likely to have causes other than immunodeficiency (eg, inadequate treatment, resistant organisms, other disorders that predispose to infection). Both clinical and laboratory findings are needed for diagnosis.
(See also Overview of Immunodeficiency Disorders.)
Immunodeficiency can be
Primary: Genetically determined, typically manifesting during infancy or childhood
Secondary: Acquired, the most common cause of immunodeficiency
There are many causes of secondary immunodeficiency, but most immunodeficiencies result from one or more of the following:
Systemic disorders (eg, diabetes, undernutrition, HIV infection)
Immunosuppressive treatments (eg, cytotoxic chemotherapy, bone marrow ablation before transplantation, radiation therapy)
Prolonged serious illness (particularly in critically ill, older, and/or hospitalized patients)
Primary immunodeficiencies are classified by the main component of the immune system that is deficient, absent, or defective:
Manifestations of immunodeficiency
Immunodeficiency typically manifests as recurrent infections. However, more likely causes of recurrent infections in children are repeated exposures to infection at day care or school (infants and children may normally have up to 10 respiratory infections/year), and more likely causes in children and adults are inadequate duration of antibiotic treatment, resistant organisms, and other disorders that predispose to infection (eg, congenital heart defects, allergic rhinitis, ureteral stenosis or urethral stenosis, immotile cilia syndrome, asthma, cystic fibrosis, severe dermatitis).
Immunodeficiency should be suspected when recurrent infections are the following:
Severe
Complicated
In multiple locations
Refractory to standard treatment, ie, require multiple courses of oral antibiotics or any need for IV antibiotics to resolve
Caused by unusual organisms
Present in family members
Initially, infections due to immunodeficiency are typically upper and lower respiratory tract infections (eg, sinusitis, bronchitis, pneumonia) and gastroenteritis, but they may be serious bacterial infections (eg, meningitis, sepsis).
Immunodeficiency should also be suspected in infants or young children with chronic diarrhea and failure to thrive, especially when the diarrhea is caused by unusual viruses (eg, adenovirus) or fungi (eg, Cryptosporidium). Other signs include skin lesions (eg, eczema, warts, abscesses, pyoderma, alopecia), oral or esophageal thrush, oral ulcers, and periodontitis.
Less common manifestations include severe viral infection with herpes simplex or varicella zoster virus and central nervous system problems (eg, chronic encephalitis, delayed development, seizure disorder). Frequent use of antibiotics may mask many of the common symptoms and signs. Immunodeficiency should be considered particularly in patients with infections and an autoimmune disorder (eg, hemolytic anemia, thrombocytopenia).
Evaluation of Suspected Immunodeficiency
History and physical examination are helpful but must be supplemented by immune function testing. Prenatal testing is available for many disorders and is indicated if there is a family history of immunodeficiency and the mutation has been identified in family members.
History
Clinicians should determine whether patients have risk factors for infection or a history of symptoms of secondary immunodeficiency disorders and/or risk factors for them. Family history is very important.
Age when recurrent infections began is important:
Onset before age 6 months suggests a T-cell defect because maternal antibodies are usually protective for the first 6 to 9 months.
Onset between the age of 6 and 12 months may suggest combined B- and T-cell defects or a B-cell defect, which becomes evident when maternal antibodies are disappearing (at about age 6 months).
Onset much later than 12 months usually suggests a B-cell defect or secondary immunodeficiency.
In general, the earlier the age at onset in children, the more severe the immunodeficiency. Often, certain other primary immunodeficiencies (eg, common variable immunodeficiency [CVID]) do not manifest until adulthood.
Certain infections suggest certain immunodeficiency disorders (see table Some Clues in Patient History to Type of Immunodeficiency); however, no infection is specific to any one disorder, and certain common infections (eg, respiratory viral or bacterial infections) occur in many.
Physical examination
Patients with immunodeficiency may or may not appear chronically ill. Macular rashes, vesicles, pyoderma, eczema, petechiae, alopecia, or telangiectasia may be evident.
