I Have a Child With a Possible Underlying Immunodeficiency

When should I start worrying that a child might have underlying immunodeficiency?
When a patient has “too many” infections, recurrent invasive infections, infections that don’t respond to the usual treatment, infections with unusual organisms, or recurrent infections associated with significant growth and/or developmental delay, an underlying immunodeficiency is worth thinking about.

How many infections are “Too many”?
Remember, 8-10 episodes of upper respiratory infection is NOT unusual in children less than 5 years of age, particularly if the child is in out-of-home childcare with other children. However, some general rules of thumb for “too many” are:

• 10 or more episodes of otitis media/year (infants/children)
• 2 or more episodes of otitis media/year (adolescent/adult)
• 2 or more episodes bacterial pneumonia/year
• 2 or more episodes severe sinusitis/year
• 2 or more episodes severe gastroenteritis/year
• 2 or more life-threatening infections per lifetime

Which types of infections should raise the question of underlying immunodeficiency?
Invasive infections such as sepsis, bacterial meningitis, and recurrent soft tissue abscesses should prompt a consideration of underlying immunodeficiency. Infections that are particularly difficult to treat are also a red flag. Examples include those requiring prolonged courses of antimicrobials, parenteral therapy (when oral therapy usually suffices), surgical debridement, or those that recur despite an adequate course of usual therapy

What microbes should immediately raise the red flag for a possible underlying immunodeficiency?
Although not a complete list, infections with Pneumocystis, invasive fungi, herpesviruses (T-cell defects, HIV); Pseudomonas, Burkholderia, Serratia, Aspergillus, recurrent Staphylococcal (phagocyte defect); Neisseria (even single episode), recurrent encapsulated organisms- pneumococcus or hemophilus (complement) all warrant consideration of immunodeficiency.

How common is immunodeficiency?
Acquired immunodeficiency due to HIV infection, chronic steroid use, nephrotic syndrome (loss of immunoglobulin), and asplenia (trauma or sickle cell) are all more common that all other inherited Immunodeficiencies combined. The overall incidence of inherited immunodeficiency is 1:5000. The most common type is a B Cell defect (50%), followed by combined B and T cell defects (30%), T cell defects (10%), phagocyte defects (10%) and complement deficiencies (rare). However, it should be remembered that up to 10% of all individuals with a single episode of invasive meningococcal disease have an underlying complement deficiency. See table below for summary of inherited Immunodeficiencies.

What are some other reasons (other than an underlying immunodeficiency) for recurrent infections
Increased exposure is the most common reason for recurrent minor upper respiratory infection, as occurs with attendance in out-of-home childcare: Up to 2/3 children have > 60 days respiratory illness/year. Other higher risk groups include children with atopy (asthma, allergic rhinitis), children exposed to passive smoke, children with anatomic abnormalities of the upper respiratory system (including immotile cilia syndrome), children with malnutrition, or children with Cystic Fibrosis. Munchausen Syndrome is rarely a cause of recurrent infection.

What are specific questions I should ask when taking a history if I am worried about the possibility of an underlying immunodeficiency?

• What age did the recurrent infections start?
  • Infections due to immunoglobulin deficiencies tend to start >6 months age due to waning maternal antibody, whereas those due to phagocyte and cell mediated immunity deficiencies start earlier
• What is the frequency and type of infections?
  • Too many “routine” infections or more than one unusual/severe/invasive infections.
• What is the severity of infections?
  • Did treatment require hospitalization, prolonged course of oral antibiotics, intravenous antibiotics or surgical excision/drainage?
• When did the umbilical stump separate?
  • >3 weeks may indicate neutrophil defect such as lazy leukocyte syndrome
• Get a complete vaccination history
  • Were there any unusual reactions to live vaccines?
• What infectious pathogens have caused prior infections?
  • Certain pathogens raise red flag for underlying immunodeficiency, even if they only occur once: Examples: Pneumocystis, Pseudomonas, Aspergillus, Nocardia
• Were there any unexplained childhood deaths in the extended family?
  • Also ask specifically if any known family history of immunodeficiency
• Is there a history of chronic intractable diarrhea or chronic severe eczema
  • Often seen in conjunction with cell mediated immunity defects

What specific findings on physical exam are clues to an underlying immunodeficiency?
Low weight for height and failure to thrive in conjunction with recurrent infections might be a clue. Hepatomegaly and/or splenomegaly can be seen in children with HIV infection, as well as other immunodeficiencies. Severe periodontal disease (gingivitis, apthous ulcers, toothlessness) may be seen in children with phagocytic defects. An abundance of lymph nodes (particularly if outside the cervical region), or NO palpable lymph nodes are also red flags. Cutaneous findings such as severe eczema (T cell defects, Job Syndrome, Wiscott Aldrich), or recurrent/severe candidal infections of the oropharynx (thrush) or nails are also concerning (T cell defect).

What laboratory tests should I send as an initial basic screening for immunodeficiency?
To screen the major arms of the immune system, the following is recommended:

• A basic CBC including manual differential and peripheral smear. Abnormalities worth pursuing include lymphopenia, neutropenia, neutrophilia, eosinophilia, thrombocytopenia, platelets with giant granules, or Howell-Jolly bodies.
• Quantitative T and B Cell subsets (which gives absolute numbers and percentages. As a rough guide, normal total lymphocyte counts are as follows: 7000 infancy, 4000 childhood, 2000 adolescent (50% TCells, 25% NK Cells, 25% B cells)
• HIV testing: Antibody testing and/or PCR depending on age
• Quantitative Immunoglobulins (IgG, IgA, IgM, IgE, IgD). IgG subsets are not recommended.
• Remember that Ig Levels are AGE SPECIFIC, high levels may also be abnormal (HIV, Hyper IGM syndrome), and normal levels do not always indicate normal function
• Complement testing: CH50/ AH50
• Phagocyte function: NBT (Oxidative burst and killing)
• CXR: (Bronchiectasis, pneumatoceles, absence of thymic tissue, cardiac defects

When should I refer to Infectious Diseases or Immunology?
Anytime history or physical suggests immunodeficiency, referral may be indicated. Basic screening laboratory tests (above) can be done in your office, but if tests are not available, referral can be arranged for this purpose. Abnormalities on basic screening should prompt referral for advanced laboratory testing.

Summary of Types of Inherited Immunodeficiencies: