You're the resident on call one summer night at a tertiary care hospital, when a 5-year-old boy is transferred from a community hospital for further management of sepsis and evaluation of reported "blast cells" on a peripheral blood smear. Upon his arrival in the emergency department, the boy has a two-day history of fever, petechiae, cough, lethargy, and diminished appetite. There's a note in the chart that his right eye and cheek are swollen and that he's complaining of arthralgias of the lower extremities, bilaterally. You head down to see him.
The medical history is significant: polyarticular arthritis of unknown cause that was diagnosed when your new patient was 10 months old and congenital hypothyroidism diagnosed shortly after birth, for which he takes levothyroxine daily. His guardian (a maternal aunt, not either biologic parent) tells you that the boy is "always sick," but she can document only one hospitalization, at 3 years old for pneumonia, which required a prolonged course of antibiotics.
The child has no siblings, and is not attending preschool or day care. His biologic mother is undergoing treatment for lymphoma; otherwise, nothing significant is reported in the family history. He lives with his maternal aunt and uncle. There is one smoker but no pets in the household.
The admission review of systems, you note, is negative for any recent sick contacts, headache, visual disturbances, nasal congestion, sore throat, chest or abdominal pain, vomiting, diarrhea, or neurologic complaints. He has no history of recent trauma to the swollen eye.
You enter the ED and find an acutely ill child awaiting you. Your physical examination is worrisome—here is a pale, lethargic, irritable child. Rectal temperature is 35.7°C; blood pressure, 107/71 mm Hg; pulse, 133/min; respirations, 22/min; and oxygen saturation, 97% while breathing room air. You observe right periorbital swelling and erythema of the right cheek, without proptosis and with intact extraocular muscle function.
Other physical findings include decreased breath sounds at the base of both lungs; weak pulses in all extremities; clear heart sounds without murmurs, thrills, rubs, or gallops; delayed capillary refill (4 sec); a liver edge approximately 5 to 6 cm below the costal margin; a spleen palpable 3 to 4 cm below the costal margin; and diffuse petechiae.
So, you wonder, what is going on with this child?
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Какие будут предложения?
Highest on the list in your immediate differential diagnosis are infectious causes; you presume that he has sepsis with disseminated intravascular coagulation, pneumonia, and facial cellulitis. Immediately, you obtain specimens for culture of blood and urine, then administer an intravenous bolus of normal saline (20 cc/kg) and ceftriaxone as supportive treatment.
Admission laboratory tests show a white blood cell count of 10.7 X 103/μL; hemoglobin, 9 g/dL; hematocrit, 27%; and platelet count, of 22 X 103/μL. The WBC count differential shows an absolute neutrophil count of 2 X 103/μL neutrophils and 7.5 x 103/μL lymphocytes. A peripheral blood smear reveals atypical lymphocytes but no evidence of blasts—despite the report of the community hospital from which the boy was referred.
Levels of serum electrolytes and liver enzymes are within normal ranges. The alkaline phosphatase level is 54 U/L; uric acid, 2.3 mg/dL; albumin, 2.6 g/dL; prothrombin time, 14.6 sec; International Normalized Ratio (INR), 1.3; activated partial thromboplastin time, 35 seconds; fibrinogen, 96 g/L, lactate dehydrogenase, 1,037 IU/L; and D-dimer, 3.06.
A chest radiograph demonstrates pneumonia with infiltrates in the lower lobes bilaterally. You continue IV maintenance fluids and ceftriaxone; the patient is admitted to the pediatric hematology-oncology service for further evaluation and management.
Several days pass; the boy responds well. Pneumonia, cellulitis, and petechiae resolve. Despite antibiotic therapy, however, the splenomegaly, thrombocytopenia, anemia, and joint pain persist and he develops a fever.
