This article is more than 5 years old. Information may no longer be current.
Identify the immunodeficiency
This series will feature various questions focusing on immunocompromised patients.
Click Here to Manage Email Alerts
A 34-month-old boy presented with two weeks of fever, diarrhea and cough.
He had been evaluated several days earlier and was prescribed amoxicillin/clavulanic acid for acute otitis media; however, his parents failed to fill the prescription. His cough progressed and became productive. A chest radiograph revealed bilateral patchy infiltrates. The patient was then admitted for IV antibiotics and further diagnostic evaluation.
Pregnancy and delivery at term were uncomplicated. His medical history was significant for gastroesophageal reflux and multiple otitis media episodes, requiring antibiotics every one to two months until he was 2 years old. His immunizations were up to date. Over the past year, the patient’s weight gain had been poor, and he had begun to fall off the growth curve. Three weeks prior to admission, he was diagnosed with sinusitis and completed a two-week cefazolin course.
On admission, the following labs were obtained: white blood cell count 16.1 × 103/mm3, with 3% neutrophils, 68% lymphocytes, 17% monocytes and 9% basophils. Blood and urine cultures demonstrated no growth. After several days of antibiotic therapy with little clinical improvement, a chest CT was obtained that showed bilateral interstitial infiltrates as well as some areas of bronchiectasis. On further discussion, the family disclosed that a maternal uncle had required frequent infusions because of an immune deficiency.
What is the most likely diagnosis?
- X-linked agammaglobulinemia
- Hyper-IgM syndrome
- Severe combined immune deficiency (SCID)
- Primary ciliary dyskinesia (PCD)
Answer
The correct answer is A, X-linked agammaglobulinemia (XLA).
The patient’s serum specific immunoglobulins were: IgG 42mg/dL, IgA 13 mg/dL and IgM 7 mg/dL (normal values for age, IgG 441-1135 mg/dL, IgA 22-159 mg/dL and IgM 47-200 mg/dL). The uncle had been receiving IV immune globulin. Antibody titers to tetanus and varicella were also quite low. Flow cytometry revealed no CD19-positive cells (B-lymphocytes), and mutation analysis showed a disease-associated mutation in the Bruton’s tyrosine kinase (Btk) gene. Btk is necessary for B-cell maturation and immunoglobulin expression on the cell surface. Patients with XLA have low or undetectable Btk kinase activity. More than 250 mutations in the Btk gene have been recognized.
Maternally transmitted IgG protects most boys with XLA during the first six to nine months. Thereafter, these children often acquire infections with Streptococcus pneumoniae, Haemophilus influenzae and other pyogenic organisms, necessitating immunoglobulin therapy (IV or subcutaneous) and often prophylactic antibiotics. Excluding some hepatitis viruses and enteroviruses, viral and fungal infections are generally managed normally because this is a disease primarily of B cells.
Flow cytometry
XLA should be suspected with the finding of hypoplastic tonsillar tissue or the absence of palpable lymph nodes on exam. Low serum of IgG, IgA, IgM and IgE (usually less than 100 mg/dL total immunoglobulin) also support an XLA diagnosis. Finally, flow cytometry is an important test to determine the absence of circulating B cells, which distinguishes XLA from other immune deficiencies.
The most common cause of Hyper-IgM syndrome, CD40 ligand deficiency, is also X-linked and has a similar presentation. Boys generally become symptomatic before the second year of life. Recurrent pyogenic infections are common, including otitis media, sinusitis, pneumonia and tonsillitis. In contrast to patients with XLA, these patients may present with Pneumocystis carinii pneumonia, have normal numbers of circulating B cells. Circulating T cells are also present in normal number, but antigen-specific T-cell function is decreased.
Although a history of diarrhea, pneumonia and recurrent otitis media may be consistent with the initial presentation of a child with SCID, this is unlikely in our patient. Infants with SCID typically present shortly after birth with severe infections and lymphopenia (less than 2 × 103/mm3). Serum immunoglobulin concentrations are diminished to absent, and no antibodies are formed after immunizations.
PCD is also known as immotile cilia syndrome. PCD should be included in the differential diagnosis of children with chronic or recurring respiratory infections, especially if there is associated otitis media. About half of these patients have Kartagener syndrome and have the associated situs inversus. For all patients with PCD, chest radiographs may demonstrate hyperinflation, bronchial wall thickening and peribronchial infiltrates. Unlike XLA, patients with PCD demonstrate intact cell-mediated and humoral immunity.
For more information:
- Winkelstein JA, Marino MC, Lederman HM, et al. X-linked Agammaglobulinemia: report on a United States registry of 201 patients. Medicine. 2006;85:193-202.
- Behrman RE. Primary combined antibody and cellular immunodeficiencies. In: Behrman RE, Kliegman R, Jenson HB, eds. Nelson Textbook of Pediatrics. 17th ed. Philadelphia, Pa.: Saunders; 2004.
- Lopez-Granados E, Pèrez de Diego R, Ferreira Cerdán A, et al. A genotype-phenotype correlation study in a group of 54 patients with X-linked Agammaglobulinemia. J Allergy Clin Immunol. 2005;116:690-697.
- Notarangelo L, Casanova JL, Conley ME, et al. Primary immunodeficiency diseases: an update from the International Union of Immunological Societies Primary Immunodeficiency Diseases Classification Committee Meeting in Budapest, 2005. J Allergy Clin Immunol. 2006;117:883-896.
- Acknowledgments: The authors thank Dr. Steven Holland, for his careful editing of the case, and Margaret Brown for the figure of flow cytometry.
- Eleanor Martin and Jason Mitchell are the chief pediatric residents at Georgetown University Hospital.