Clinical and Laboratory Manifestations of Primary Immunodeficiencies

Brandy Merritt, MD*
University of Tennessee
Chattanooga, Tennessee, USA

Mark E. Rowin, MD**
University of Tennessee
Chattanooga, Tennessee, USA

Primary immunodeficiencies are rare, occurring in approximately one in 10,000 births. However, they may be over-represented in the intensive care unit population, as these patients often can present with overwhelming sepsis or infectious complications. Fortunately, the most common immunodeficiencies (e.g., transient hypogammaglobulinemia of infancy and selective immunoglobulin [Ig] A deficiency) are not likely to cause overwhelming infection. Defects in B-cell number or function are the most likely immune disorders to cause an increased risk of infectious morbidity and mortality rates; nearly 40% to 50% of immune disorders are included in this category. T-cell and combined B-cell/T-cell defects are the next most prevalent at 20% to 30%. Disorders of phagocyte function or number comprise about 15% to 20% of primary immune disorders, whereas disorders of the complement system and the intracellular inflammatory cascade are the most rare at <5%.

Evaluation for immunodeficienciesstarts with clinical suspicion. Intensive care clinicians have a poor history of diagnosing immune disorders. For example, the most frequent primary immunodeficiency is common variable immunodeficiency (CVID), which typically manifests with recurrent infections in late adolescence; however, most patients are not diagnosed until age 30.(1) One study shows the median age of diagnosis for T-cell and B-cell defects in children was 17 months, yet the first clinical manifestation occurred at four months.(2)

Diagnostic Clues in Immunodeficiency
Although many of the signs of immune disorders are nonspecific, certain laboratory values and clinical traits may increase a clinician’s suspicion. As is the case with any medical admission, a detailed history – particularly an infection history – is the single most important step in evaluating potential immunodeficiencies. Infection histories should include the date, duration, site and severity of the infection as well as the organism(s) responsible. Common pathogens in immunocompetent patients continue to be common pathogens in those with immunodeficiencies.

The patient’s age at initial infection also provides important diagnostic clues. Abnormalities in the innate or T-cell-mediated adaptive immune system tend to present within the first four months of life. Symptoms might include failure to thrive, chronic diarrhea, and severe or persistent infections. After four months of life, children who present with recurrent or severe bacterial infections – particularly involving the respiratory or gastrointestinal tracts – may have an abnormality in the B-cell portion of the adaptive immune response. These deficits become apparent as passively acquired maternal antibodies wane and exposure to potential pathogens increases.

No one physical finding is pathognomonic for primary immune dysfunction, but skin findings are common among individuals with immunodeficiencies. The presence of cutaneous abscesses, poor or abundant scar formation, or paronychia offers insight into host defenses. Examples include petechiae (Wiskott-Aldrich syndrome), telangiectasias (ataxiatelangiectasia syndrome), eczematoid rash (hyper-IgE syndrome and Wiskott-Aldrich syndrome), chronic skin abscesses (chronic granulomatous disease), severe seborrhea-like dermatitis (many T-cell deficiencies), abnormal scar formation and retained umbilical cord (leukocyte defects). Chronic rhinitis, gingivitis, periodontal disease, tooth loss and severe aphthous ulcers also are common clinical findings in patients with primary immunodeficiency disorders.

Initial Laboratory Evaluation for Immunodeficiency
Screening laboratory tests can support the suspicion of an immunocompromised status, but they do not replace a detailed  history and physical examination. When categorizing immunodeficiencies, one should evaluate both the innate (macrophages, granulocytes, complement) and adaptive (B-cell and T-cell, immunoglobulin) components of the immune system. The initial laboratory evaluation for a patient with suspected immunodeficiency should include a complete blood count with differential, peripheral blood smear, erythrocyte sedimentation rate, and quantitative immunoglobulin levels (IgA, IgM and IgG). Additional testing for primary immunodeficiencies should be performed if indicated by history, physical examination and screening laboratory tests (see Table 1).

A complete blood count and peripheral smear provide useful information, allowing assessment of the number and morphology of leukocytes and platelets as well as the presence of Howell-Jolly bodies. Absolute granulocyte and lymphocyte counts should be calculated. Granulocyte counts <1000 cells/mm3 should arouse suspicion of bone marrow suppression or congenital neutropenia. Lymphopenia, defined as <2500 lymphocytes/mm3, is strongly suggestive of T-cell deficiency, as T cells typically account for >70% of circulating lymphocytes (see Figure 1).(3) If lymphopenia is noted, a total lymphocyte count (CD3 +) plus T-cell (CD4 and CD8) and B-cell quantification should follow. T-cell function can be assessed by Candida skin testing in children >6 years of age.

