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Approach to the Patient With Suspected Immunodeficiency

By

James Fernandez

, MD, PhD, Cleveland Clinic Lerner College of Medicine at Case Western Reserve University

Last full review/revision Dec 2019| Content last modified Dec 2019
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NOTE: This is the Professional Version. CONSUMERS: Click here for the Consumer Version
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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.

Immunodeficiency can be

  • Primary: Genetically determined, typically manifesting during infancy or childhood

  • Secondary: Acquired

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

  • Resistant to treatment

  • 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

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.

Table
icon

Some Clues in Patient History to Type of Immunodeficiency

Finding

Immunodeficiency

Recurrent Streptococcus pneumoniae and Haemophilus influenzae infections

Ig, C2, or IRAK-4 deficiency

Recurrent Giardia intestinalis (lamblia) infection

Antibody deficiency syndromes

Familial clustering of autoimmune disorders (eg, SLE, pernicious anemia)

Pneumocystis infections, cryptosporidiosis, or toxoplasmosis

T-cell disorders or occasionally Ig deficiency

Viral, fungal, or mycobacterial (opportunistic) infections

T-cell disorders

Clinical infection due to live-attenuated vaccines (eg, varicella, polio, BCG)

T-cell disorders

Graft-vs-host disease due to blood transfusions

T-cell disorders

Staphylococcal infections, infections with gram-negative organisms (eg, Serratia or Klebsiella), or fungal infections (eg, aspergillosis)

Skin infections

Neutrophil defect or Ig deficiency

Recurrent gingivitis

Neutrophil defect

Recurrent neisserial infections

Recurrent sepsis

Certain complement deficiencies, hyposplenism, or IgG deficiency

Family history of childhood death or of infections in a maternal uncle that are similar to those in the patient

BCG = bacille Calmette-Guérin; C = complement; Ig = immunoglobulin; IRAK = IL-1R-associated kinase; SLE = systemic lupus erythematosus.

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.

Other characteristic findings tentatively suggest a clinical diagnosis (see table Characteristic Clinical Findings in Some Primary Immunodeficiency Disorders).

Table
icon

Characteristic Clinical Findings in Some Primary Immunodeficiency Disorders

Age Group

Findings*

Disorder

< 6 months

Diarrhea, failure to thrive

Life-threatening infections (eg, pneumonia, sepsis, meningitis)

Maculopapular rash, splenomegaly

Severe combined immunodeficiency when accompanied by graft-vs-host disease (eg, caused by transplacentally transferred T cells)

Hypocalcemic tetany, a congenital heart disorder, characteristic facial appearance with low-set ears, developmental delay

Recurrent pyogenic infections, sepsis

C3 deficiency

Oculocutaneous albinism, neurologic changes, lymphadenopathy

Cyanosis, a congenital heart disorder, midline liver

Congenital asplenia

Delayed umbilical cord detachment, leukocytosis, periodontitis, poor wound healing

Abscesses, lymphadenopathy, antral obstruction, pneumonia, osteomyelitis

Recurrent staphylococcal abscesses of the skin, lungs, joints, and viscera; pneumatoceles; coarse facial features; pruritic dermatitis

Chronic gingivitis, recurrent aphthous ulcers and skin infections, severe neutropenia

Severe congenital neutropenia

Gastrointestinal bleeding (eg, bloody diarrhea), eczema

6 months to 5 years

Paralysis after oral polio immunization

Severe progressive infectious mononucleosis

Persistent oral candidiasis, nail dystrophy, endocrine disorders (eg, hypoparathyroidism, Addison disease)

> 5 years (including adults)

Ataxia, recurrent sinopulmonary infections, neurologic deterioration, telangiectasias

Recurrent Neisseria meningitis

C5, C6, C7, or C8 deficiency

Recurrent sinopulmonary infections, malabsorption, splenomegaly, autoimmune disorders, nodular lymphoid hyperplasia of the gastrointestinal tract, giardiasis, lymphoid interstitial pneumonia, bronchiectasis

Progressive dermatomyositis with chronic echovirus encephalitis

X-linked agammaglobulinemia

* In addition to infection.