Cervical lymph nodes and adenoid and tonsillar tissue are typically very small or absent in X-linked agammaglobulinemia, X-linked hyper-IgM syndrome, severe combined immunodeficiency (SCID), and other T-cell immunodeficiencies despite a history of recurrent infections. In certain other immunodeficiencies (eg, chronic granulomatous disease), lymph nodes of the head and neck may be enlarged and suppurative.
Tympanic membranes may be scarred or perforated. The nostrils may be crusted, indicating purulent nasal discharge.
Chronic cough is common, as are lung crackles, especially in adults with CVID.
The liver and spleen are often enlarged in patients with CVID or chronic granulomatous disease. Muscle mass and fat deposits of the buttocks are decreased.
In infants, skin around the anus may break down because of chronic diarrhea. Neurologic examination may detect delayed developmental milestones or ataxia. Delayed umbilical cord separation may suggest leukocyte adhesion deficiency.
Other characteristic findings tentatively suggest a clinical diagnosis (see table Characteristic Clinical Findings in Some Primary Immunodeficiency Disorders).
Initial testing
If a specific secondary immunodeficiency disorder is suspected clinically, testing should focus on that disorder (eg, diabetes, HIV infection, cystic fibrosis, primary ciliary dyskinesia).
Tests are needed to confirm a diagnosis of immunodeficiency (see table Initial and Additional Laboratory Tests for Immunodeficiency). Initial screening tests should include
Complete blood count (CBC) with manual differential
Quantitative immunoglobulin (Ig) measurements
Antibody titers
Skin testing for delayed hypersensitivity
If results are normal, immunodeficiency (especially Ig deficiency) can be excluded. If results are abnormal, further tests in specialized laboratories are needed to identify specific deficiencies. If chronic infections are objectively documented, initial and specific tests may be done simultaneously. If clinicians suspect that immunodeficiency may be still developing, tests may need to be repeated, with monitoring over time, before a definitive diagnosis is made.
CBC can detect abnormalities in one or more cell types (eg, white blood cells, platelets) characteristic of specific disorders, as in the following:
Neutropenia (absolute neutrophil count < 1200 cells/mcL [1.2 x 109/L]) may be congenital or cyclic or may occur in aplastic anemia.
Lymphopenia (lymphocytes < 2000/mcL [2.0 X 109/L] at birth, < 4500/mcL [4.5 x 109/L] at age 9 months, or < 1000/mcL [1.0 X 109/L] in older children or adults) suggests a T-cell disorder because 70% of circulating lymphocytes are T cells.
Leukocytosis that persists between infections may occur in leukocyte adhesion deficiency.
Thrombocytopenia in male infants suggests Wiskott-Aldrich syndrome.
Anemia may suggest anemia of chronic disease or autoimmune hemolytic anemia, which may occur in CVID and other immunodeficiencies.
However, many abnormalities are transient manifestations of infection, drug use, or other factors; thus, abnormalities should be confirmed and followed.
Peripheral blood smear should be examined for Howell-Jolly bodies (residual fragments of the nucleus in red blood cells [RBCs]) and other unusual RBC forms, which suggest primary asplenia or impaired splenic function. Granulocytes may have morphologic abnormalities (eg, giant granules in Chédiak-Higashi syndrome).
Quantitative serum Ig levels are measured. Low serum levels of IgG, IgM, or IgA suggest antibody deficiency, but results must be compared with those of age-matched controls. An IgG level < 200 mg/dL (< 2 g/L) usually indicates significant antibody deficiency, although such levels may occur in protein-losing enteropathies or nephrotic syndrome.
IgM antibody function can be assessed by measuring isohemagglutinin titers (anti-A, anti-B). All patients except infants < 6 months and people with blood type AB have natural antibodies at a titer of ≥ 1:8 (anti-A) or ≥ 1:4 (anti-B). Antibodies to blood groups A and B and to some bacterial polysaccharides are selectively deficient in certain disorders (eg, Wiskott-Aldrich syndrome, complete IgG2 deficiency).
