Approach to primary immunodeficiencies: Clinical sciences

Primary immunodeficiencies are inherited conditions that are characterized by defects in one or more components of the immune system. Patients with immunodeficiencies have increased susceptibility to infection and are at risk for autoimmune and inflammatory conditions, as well as malignancies. Primary immunodeficiencies can be categorized according to characteristic history and exam features as well as characteristic pathogens.

Now, if a pediatric patient presents with a chief concern suggesting a primary immunodeficiency, first perform an ABCDE assessment to determine if they are stable or unstable. If unstable, stabilize the airway, breathing, and circulation. Then, obtain IV access, put your patient on continuous vital sign monitoring, and provide supplemental oxygen if needed. Finally, administer IV antibiotics and consider IV immunoglobulin.

Next, obtain a focused history and physical examination and look for signs suggesting severe combined immunodeficiency, or SCID. SCID is a primary T cell deficiency associated with severe humoral and cellular immune deficits, which is considered a life-threatening medical emergency.

Affected patients are typically 6 months or younger and experience frequent, atypical, or opportunistic infections caused by bacteria, fungi, viruses, or parasites. Caregivers commonly report chronic diarrhea, and if newborn screening is available, results may confirm SCID.

The physical exam often reveals oral ulcers, decreased or absent lymphoid tissue, and possibly mucocutaneous candidiasis. You might also notice signs of Omenn syndrome, including scaly skin, alopecia, and edema.

With these findings, consider SCID and obtain a CBC with differential, serum immunoglobulin levels, flow cytometry for T and B cells, and a chest X-ray. Labs typically reveal decreased lymphocytes and immunoglobulin levels, and decreased T and B cell counts or function; while the X-ray is likely to demonstrate a small or absent thymus. These combined findings confirm SCID.

Now that we have discussed unstable patients, let’s return to the ABCDE assessment and take a look at stable ones. Your next step here is to obtain a focused history and physical exam. The patient or caregiver will typically report recurrent, severe, or opportunistic infections. Patients may also have an abnormal newborn screen, a personal history of an autoimmune disorder, or a family history of immunodeficiency. Additionally, the growth chart might reveal poor growth and suboptimal weight gain.

Here’s a clinical pearl! During your evaluation, remember to rule out secondary causes of immunodeficiency, including HIV infection, malnutrition, physiological or psychosocial stress, malignancy, and medications like corticosteroids or chemotherapy.

At this point, you should consider a primary immunodeficiency and order a CBC with differential and serum immunoglobulin levels. Then, assess for characteristic features that suggest an associated syndrome.

Now, your patient might have a midline facial defect such as cleft lip or palate, hypertelorism, or features that suggest CHARGE syndrome including Coloboma, Heart defects, Atresia of the choanae, Restricted growth or development, Genital hypoplasia, and Ear anomalies. If this is the case, consider DiGeorge Syndrome.

Patients with DiGeorge may have frequent opportunistic infections, as well as seizures or a conotruncal heart defect. The physical exam typically reveals characteristic facial features, such as a long face, hypertelorism, and a broad nose. Labs often demonstrate a decreased lymphocyte count and possibly decreased IgA or IgM levels.

Since the thymus produces T-cells, it’s important to order flow cytometry for T cells; and a genetic analysis to look for the classic chromosomal deletion. Lastly, order a serum calcium level, a chest X-ray to assess the thymus, and a neck ultrasound to assess the parathyroid glands.

Flow cytometry typically reveals a decreased T cell count with normal function, and genetic analysis confirms a 22q11 deletion. You’ll often see a decreased serum calcium level, an absent or hypoplastic thymus on chest X-ray, and absent or hypoplastic parathyroid glands on ultrasound. With these results, diagnose DiGeorge Syndrome.

Here’s a clinical pearl! The severity of immunodeficiency in DiGeorge syndrome depends on thymic function. Children with mild thymic hypoplasia have few infections, while those with complete DiGeorge syndrome and an absent thymus experience profound T-cell deficiency and severe life-threatening infections.

Okay, let’s switch gears and discuss patients with oculocutaneous albinism. This finding should make you consider Chediak-Higashi syndrome. Affected patients typically have frequent Staph. aureus infections, photophobia, and prolonged bleeding. The exam usually reveals nystagmus; sparse, silvery hair; and possibly gingivitis and hepatosplenomegaly. Labs might show decreased neutrophils, a normal platelet count, and normal immunoglobulin levels.

Your next step is to perform a Wright or peroxidase stain on a peripheral blood smear or bone marrow biopsy. If this demonstrates large granules or inclusions in all nucleated blood cells, diagnose Chediak-Higashi syndrome.

Now, let’s discuss patients with ataxia. This finding should make you think of Ataxia-Telangiectasia. Affected patients experience chronic sinopulmonary infections and severe, progressive at ataxia. History might also reveal malignancies, like lymphoma or leukemia; and the exam demonstrates oculocutaneous telangiectasias and neuropathy. Lab findings show absent IgA, possibly with decreased IgG or elevated IgM. Next, perform genetic analysis. If it identifies an ATM gene mutation, diagnose Ataxia-Telangiectasia.

Alright, let’s move on to patients with eczema. Eczema is associated with Hyper-IgE syndrome and Wiskott-Aldrich syndrome. To differentiate the two, assess for coarse facial features. If present, consider Hyper-IgE syndrome. These patients have frequent Staph. aureus and Candida albicans infections, as well as recurrent skin abscesses and pneumonia with pneumatoceles.

On physical exam, you may notice eczema and skin abscesses, without signs of inflammation. Labs typically demonstrate elevated eosinophils; markedly high IgE levels; and normal IgG, IgA, and IgM levels. With these findings, diagnose Hyper-IgE syndrome.

On the other hand, if your patient has eczema without coarse facial features, consider Wiskott-Aldrich syndrome. Due to an X-linked recessive inheritance, these patients are usually biologically male. Most have recurrent sinopulmonary infections caused by Streptococcus pneumoniae and other encapsulated bacteria. Many also have prolonged bleeding, which is often noticed during circumcision; as well as bloody diarrhea; and possibly Ebstein-Barr Virus-related malignancies.

Exam findings typically include eczema and purpura, while labs show low platelets, decreased IgM, elevated IgA and IgE, and possibly decreased IgG. Next, order a genetic analysis. If there’s a mutation of the Wiskott-Aldrich syndrome protein or WASP gene, you’ve confirmed the diagnosis of Wiskott-Aldrich syndrome.