The presentation, a persistent neutropenia, and the history of multiple infections prompt you to expand the differential diagnosis and pursue infectious, rheumatologic and oncologic work-ups. But a battery of tests all return negative, including blood cultures; culture for adenoviruses; and HIV, cytomegalovirus, Epstein-Barr virus, parvovirus B19, antinuclear antibody, and rheumatoid factor. Bone-marrow examination reveals no evidence of malignancy.
During this expanded work-up—which takes you several days into the hospital course—other family members visit the boy, giving you the opportunity to ask more questions about the family history. Here's a revelation: One relative reports the death of a maternal uncle from overwhelming infection and that another uncle receives "monthly IV medicine."
You promptly engage an immunologic work-up. Sure enough, the patient has a diminished CD4 count of 15% (normal, 34% to 58%); an increased CD8 count of 81% (normal, 12% to 38%); and a CD4:CD8 of 0.2 (normal ratio, 0.9 to 4.. Serum immunoglobulin levels are markedly reduced: IgG, 46 mg/dL (normal, 325 to 1,300 mg/dL); IgA, 8 mg/dL (normal 25 to 240 mg/dL); and IgM, 3 mg/dL (normal, 25 to 240 mg/dL). No B lymphocytes are present in peripheral blood. Based on this information—absent peripheral B lymphocytes, agammaglobulinemia, and a family history of agammaglobulinemia—you're able to make a diagnosis:
- X-linked agammaglobulinemia—specifically, a subtype known as Bruton's agammaglobulinemia.
Described in 1952, Bruton's agammaglobulinemia was one of the first congenital immunodeficiencies to be recognized. It is an X-linked, recessive disorder that occurs in 1 of every 50,000 live births. The responsible genetic mutation was localized, in 1993, to the long arm of the X chromosome (Xq 21.3-q22).
The disorder is a result of a mutation in the gene that encodes for a cytoplasmic tyrosine kinase known as Bruton's tyrosine kinase (BTK). Absence of this enzyme results in defective development of B-cell precursors and subsequent abnormalities in antibody function.
Affected males with X-linked agammaglobulinemia (XLA), including Bruton's subtype, usually experience recurrent infections—predominantly bacterial but occasionally viral (enteroviruses) or parasitic (Giardia lamblia or Cryptosporidium). Bacterial infections are often caused by encapsulated, pyogenic organisms such as Streptococcus pneumoniae, Streptococcus agalactiae, Haemophilus influenzae, and Campylobacter spp. Such infections usually develop after maternal antibody wanes between 5 to 7 months of age. As in the case of your patient, however, infections may manifest later in life.
The most common infections are conjunctivitis, sinusitis, otitis, pneumonia, septic arthritis, meningitis, and septicemia. Some patients also have chronic viral infections with enteroviruses and hepatitis viruses; some develop progressive central nervous system infections with echoviruses and coxsackieviruses. Because of XLA, the family history may be positive for these infections, in a recurrent or chronic pattern, in male members and, even, death in young boys.
Some of the other findings noted in your patient are also associated with Bruton's agammaglobulinemia:
* Arthritis is a complication of the disorder, although its exact cause is uncertain. Chronic arthritis may be autoimmune, resulting from joint infection with an enterovirus or Ureaplasma urealyticum, or may be associated with an elevated number of circulating CD8 T cells.
* Autoimmune disease, such as hypothyroidism, coexists in 20% of patients. Recall that your patient was diagnosed with congenital hypothyroidism and has been receiving chronic levothyroxine therapy.
Affected persons are also predisposed to lymphoreticular malignancies such as lymphoma (5% of cases) and thymoma. (Of interest was the fact that the patient's biologic mother has lymphoma.) On physical exam, patients may exhibit a paucity of lymphoid tissue, adenoids, tonsils, and peripheral lymph nodes.