Adapted from Stiehm, ER, Conley ME: Immunodeficiency diseases: General considerations, in Immunodeficiency Disease in Infants and Children, ed 5, edited by ER Stiehm. Philadelphia, WB Saunders Company, 2004.

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

Table
icon

Initial and Additional Laboratory Tests for Immunodeficiency

Type

Initial Tests

Additional Tests

IgG, IgM, IgA, and IgE levels

Isohemagglutinin titers

Antibody response to vaccine antigens (eg, Haemophilus influenzae type b, tetanus, diphtheria, conjugated and nonconjugated pneumococcal, and meningococcal antigens)

B-cell phenotyping and count using flow cytometry and monoclonal antibodies to B cells

Flow cytometry for CD40 and CD40 ligand

Evaluation for mutations in genes that encode BTK and NEMO

Sweat test

Absolute lymphocyte count

Delayed hypersensitivity skin tests (eg, using Candida)

Chest x-ray for size of thymus in infants only

T-cell phenotyping and count using flow cytometry and monoclonal antibodies to T cells and subsets

T-cell proliferative response to mitogens

TREC test (a genetic test that identifies infants with abnormal T cells or a low T-cell count due to SCID or other disorders)

Phagocytic cell count and morphology

Flow cytometric oxidative burst measurement using dihydrorhodamine 123 (DHR) or nitroblue tetrazolium (NBT)

Flow cytometry for CD18 and CD15

Neutrophil chemotaxis

C3 level

C4 level

CH50 activity (for total activity of the classical pathway) and AH50 activity (for total activity of the alternate complement pathways)

C1 inhibitor level and function

Specific component assays

AH50 = alternate complement hemolytic assay; BTK = Bruton tyrosine kinase; C = complement; CH = hemolytic complement; Ig = immunoglobulin; NEMO = nuclear factor–kappa-B essential modulator; SCID = severe combined immunodeficiency; TREC = T-cell receptor excision circle.

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 antibodies 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.

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.

Table
icon

Specific and Advanced Laboratory Tests for Immunodeficiency*

Test

Indications

Interpretation

Humoral immunity deficiency

IgE level measurement

Abscesses

Levels are high in patients with abscesses and pneumatoceles (hyper-IgE syndrome), partial T-cell deficiencies, allergic disorders, or parasitic infections.

Levels may be high or low in patients with incomplete B-cell defects or deficiencies.

Isolated deficiency is not clinically significant.

B-cell quantification via flow cytometry

Low Ig levels

< 1% B cells suggests X-linked agammaglobulinemia.

B cells are absent in Omenn syndrome.

Lymph node biopsy

For some patients with lymphadenopathy, to determine whether germinal centers are normal and to exclude cancer and infection

Interpretation varies by histology.

Genetic testing (genetic sequencing or mutation analysis)†

B cells < 1% (detected by flow cytometry)

Suspicion of a disorder with one or more characteristic mutations

Abnormalities in genes suggest or confirm a diagnosis, as in the following:

Results can also provide prognostic information.

T-cell deficiency

T-cell enumeration using flow cytometry and monoclonal antibodies§

Lymphopenia, suspected SCID or complete DiGeorge syndrome

Interpretation varies by molecular type of SCID.

T-cell proliferation assays to mitogens, antigens, or irradiated allogeneic WBCs

Low percentage of T cells, lymphopenia, suspected SCID or complete DiGeorge syndrome

Low or absent uptake of radioactive thymidine during cell division indicates a T-cell or combined defect.

Detection of antigens (eg, class II MHC molecules) using monoclonal antibodies or serologic HLA typing

Suspected MHC deficiency, absence of MHC stimulation by cells

Absence of class I or class II HLA antigens by serologic HLA typing is diagnostic for MHC antigen deficiency.

RBC adenosine deaminase assay

Severe lymphopenia

Levels are low in a specific form of SCID.

Purine nucleoside phosphorylase assay

Severe persistent lymphopenia

Levels are low in combined immunodeficiency with normal or elevated Ig levels.