IgG antibody titers can be assessed in immunized patients by measuring antibody titers before and after administration of vaccine antigens (Haemophilus influenzae type B, tetanus, diphtheria, conjugated or nonconjugated pneumococcal, and meningococcal antigens); a less-than-twofold increase in titer at 2 to 3 weeks suggests antibody deficiency regardless of Ig levels. Natural antibodies (eg, antistreptolysin O, heterophil antibodies) may also be measured.
With skin testing, most immunocompetent adults, infants, and children react to 0.1 mL of Candida albicans extract (1:100 for infants and 1:1000 for older children and adults) injected intradermally. Positive reactivity, defined as erythema and induration > 5 mm at 24, 48, and 72 hours, excludes a T-cell disorder. Lack of response does not confirm immunodeficiency in patients with no previous exposure to Candida.
Chest x-ray may be useful in some infants; an absent thymic shadow suggests a T-cell disorder, especially if the x-ray is obtained before onset of infection or other stresses that may shrink the thymus. Lateral pharyngeal x-ray may show absence of adenoidal tissue.
Additional testing
If clinical findings or initial tests suggest a specific disorder of immune cell or complement function, other tests are indicated.
If patients have recurrent infections and lymphopenia, lymphocyte phenotyping using flow cytometry and monoclonal antibodies to T, B, and natural killer (NK) cells is indicated to check for lymphocyte deficiency.
If cellular immunity deficiency is suspected, a complete blood count with differential can be done to identify infants with low absolute lymphocyte counts. If tests show that lymphocytes are low in number or absent, a flow cytometry assay followed by in vitro mitogen stimulation studies are done to assess T-cell quantity and function. If major histocompatibility complex (MHC) antigen deficiency is suspected, serologic (not molecular) human leukocyte antigen (HLA) typing is indicated.
All US states now screen newborns with T-cell receptor excision circles (TREC) to assess for absent or dysfunctional T cells. Circles of DNA are normally created as T cells pass through the thymus and undergo rearrangement of their receptor genes, and the presence of these circles on TREC analysis provides a measure of T cell maturation. Absence of these circles on screening TREC analysis is a feature of SCID.
If humoral immunity deficiency is suspected, patients may be tested for specific mutations—for example, in the genes that encode for Bruton tyrosine kinase (BTK), CD40 and CD40 ligand, and nuclear factor-kappa-B essential modulator (NEMO). A sweat test is typically done during the evaluation to rule out cystic fibrosis.
If combined cellular and humoral immunity is impaired and SCID is suspected, patients can be tested for certain typical mutations (eg, in the interleukin (IL-2) receptor gamma [IL-2RG, or IL-2Rγ] gene).
If phagocytic cell defects are suspected, CD15 and CD18 are measured by flow cytometry and neutrophil chemotaxis is tested. A flow cytometric oxidative (respiratory) burst assay (measured by dihydrorhodamine 123 [DHR] or nitroblue tetrazolium [NBT]) can detect whether oxygen radicals are produced during phagocytosis; no production is characteristic of chronic granulomatous disease.
If the type or pattern of infections suggests complement deficiency, the serum dilution required to lyse 50% of antibody-coated red blood cells is measured. This test (called CH50) detects complement component deficiencies in the classical complement pathway but does not indicate which component is abnormal. A similar test (AH50) can be done to detect complement deficiencies in the alternative pathway.
If examination or screening tests detect abnormalities suggesting lymphocyte or phagocytic cell defects, other tests can more precisely characterize specific disorders (see table Specific and Advanced Laboratory Tests for Immunodeficiency).
Gene sequencing techniques are becoming increasingly used to elucidate immunodeficiency disorders with unusual features. Identification of monogenetic defects in the setting of primary immunodeficiency has become robust, and improvements are gradually changing how we approach the diagnosis and treatment of these diseases (1).
Prenatal and neonatal diagnosis
An increasing number of primary immunodeficiency disorders can be diagnosed prenatally using chorionic villus sampling, cultured amniotic cells, or fetal blood sampling, but these tests are used only when a mutation in family members has already been identified.
