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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 Apr 2021| Content last modified Apr 2021
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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 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 Overview of Congenital Cardiovascular Anomalies Congenital heart disease is the most common congenital anomaly, occurring in almost 1% of live births (1). Among birth defects, congenital heart disease is the leading cause of infant mortality... read more Overview of Congenital Cardiovascular Anomalies , allergic rhinitis Allergic Rhinitis Allergic rhinitis is seasonal or perennial itching, sneezing, rhinorrhea, nasal congestion, and sometimes conjunctivitis, caused by exposure to pollens or other allergens. Diagnosis is by history... read more , ureteral stenosis Ureteral stenosis Ureteral anomalies frequently occur with renal anomalies but may occur independently. Complications include Obstruction, vesicoureteral reflux, infection, and calculus formation (due to urinary... read more or urethral stenosis Urethral Anomalies Congenital anomalies of the urethra in boys usually involve anatomic abnormalities of the penis and vice versa. In girls, urethral anomalies may exist without other external genital abnormalities... read more Urethral Anomalies , immotile cilia syndrome, asthma Asthma Asthma is a disease of diffuse airway inflammation caused by a variety of triggering stimuli resulting in partially or completely reversible bronchoconstriction. Symptoms and signs include dyspnea... read more , cystic fibrosis Cystic Fibrosis Cystic fibrosis is an inherited disease of the exocrine glands affecting primarily the gastrointestinal and respiratory systems. It leads to chronic lung disease, exocrine pancreatic insufficiency... read more Cystic Fibrosis , severe dermatitis Definition of Dermatitis The meaning of the word "dermatitis" is inflammation of the skin. However, in clinical dermatology, dermatitis is used to describe a variety of different skin conditions that share the same... read more ).

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 Sinusitis Sinusitis is inflammation of the paranasal sinuses due to viral, bacterial, or fungal infections or allergic reactions. Symptoms include nasal obstruction and congestion, purulent rhinorrhea... read more Sinusitis , bronchitis Acute Bronchitis Acute bronchitis is inflammation of the tracheobronchial tree, commonly following an upper respiratory infection that occurs in patients without chronic lung disorders The cause is almost always... read more , pneumonia Overview of Pneumonia Pneumonia is acute inflammation of the lungs caused by infection. Initial diagnosis is usually based on chest x-ray and clinical findings. Causes, symptoms, treatment, preventive measures, and... read more ) and gastroenteritis Overview of Gastroenteritis Gastroenteritis is inflammation of the lining of the stomach and small and large intestines. Most cases are infectious, although gastroenteritis may occur after ingestion of drugs and chemical... read more , but they may be serious bacterial infections (eg, meningitis Acute Bacterial Meningitis Acute bacterial meningitis is rapidly progressive bacterial infection of the meninges and subarachnoid space. Findings typically include headache, fever, and nuchal rigidity. Diagnosis is by... read more , sepsis Sepsis and Septic Shock Sepsis is a clinical syndrome of life-threatening organ dysfunction caused by a dysregulated response to infection. In septic shock, there is critical reduction in tissue perfusion; acute failure... read more ).

Immunodeficiency should also be suspected in infants or young children with chronic diarrhea and failure to thrive Failure to Thrive (FTT) Failure to thrive is weight consistently below the 3rd to 5th percentile for age and sex, progressive decrease in weight to below the 3rd to 5th percentile, or a decrease in 2 major growth percentiles... read more , 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.

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 Common Variable Immunodeficiency (CVID) Common variable immunodeficiency (acquired or adult-onset hypogammaglobulinemia) is characterized by low immunoglobulin (Ig) levels with phenotypically normal B cells that can proliferate but... read more [CVID]) do not manifest until adulthood.

Certain infections suggest certain immunodeficiency disorders (see table Some Clues in Patient History to Type of Immunodeficiency Some Clues in Patient History to Type of Immunodeficiency Immunodeficiency typically manifests as recurrent infections. However, recurrent infections are more likely to have causes other than immunodeficiency (eg, inadequate treatment, resistant organisms... read more ); however, no infection is specific to any one disorder, and certain common infections (eg, respiratory viral or bacterial infections) occur in many.

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Physical examination

Patients with immunodeficiency may or may not appear chronically ill. Macular rashes, vesicles, pyoderma, eczema, petechiae, alopecia, or telangiectasia may be evident.

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.

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Initial testing

  • Complete blood count (CBC) with manual differential

  • Quantitative immunoglobulin (Ig) measurements

  • Antibody titers

  • Skin testing for delayed hypersensitivity

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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:

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 Chédiak-Higashi Syndrome Chédiak-Higashi syndrome is a rare, autosomal recessive syndrome characterized by impaired lysis of phagocytized bacteria, resulting in recurrent bacterial respiratory and other infections and... read more ).

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 Overview of Nephrotic Syndrome Nephrotic syndrome is urinary excretion of > 3 g of protein/day due to a glomerular disorder plus edema and hypoalbuminemia. It is more common among children and has both primary and secondary... read more .

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 Cellular immunity deficiencies Immunodeficiency disorders are associated with or predispose patients to various complications, including infections, autoimmune disorders, and lymphomas and other cancers. Primary immunodeficiencies... read more 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 cirlces 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 Humoral immunity deficiencies Immunodeficiency disorders are associated with or predispose patients to various complications, including infections, autoimmune disorders, and lymphomas and other cancers. Primary immunodeficiencies... read more 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 phagocytic cell defects Phagocytic cell defects Immunodeficiency disorders are associated with or predispose patients to various complications, including infections, autoimmune disorders, and lymphomas and other cancers. Primary immunodeficiencies... read more 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 Complement deficiencies Immunodeficiency disorders are associated with or predispose patients to various complications, including infections, autoimmune disorders, and lymphomas and other cancers. Primary immunodeficiencies... read more , 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.

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 Evaluation reference Immunodeficiency typically manifests as recurrent infections. However, recurrent infections are more likely to have causes other than immunodeficiency (eg, inadequate treatment, resistant organisms... read more ).

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Prenatal and neonatal diagnosis

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 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 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

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 (1 Treatment references Immunodeficiency typically manifests as recurrent infections. However, recurrent infections are more likely to have causes other than immunodeficiency (eg, inadequate treatment, resistant organisms... read more ).

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 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 Graft-vs-host disease (GVHD) The most common complications of transfusion are Febrile nonhemolytic reactions Chill-rigor reactions The most serious complications, which have very high mortality rates, are Acute hemolytic... read more 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:

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 (3 Primary immunodeficiency references Immunodeficiency disorders are associated with or predispose patients to various complications, including infections, autoimmune disorders, and lymphomas and other cancers. Primary immunodeficiencies... read more ).

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 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 Primary immunodeficiency references Immunodeficiency disorders are associated with or predispose patients to various complications, including infections, autoimmune disorders, and lymphomas and other cancers. Primary immunodeficiencies... read more ). The comparative effectiveness of gene therapy versus replacement therapy and hematopoietic stem cell transplantation for specific disorders remains unclear.

Treatment references

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.

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