Common screening labs for B-lymphocyte function include IgA, IgM, total IgG levels, isohemagglutinins and antibodies to diphtheria, tetanus or Haemophilus influenzae (in a patient known to be immunized). Abnormalities in immunoglobulin levels should be repeated, as hypogammaglobulinemia will resolve in 48% of patients.(4) Isolated IgG subclass deficiencies are common and not consistently linked to immune defects.(5)

Chest radiographs (CXR) provide important information and identify chronic lung disease, presence of thymus, situs inversus or anatomic abnormalities. Thymic shadow is typically absent in T-cell deficiencies. CXR in DiGeorge syndrome may also demonstrate the presence of associated truncoconal cardiovascular defects.

Unique Clinical Aspects of Severe Immunodeficiencies
The most severe B-cell defect is X-linked agammaglobulinemia (XLA), also known as Bruton’s agammaglobulinemia. Both antibodies and B cells with be lacking in laboratory results. The mean age of XLA diagnosis is 3.5 years.(6) Unique physical examination findings include a lack of tonsillar development. Neutropenia is present in 11% of XLA patients.(7) The initial presentation is often severe respiratory tract infections in the first year of life, but patients also may present with pyoderma, gastroenteritis, meningitis, osteomyelitis or conjunctivitis.(8) The most common infectious agents are pneumococcus, Haemophilus, Staphylococcus and Giardia.

Normal numbers of B lymphocytes are seen in CVID, but little or no IgG, IgM, or IgA production. CVID is the most common primary immunodeficiency presenting in adults. While XLA occurs predominately in boys, CVID is equally distributed between the sexes. It presents with recurrent bacterial infections after six months of age and frequently is associated with autoimmune disorders, such as rheumatoid arthritis and immune thrombocytopenic purpura.(8,9)

Hyper-IgM syndromes, characterized by loss of antibody class switching, are caused by defective CD40 signaling in T and B cells and result in low levels of IgG, IgA and IgE, while IgM is very high. This typically is an X-linked disorder, but autosomal recessive cases are reported.(8) Neutropenia is a prominent laboratory finding. As with other combined Band T-cell defects, multiple bacterial, fungal, viral and parasitic pathogens can cause infection, especially Pneumocystis and Cryptosporidium.(10,11)

Wiskott-Aldrich syndrome, another combined T- and B-cell defect, is caused by cytoskeleton malformation through mutation of the Wiskott-Aldrich syndrome protein gene. Patients have thrombocytopenia, eczema, recurrent petechiae and frequent staphylococcal infections. They are at increased risk of fungal infections, especially Aspergillus and Candida.(10) Thrombocytopenia frequently is the only laboratory abnormality, but the astute clinician will note small platelet size on peripheral blood smear.

Disorders of T cells present earlier than B-cell defects, often within the first few months of life. T-cell disorders are much more likely to present with failure to thrive, diarrhea and frequent pneumonias.(8) Examples include DiGeorge syndrome and severe combined immunodeficiency syndrome. DiGeorge syndrome results from microdeletion of chromosome 22q11, leading to thymic and parathyroid gland hypoplasia. Clinical presentation is variable, with patients demonstrating heart abnormalities. The most common of these is truncus arteriosus, but tetralogy of Fallot, interrupted aortic arch or ventriculoseptal defects have been described. Facial anomalies (cleft palate and hypertelorism), and hypocalcemia may also be seen.

Severe combined immunodeficiency (SCID) is a rare but serious defect involving all lymphocytes. It commonly is transmitted as an X-linked recessive trait and thus is found mostly in boys. On laboratory evaluation, the affected infant will have absolute lymphocyte counts below 2500/mm3.3 Thrush and Candida diaper dermatitis are common clinical findings.(10,12) CXR findings universally are devoid of thymic shadows.

The innate immune system is composed of neutrophils, macrophages, monocytes and the complement system. Chronic granulomatous disease (CGD) and leukocyte adhesion defect (LAD) are two common defects in innate immunity. CGD can be either an X-linked or autosomal recessive disorder. Monocytes and neutrophils in CGD lack respiratory burst capability. Infections with catalase-producing organisms such as Staphylococcus are most frequent in these patients. CGD also has the highest incidence of fungal infection, especially with Aspergillus and Candida.(10) Flow cytometry with rhodamine dye establishes the diagnosis. The nitroblue tetrazolium dye test is no longer recommended.(5)

LAD is much less common than CGD. Patients with LAD may present with severe infections in infancy. A complete blood count typically demonstrates an elevated neutrophil count. The initial manifestation may be cellulitis of the umbilicus and delayed separation of the umbilical cord.

Complement deficiencies are rare and typically do not present early in childhood. Patients exhibit a wide array of symptoms, depending on which of the 11 components of the complement system is affected. Conditions range from recurrent mild pyogenic infections to severe bacterial infections, typically with pneumococcus or Neisseria. Total hemolytic complement activity (CH50) screening will detect suspected terminal complement deficiencies.(13)

In summary, clinicians often attribute frequent infections to normal childhood occurrences. However, they must be attuned to when recurrent infections are no longer considered “normal.” Failure to diagnose immunodeficiencies can lead to serious, and often fatal, sequelae. Clinicians can have a direct impact on the immunodeficient patient population through early recognition of the clinical and laboratory presentations of primary immunodeficiencies in the intensive care unit.

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