X-linked agammaglobulinemia, Wiskott-Aldrich syndrome, ataxia-telangiectasia, X-linked lymphoproliferative syndrome, all forms of SCID (using the TREC test, now done to screen all newborns in the US), and all forms of chronic granulomatous disease can be detected.
Sex determination by ultrasonography can be used to exclude X-linked disorders.
Evaluation reference
1. Chinn IK, Orange JS: A 2020 update on the use of genetic testing for patients with primary immunodeficiency. Expert Rev Clin Immunol 16(9):897–909, 2020. doi: 10.1080/1744666X.2020.1814145
Prognosis for Suspected Immunodeficiency
Prognosis depends on the primary immunodeficiency disorder.
Most patients with an Ig or a complement deficiency have a good prognosis with a near-normal life expectancy if they are diagnosed early, are treated appropriately, and have no coexisting chronic disorders (eg, pulmonary disorders such as bronchiectasis).
Other immunodeficient patients (eg, those with a phagocytic cell defect or combined immunodeficiencies, such as Wiskott-Aldrich syndrome or ataxia-telangiectasia) have a guarded prognosis; most require intensive and frequent treatment.
Some immunodeficient patients (eg, those with SCID) die during infancy unless immunity is provided through stem cell transplantation. All forms of SCID could be diagnosed at birth if a T-cell receptor excision circle (TREC) test were routinely done in neonates. Suspicion for SCID, a true pediatric emergency, must be high because prompt diagnosis is essential for survival. If SCID is diagnosed before patients reach age 3 months, transplantation of stem cells from a matched or half-matched (haploidentical) relative is lifesaving in 95%.
Pearls & Pitfalls
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Treatment of Suspected Immunodeficiency
Avoidance of live vaccines and exposure to infection
Antibiotics and sometimes surgery
Replacement of missing immune components
Treatment of immunodeficiency disorders generally involves preventing infection, managing acute infection, and replacing missing immune components when possible.
Infection prevention
Haemophilus influenzae type b (Hib) vaccines are the recommended risk-specific vaccines, but their effectiveness varies with the degree of immunodeficiency (1).
Messenger RNA-based and adenovirus-based vaccines for prevention of COVID appear to be safe in patients with a primary immunodeficiency. but it is as yet unclear how much these vaccines will raise antibody titers and how long they will continue to be protective. It is likely that patients with humoral and B-cell deficiencies will have a decreased response.
Patients at risk of serious infections (eg, those with SCID, chronic granulomatous disease, Wiskott-Aldrich syndrome, or asplenia) or of specific infections (eg, with Pneumocystis jirovecii
To prevent graft-vs-host disease after transfusions, clinicians should use blood products from cytomegalovirus-negative donors; the products should be filtered to remove white blood cells and irradiated (15 to 30 Gy).
Management of acute infection
After appropriate cultures are obtained, antibiotics that target likely causes should be given promptly. Sometimes surgery (eg, to drain abscesses) is needed.
Replacement of missing immune components
Such replacement helps prevent infection. Therapies used in more than one primary immunodeficiency disorder include the following:
IV immune globulin (IVIG) is effective replacement therapy in most forms of antibody deficiency. The usual dose is 400 mg/kg once a month; treatment is begun at a low infusion rate. Some patients need higher or more frequent doses. IVIG 800 mg/kg once a month helps some antibody-deficient patients who do not respond well to conventional doses, particularly those with a chronic lung disorder. High-dose IVIG aims to keep IgG trough levels in the normal range (> 600 mg/dL [> 6 g/L]).
Subcutaneous immune globulin (SCIG) can be given instead of IVIG. SCIG can be given at home, usually by patients themselves. The usual dose is 100 to 150 mg/kg once a week. Because SCIG and IVIG differ in bioavailability, the dose of SCIG may need to be adjusted if patients are switched from IVIG. With SCIG, local site reactions are a risk, but SCIG seems to have fewer systemic adverse effects.