The immunologic profile
A picture of low or absent pan-immunoglobulin levels (each component at less than 200 mg/dL) is the diagnostic rule for Bruton's agammaglobulinemia. Specific antibodies to blood-group antigens are absent; patients fail to fully respond to routine childhood immunization. Mature B cells are absent on flow cytometric analysis. Radiographs may confirm the absence or paucity of lymphoid tissue. Neutropenia, which may be transient, persistent, or cyclic, is observed in approximately 25% of patients.
Chromosomal analysis was deemed unnecessary in this patient because agammaglobulinemia, evidence of X-linked inheritance, and absent circulating B lymphocytes are, taken together, usually sufficient to make a reliable diagnosis of Bruton's agammaglobulinemia.
Regular administration of IV immunoglobulin (IVIG)—typically, every three or four weeks—is necessary to maintain a normal level of total IgG in these patients. Antibiotic therapy is indicated in the presence of severe infection and for prophylaxis against such complications as bronchiectasis, hypoxemia, pulmonary fibrosis, and cor pulmonale.
Your patient responded well to IVIG. It is likely, although unprovable, that the facial cellulitis and pneumonia were bacterial, even though blood cultures were negative. The marked increase in CD8 T cells at presentation suggests recent or concurrent viral infection, even though all viral cultures and polymerase chain reaction studies were negative.
After discharge, the boy continued to have a marked CD8 T-cell lymphocytosis, which may be involved in the pathogenesis of the chronic polyarticular arthritis associated with agammaglobulinemia. He now receives monthly IVIG, outpatient physical therapy, and a nonsteroidal anti-inflammatory drug for joint pain (the latter was initiated after the platelet count rebounded).
How did this go undetected?
Even though your patient had been followed regularly by a community pediatrician, he came into your care suffering a life-threatening illness from an underlying immune deficiency because his was a relatively late (and dramatic) presentation of Bruton's agammaglobulinemia. In retrospect, however, he did have earlier subtle signs of an underlying problem: The history of protracted pneumonia and intermittent infection, combined with joint disease and hypothyroidism, strongly suggest some abnormality.
Detection of an immune deficiency can be accelerated by making inquiries of parents when a child's medical history suggests such a condition. Acute respiratory infections, for example, are common in healthy children—typically, at a rate of four to nine, or more, a year—and are primarily viral. But the pattern of illness in an otherwise healthy child is usually distinctive: Infections occur primarily in the winter and are punctuated by periods of good health. Such a pattern may be absent in a child who has an immune deficiency. It is necessary to distinguish the child who has common, frequent infections because of increased risk—attending day care, having school-aged siblings or a history of atopy or cystic fibrosis, being exposed to smoke passively—from the child who has an underlying immune dysfunction.
Other important variables to address in taking the history against a background of frequent infectious illness include age, the duration of illnesses, any history of complications, and the record of response to antibiotics. Also, the importance of a detailed family history cannot be undervalued—in this case, awareness of the problems of the patient's relatives would have provided an early clue to an X-linked disorder.
Closing questions
Most pediatric clinicians are routinely faced with the challenge of caring for a child who recurrently ill with infections. Some of the pertinent questions that need answering during the work-up of such a patient include:
* What risk factors might be increasing the incidence of infection?
* Is there reason to entertain a suspicion of immunodeficiency?
* What are the characteristic features of, and how does one evaluate and, later, manage a patient who has, a primary immunodeficiency?
Delving deeply into the history of the child who is "always sick" and making the diagnosis of immunodeficiency early may be essential for improving his (her) quality of life—and, even, for preventing a lethal outcome. That's X-actly the lesson to take away!
. Serum immunoglobulin levels are markedly reduced: IgG, 46 mg/dL (normal, 325 to 1,300 mg/dL); IgA, 8 mg/dL (normal 25 to 240 mg/dL); and IgM, 3 mg/dL (normal, 25 to 240 mg/dL). No B lymphocytes are present in peripheral blood. Based on this information—absent peripheral B lymphocytes, agammaglobulinemia, and a family history of agammaglobulinemia—you're able to make a diagnosis: