July 2003

A 15-month-old male was admitted to the hospital in respiratory distress after two days of worsening respiratory symptoms. He went straight to the pediatric intensive care unit (PICU), where he soon required intubation and ventilator-assisted breathing. He was also found to be febrile with a temperature of 101° F and tachycardic with a pulse rate of 120. Examination revealed coarse breath sounds with ventilator noise. His capillary refill was two seconds. His chest radiograph on admission and about 36 hours later are shown in figures 1 & 2 respectively. Initial blood work revealed a white blood cell count of 1,900 with no granulocytes, 50% lymphocytes and 48% monocytes. Multiple blood cultures for fungi and bacteria were negative, but a tracheal aspirate via the endotracheal tube was sent for culture, ultimately growing multiple organisms, including Moraxella catarrhalis, Escherichia coli, Streptococcus pneumoniae and Staphylococcus aureus. Antibiotic treatment was initiated on admission with vancomycin plus ceftriaxone (Rocephin, Roche). The patient remained on the ventilator for four days, then transferred to the ward on hospital day 11.

The patient’s past medical history is positive for being admitted approximately six months earlier at a local hospital with asthma and thrush. He had also been seen on several other occasions over the past few months for various infections, including otitis media and herpes stomatitis.

His immunizations were current through 6 months and his developmental and family histories were normal or unremarkable. Because of his frequent infection history over the last six months and this current severe pneumonia, an immune evaluation was initiated. Quantitative immunoglobulins, compliment screen, HIV antibody, antibodies to vaccine antigens, nitroblue tetrazolium (NBT) dye test, cellular assay and bone marrow aspirate were performed. The results showed an IgG below detectable levels & low levels of other immunoglobulins, no antibodies to tetanus or Haemophilus influenzae type b, and the bone marrow exam revealed maturation arrest, however, his neutrophil count normalized as he recovered. Cellular analysis revealed that he had no detectable B cells. The rest of the tests were normal.

What’s Your Diagnosis?

1. Common variable immunodeficiency
2. Transient hypogammaglobulinemia of infancy
3. Chronic granulomatous disease
4. X-linked agammaglobulinemia

Answer

This case is most consistent with X-linked agammaglobulinemia. U. S. Army Col. Ogden C. Bruton MD, first described this condition while he was chief of pediatrics at Walter Reed Army Medical Center (Pediatrics. 1952;9:722-727). As the name indicates, this is an X-linked disorder marked by a severe deficiency or absence of IgG secondary to few to no B-cells production. There are usually low levels of the other immunoglobulins as well. These patients tend to be healthy during the first six months of life because of passive antibody acquired prior to birth. By 1 to 2 years of age, frequent, severe infections are usually being seen, and diagnosis is typically made by 2 to 3 years of age. In families with one boy already diagnosed, the condition will probably be picked up much earlier, as it has an X-linked recessive inheritance. To read more about this disorder at the genetic and molecular level, I would recommend E. Richard Stiem’s textbook, Immunologic Disorders in Infants & Children. I have the 4th edition from 1996. I do not know if a newer one exists, but I have found this book very helpful with sorting out immune problems in children. Information on this disorder can be found in chapter 11, page 302, by Hans D. Ochs of Seattle and Jerry Winkelstein of Johns Hopkins.

Treatment consists of monthly infusions of intravenous immune globulins (IVIG) at doses sufficient enough to have trough levels of IgG around 500 mg/dl. This usually means beginning with a dose of about 400 mg/kg per infusion. In the days prior to the availability of IVIG, these patients had to take large, painful doses of intramuscular immune globulins, which did not achieve the degree of antibody level as the IV preparation. Therefore, protection from severe infections was not as successful.

The presentation can be variable from frequent episodes of otitis media, sinusitis and pneumonia to meningitis with sepsis. No two patients present the same. I recall consulting on a couple of adolescent brothers with Bruton disease who were both deaf from bacterial meningitis. However, after IVIG became available, they did very well. After the patient presented was diagnosed, his younger brother was screened and found to have the defect also. They both had ports placed and began the monthly regimen of IVIG. This patient recovered (figure 3) and discharged on hospital day 15.