T-cell receptor and signal transduction assays

Phenotypically normal T cells that do not proliferate normally in response to mitogen antigen

Interpretation varies by test.

T-cell receptor excision circle (TREC) test

Screening for SCID and other T-cell disorders

Low numbers suggest a defect that disrupts development or maturation of T cells or that causes apoptosis of T cells.

Combined humoral and cellular immunity deficiencies

Genetic testing

A suspected combined immunodeficiency disorder

Abnormalities in genes suggest or confirm certain disorders; for example, abnormalities in NEMO suggest combined immunodeficiency with defects of NF–kappa B regulation, and abnormalities in IL-2RG suggest SCID.

Phagocytic cell defects

Assays for oxidant products (hydrogen peroxide, superoxide) or proteins (CR3 [CD11] adhesive glycoproteins, NADPH oxidase components)

History of staphylococcal abscesses or certain gram-negative or fungal infections (eg, Serratia marcescens, aspergillosis)

Abnormalities confirm phagocytic cell defects or deficiencies.

Phosphorylation assays for signal transducer and activator of transcription (STAT), including STAT1 and STAT4

Recurrent mycobacterial infections

This test is the first one done to check for Mendelian susceptibility to mycobacterial disease (MSMD).

Complement deficiency

Measurement of levels of specific complement components

Suspicion of a complement disorder

Interpretation varies by test.

* Some of these tests may be used for screening or initial testing.

† Genetic panels for primary immunodeficiencies and for specific diseases such as CVID or SCID are commercially available.

‡ SAP is also called SH2 domain protein 1A [SH2D1A], or DSHP.

§ Test uses anti-CD3 for all T cells, anti-CD4 for helper T cells, anti-CD8 for cytotoxic T cells, anti-CD45RO or anti-CD45RA for activated and naive T cells, anti-CD25 for regulatory T cells, and anti-CD16 and anti-CD56 for natural killer cells.

BTK = Bruton tyrosine kinase; CH = hemolytic complement; CR = complement receptor; CVID = common variable immunodeficiency; HLA = human leukocyte antigen; Ig = immunoglobulin; IL2RG = interleukin-2 receptor gamma; MHC = major histocompatibility complex; NADPH = nicotinamide adenine dinucleotide phosphate; NEMO = NF–kappa-B essential modifier; NF–kappa-B = nuclear factor-kappa-B; RBC = red blood cell; SAP = SLAM-associated protein; SCID = severe combined immunodeficiency; SLAM = signaling lymphocyte activation molecule; WBC = white blood cell.

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.

Prognosis

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 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

  • To prevent early death, strongly consider screening all neonates for SCID using a T-cell receptor excision circle (TREC) test.

Treatment

  • 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

Infection can be prevented by advising patients to avoid environmental exposures and not giving them live-virus vaccines (eg, varicella, rotavirus, measles, mumps, rubella, herpes zoster, yellow fever, oral polio, intranasal influenza vaccines) or BCG (bacille Calmette-Guérin). Pneumococcal, meningococcal, and Haemophilus influenzae type b (Hib) vaccines are the recommended risk-specific vaccines, but their effectiveness varies with the degree of immunodeficiency.

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 in patients with T-cell disorders) can be given prophylactic antibiotics (eg, trimethoprim/sulfamethoxazole 5 mg/kg orally twice a day).

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.

Usually, self-limited viral infections cause severe persistent disease in immunocompromised patients. Antivirals (eg, oseltamivir, peramivir, or zanamivir for influenza; acyclovir for herpes simplex and varicella-zoster infections; ribavirin for respiratory syncytial virus or parainfluenza 3 infections) may be lifesaving.

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.

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 deficiency (1).

Treatment reference

  • 1. 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

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, and prescribe prophylactic antibiotics for patients with certain disorders.

  • Consider 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.

Drugs Mentioned In This Article

Drug Name Select Trade
Gammagard S/D
No US brand name
TAMIFLU
Peramivir
VIRAZOLE
ZOVIRAX
RELENZA
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