Hematopoietic stem cell transplantation using bone marrow, umbilical cord blood, or adult peripheral blood stem cells is effective for lethal T-cell and other immunodeficiencies. Pretransplantation chemotherapy is unnecessary in patients without T cells (eg, those with SCID). However, patients with intact T-cell function or partial T-cell deficiencies (eg, Wiskott-Aldrich syndrome, combined immunodeficiency with inadequate but not absent T-cell function) require pretransplantation chemotherapy to ensure graft acceptance. When a matched sibling donor is unavailable, haploidentical bone marrow from a parent can be used. In such cases, mature T cells that cause graft-vs-host disease must be rigorously depleted from parental marrow before it is given. Umbilical cord blood from an HLA-matched sibling can also be used as a source of stem cells. In some cases, bone marrow or umbilical cord blood from a matched unrelated donor can be used, but after transplantation, immunosuppressants are required to prevent graft-vs-host disease, and their use delays restoration of immunity. The survival of patients after stem cell transplantation is now ≥ 80% (2).
Investigational therapy
Gene therapy refers to the introduction of an exogenous gene (transgene) into one or more cell type with the hopes of correcting for a missing or malfunctioning gene known to cause disease.
Gene therapy using gamma-retroviral vectors has been used for adenosine deaminase (ADA) deficiency (a type of SCID) and has resulted in vector insertion in oncogenes, with some cures; leukemias have not developed to date.
In mouse models of chronic granulomatous disease, CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats and CRISPR-associated protein 9) technology has been used to correct the CYBB mutation.
In preclinical studies using human and mouse models of Artemis-deficient stem cells, a lentiviral vector carrying the human Artemis DCLRE1C cDNA under transcriptional regulation of its own human Artemis promoter has been used to correct severe combined immunodeficiency (3).
Other gene therapies are being investigated for treatment of X-linked SCID, hyper IgM syndrome, chronic granulomatous disease, and X-linked agammaglobulinemia. T-cell gene therapy (CAR-T) is also being studied to correct T cell–intrinsic defects in IPEX syndrome, hyper IgM syndrome, X-linked lymphoproliferative disease, Munc 13-4 deficiency, and perforin deficiency (4). The comparative effectiveness of gene therapy versus replacement therapy and hematopoietic stem cell transplantation for specific disorders remains unclear.
Treatment references
1. Shearer WT, Fleisher TA, Sullivan K, et al: Recommendations for live viral and bacterial vaccines in immunodeficient patients and their close contacts. J Allergy Clin Immunol 133 (4): 961–966, 2014.
2. Marsh RA, Hebert KM, Keesler D, et al: Practice pattern changes and improvements in hematopoietic cell transplantation for primary immunodeficiencies. J Allergy Clin Immunol 142(6): 2004–2007, 2018.
3. Punwani D, Kawahara M, Sanford U, et al: Lentivirus mediated correction of Artemis-deficient severe combined immunodeficiency. Hum Gene Ther 28: 112–124, 2017. doi: 10.1089/hum.2016.064
4. Ferreira LMR, Muller YD, Bluestone JA, et al: Next-generation regulatory T cell therapy. Nat Rev Drug Discov 18(10): 749–769, 2019. doi: 10.1038/s41573-019-0041-4
Key Points
Consider a primary immunodeficiency if infections are unusually frequent or severe, particularly if they occur in family members, or if patients have thrush, oral ulcers, periodontitis, or certain skin lesions.
Do a complete physical examination, including the skin, all mucous membranes, lymph nodes, spleen, and rectum.
Begin testing with complete blood count (with manual differential), quantitative immunoglobulin levels, antibody titers, and skin testing for delayed hypersensitivity.
Select additional tests based on what type of immune defect is suspected (humoral, cellular, phagocytic cell, or complement).
Test the fetus (eg, using fetal blood, chorionic villus sampling, or cultured amniotic cells) if family members are known to have an immunodeficiency disorder.
Teach patients how to avoid infections, give indicated vaccines, avoid live-virus vaccines, and prescribe prophylactic antibiotics for patients with certain disorders.
Consider ongoing immune globulin replacement for antibody deficiencies and hematopoietic stem cell transplantation for severe immunodeficiencies, particularly T-cell immunodeficiencies.
Although gene therapy is still investigational, advances may make this a viable option in the future.