Common variable immunodeficiency may present clinically the same as Bruton disease, but it may show up at any age, and tends not to be quite as severe. It can also be associated with autoimmune problems, chronic diarrhea and neutropenia. They also tend to have normal or near-normal B lymphocyte numbers, but can have a mixed T- and/or B-cell defect. Treatment depends on the clinical manifestations and measurable defects. They usually require IVIG the same as Bruton’s patients, but if the patient has a defect of the T cells, clinical results may not be as good.

Transient hypogammaglobulinemia of infancy (THI) results from a slow recovery as maternal IgG is eliminated. If the baby is diagnosed as a result of an unusual or severe infection, the diagnosis of THI may not be made until after the IgG level recovers back to normal. This is usually “discovered” as the child’s IgG is being monitored during therapy with IVIG. If the trough levels are beginning to look higher than expected, the diagnosis of THI then becomes likely. Then ports can be pulled and life can happily go back to normal.

Chronic granulomatous diseases (CGD) is also an X-linked disorder in some, but an autosomal recessive form has also been described. It is a disorder of the immune system that may present with recurrent sinopulmonary infections, cutaneous abscesses, bone & joint infections, and may have gastrointestinal findings consistent with Crohn’s diseases.

The underlying problem is related to a defect in the phagocyte’s ability to kill certain organisms because of a failure of the cellular respiratory burst. This only affects those organisms that are catalase-positive, such as staphylococcus, pseudomonas, salmonella and fungi. Catalase-negative organisms produce hydrogen peroxide, which the defective phagocyte can then incorporate into the cidal process. The most notable catalase-negative organism is the streptococcus. In fact, the catalase test is one of the common ways streptococcus and staphylococcus are initially differentiated in the lab. Diagnosis is usually suspected with a positive NBT. More sensitive testing of the respiratory burst is done in some reference labs. Therapy is mainly through infection vigilance, early therapy and surgical drainage when needed, and antimicrobial prophylaxis.

Col. Ogden Bruton was one of the pioneers of military pediatrics. Born in Mount Gilead, N.C. in 1908, he went on to establish and develop the pediatric department and residency program at Walter Reed Army Medical Center in the late 1940s. In 1952, Dr. Bruton published his landmark paper on agammaglobulinemia referenced above. While managing a patient with recurrent pneumococcal infections, he discovered that this 8-year-old boy, Joseph S. Holtoner, Jr., had no gamma fraction when his serum was subjected to electrophoresis.

According to the late Col. Jim Bass, this was like many great discoveries, a bit of serendipity. Apparently, Dr. Bruton was using the child’s leftover blood from the many tests he was having done because of his frequent admissions to the hospital, to “run through” the new instrument. The genius was in recognizing the connection between the absence of the child’s gamma fraction and his recurrent infections.

Dr. Bruton also served in Europe during World War II and went on to complete a distinguished Army career. As one of the pioneers in pediatric medicine, in 1969 Dr. Bruton had a research award named in his honor, given by the Uniformed Services Section of the American Academy of Pediatrics. He always attended the annual Uniformed Services Pediatric Seminar (USPS) to give the award, but in recent years, he had been too ill to attend. He died earlier this year at the age of 94.

I took a picture in 1992 at the USPS meeting in Washington, DC (figure 4) of Dr. Bruton (middle) along with Andy Margileth (right), and the late Howard Johnson (left), both also pioneers of Navy and Air Force Pediatrics, respectively. Drs. Johnson and Margileth also have research awards named in their honor by the Uniformed Services Section. Dr. Johnson established the first pediatric residency program in the Air Force at Wilford Hall Air Force Medical Center in San Antonio. Dr. Margileth is renowned for his academic excellence in pediatrics, dermatology and pediatric infectious diseases.

These legendary names provoke pride among military pediatricians, past and present. Since military pediatricians’ pay is not that great, pride in the long, rich history of this high quality pediatric system is one of their main rewards. To read more about Ogden Bruton and the history of military pediatrics, I strongly recommend the paper published by my old friend, Col. Chuck Callahan, Chief of the Department of Pediatrics, Tripler Army Medical Center, Hawaii, in Pediatrics. 1999;1298-1303.

For more information:

• James H. Brien, DO, Pediatric Infectious Disease, Scott and White’s Children’s Health Center and Associate Professor of Pediatrics, Texas A&M University, College of Medicine, Temple, Texas. E-mail: jhbrien@aol.com.