John has three sisters, but they have not presented with severe and recurrent gram-positive bacterial infections (Fig. 3-1). On the other hand, the family has lost a boy to bacterial pneumonia, suggesting that this is an X-linked recessive immunodeficiency disorder. That is, the gene that is missing or mutated is present on the X chromosome. Because females have two X chromosomes, a gene mutation on one chromosome will not manifest as an immunodeficiency disorder when there is a normal copy of that gene on the other chromosome. Nonetheless, the female remains a carrier and can pass the defective gene to her offspring. Females who inherit two defective genes will also present with the disorder. In contrast, males have only one X chromosome and if a gene on that chromosome is mutated, the child will develop the associated disorder. Although identification of males with a similar disorder helps in the diagnosis, the absence of other affected male infants does not rule out a diagnosis of an X-linked disorder.

FIGURE 3-1 Staphylococcus aureus. Gram stain of pus from patient with a wound infected with S. aureus. Note the gram-positive cocci and the pink-colored pus cells. (Gram stain, ×1000.)

(From Hart CA, Shears P: Color Atlas of Medical Microbiology, 2nd ed. St. Louis, Mosby, 2004.)

Implications/Analysis of Clinical History

John’s problems with infections did not begin until he was several months of age, suggesting that prior to this he was protected against infection by maternally transmitted IgG antibodies. Because IgG antibodies have a half-life of about 3 weeks, the maternal IgG anti-bodies that have crossed the placenta will protect the infant for the first few months of life.

Implications/Analysis of Laboratory Investigation

The blood workup (complete blood cell count and differential) indicated a decrease in lymphocyte count. John has not presented with any viral or fungal infections so the decrease in lymphocyte count is unlikely to be caused by a defect in T cell numbers or function. Bacterial infections could also be caused by a complement or B cell dysfunction. Because there is a decrease in lymphocyte numbers but not in myeloid cells (neutrophils, monocytes), it is likely that John has a B cell defect.

Quantitative assessment of serum immunoglobulin using either nephelometry (see Case 5) or enzyme-linked immunosorbent assay (ELISA) (see Case 7) indicated that serum immunoglobulin levels were below normal (normal pediatric level: see Appendix). B cell numbers, assessed by flow cytometry using fluorescently labeled anti-CD19 antibodies, were also below normal. CD19 is a B cell marker that is initially expressed during the pro–B cell stage and continues to be expressed at all stages of B cell development, including the mature B cell. A CD19+ B cell count of less than 100 mg/dL is suggestive of a primary immunodeficiency: X-linked agammaglobulinemia (XLA).

John’s response to vaccination antigens (tetanus and diphtheria toxoids) was measured using an ELISA to assess B cell function. The antibody titers were below the level of detection. Polyclonal activation of peripheral blood B cells with a B cell polyclonal activator was also below normal.

Although bacterial infections can also result from defects in the complement system, the low B cell numbers, low serum IgG, undetectable titers to immunization antigens, and defect in B cell function suggest that this is not a complement dysfunction. However, a complement defect could be ruled out by measuring the overall activation of both the classical (CH50) and alternative (AH50) pathways (see Case 11).