CASE 3
John, a 12-month-old boy with severe gram-positive bacterial pneumonia, has been referred to the local pediatric hospital by the family’s general practitioner. In addition to the fact that this is his fourth such infection in 6 months, he has had recurrent diarrhea (Giardia lamblia) and his tonsils/adenoids are barely detectable. As well, John is below the norm for height and weight. He has received the recommended DTaP (diphtheria, tetanus toxoids, and acellular pertussis) pediatric immunizations (see Fig. 45-1). John has three healthy sisters aged 3, 5, and 7 years. The family lost a boy at 10 months of age to bacterial pneumonia 8 years ago. Blood test results show low total serum immunoglobulin levels, few B cells, but normal numbers and functioning of T cells. All tests for macrophage/neutrophil function and number are normal. Medical and family histories, as well as blood test results, were included in the file that the family physician sent to the hospital. How would you proceed?
QUESTIONS FOR GROUP DISCUSSION
RECOMMENDED APPROACH
Implications/Analysis of Family History
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.
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).
Additional Laboratory Tests
John has few B cells and low serum immunoglobulin levels, which is suggestive of an early block in B cell differentiation (so-called differentiation arrest) and is a relatively classic presentation of XLA (Bruton’s hypo- [or agamma-] globulinemia). A block at a later stage in B cell differentiation would have higher circulating B cell numbers. Molecular testing for mutations in the Btk kinase, the defect in XLA, would confirm the diagnosis.
DIAGNOSIS
John was diagnosed with X-linked agammaglobulinemia (Bruton’s hypo- or agammaglobulinemia).
THERAPY
Gamma Globulin Therapy
Conventional treatment involves the life-long replacement of the defective components (i.e., serum immunoglobulin replacement). Passive immunization with monthly intravenous injections of pooled gamma globulins (˜500 mg/kg administered over ˜4 hours) that contain IgG against a broad spectrum of bacteria, viruses, and parasites is recommended. Because many of these patients are IgA deficient the immune globulin selected must not contain any IgA, to avoid possible anaphylaxis (see Case 5).
ETIOLOGY: X-LINKED AGAMMAGLOBULINEMIA
In XLA, mutations in the X chromosome gene encoding the Btk tyrosine kinase (Bruton’s agammaglobulinemia kinase) are present in all patients. The initial B cell development block occurs at the pro-B cell to pre-B cell transition. Because this kinase plays a key role in signaling pathways that regulate activation, differentiation, and proliferation of B cells, these mutations lead to a profound dysfunction in B cell numbers and function. Molecular genetic testing may allow identification of carriers of the Btk gene and hence provide the basis for early diagnosis of XLA.
TRANSIENT HYPOGAMMAGLOBULINEMIA OF INFANCY
In all infants, signs of hypogammaglobulinemia occur around 6 months of age when passively transferred maternal antibodies have been degraded. The serum immunoglobulin level at this time is approximately 350 mg/dL, so it is not surprising that most infants experience many respiratory tract infections around this age. Transient hypogammaglobulinemia of infancy, also referred to as hypogammaglobulinemia of early childhood, presents as many of the same infections as described for John, including recurrent gastroenteritis, otitis media, and respiratory tract infections. Additionally, IgG serum levels are depressed or undetectable. In contrast to patients with XLA, however, IgM serum levels are normal, as is the B cell count. Some studies have shown that, at least in some patients, in vitro stimulation of B cells in response to direct B cell activation results in the production of IgG. In these same patients, there is a deficiency in the number and function of CD4+ T cells, suggesting that the defect in this disorder results from a maturational delay in T cell development. T cells are required for B cell activation and isotype switching.