Today is a typically hectic late-summer day on the pediatric service at your tertiary care medical center. Amid the bustle,
you've gotten a page from the emergency room to see a 5-year-old boy who has a fever and is complaining of left flank pain.
When you enter the examining room, the patient is lying in bed, resting. He looks flushed and is slightly diaphoretic.
His mother tells you that her son had been healthy until two weeks ago, when he developed an intermittent low-grade fever
for one week that was associated with vomiting, diarrhea, and fatigue. She assumed it was a "stomach bug" similar to an illness
that had already resolved in his 7-year-old brother.
After that week, the gastrointestinal symptoms subsided but the boy began complaining of a stiff neck. His primary care pediatrician
referred him to this emergency department with a concern of meningitis. The boy at no time complained of upper respiratory
symptoms, sore throat, or abdominal pain.
In the ED a week ago, evaluation of the cerebrospinal fluid revealed no white blood cells or organisms. CSF glucose and protein
levels were within the normal range. The patient was discharged with a presumptive diagnosis of viral meningitis while the
results of blood and CSF cultures were pending. His mother was instructed to bring him back to the primary care pediatrician
if his condition became worse.
Fatigue and lost appetite, so it's back to the ED
The boy's condition improved for two days; then the low-grade fever recurred and shortly reached as high as 103 F orally.
Earlier today, he was brought back to his primary care pediatrician. His mother reported that he continued to be fatigued
and had little interest in food. Headache and neck pain had become worse, but without restriction of neck movement. He had
had an episode of loose, watery stool yesterday, after which he complained of left lower flank pain. There had been no change
in urination or complaint of dysuria. The physician sent the patient back to your ED for evaluation and treatment.
On further questioning, you learn that the patient has no cough, rhinorrhea, or congestion. He has no rash or new insect bites,
and no joint pain. His mother tells you she noticed that his fevers came on in the evening and were associated with chills
and some diaphoresis. He is tolerating some food but his appetite is still poor.
The medical history is unremarkable; your patient was in good health until this illness. Immunizations are up to date; he
has had no hospitalizations, allergies, or surgery. The birth and developmental history are unremarkable.
The family medical history is significant for respiratory illness in his older brother, who was hospitalized one year ago,
during the summer, with pneumonia and a pleural effusion that required decortication. The pneumonia responded to ceftriaxone,
and the brother has since been healthy. As you've already been told, that brother recently had a "stomach bug" but recovered
and had no other illness. A 3--year-old sister is healthy. The mother is in good health but reports that she had epiglottitis
as a child that required emergency tracheotomy, and she has seasonal allergies. His father is in good health. The patient
and his family live in a suburban neighborhood. The children spend much of their time in the basement of their home, where
a dehumidifier runs constantly but is cleaned daily. The family also has a covered fish tank.
You question the mother about the boy's travel history. Two weeks ago, she explains, the family took a camping trip in a mobile
home to Niagara Falls, N.Y. There, the patient and his brother first felt ill, complaining of stomach pain. Afterwards, the
family attended a family reunion and picnic in Connecticut. The mother reports that other children at the picnic were later
found to be ill with Coxsackievirus but that her boys did not interact with the others because they were already feeling ill.
They did not eat any of the food at the picnic, and their visit was "short."
On physical examination, you find a cooperative boy, pale but flushed, breathing heavily, and somewhat uncomfortable. Vital
signs are significant for a temperature of 103 F; pulse, 120/min; blood pressure, 104/61 mm Hg; respirations, 52/min; and
O2 saturation, 99% at room air. Height and weight are both at the 50th percentile for age. The skin is clear; no lymphadenopathy
is noted, the throat is nonerythematous, and there is no nasal discharge. The tympanic membranes are normal, and the neck
is supple and with good range of motion.
The cardiac examination is significant for tachycardia; rhythm is regular, however, and no murmurs are heard. Examination
of the chest reveals that the patient is tachypneic, with decreased breath sounds at the left base, without rales; breath
sounds in all other fields are clear.
Abdominal examination reveals no tenderness, masses, or organomegaly. Extremities are warm and well perfused. There is no
costovertebral angle tenderness, but you do note that the boy leans to the left side, with guarding on that side, during your
exam.
A suspicion of pneumonia, but pyelonephritis remains a concern
You order a complete blood count, blood cultures, urinalysis with Gram stain and culture, and a chest radiograph. The white
blood cell count is 18.7 X 103/L; hemoglobin level, hematocrit, and platelet count are all within normal limits. A manual differential count shows 68%
segmented neutrophils, 6% band neutrophils, 18% lymphocytes, and 8% monocytes. Blood is sent for culture. Urine does not contain
WBCs, casts, or bacteria and is of normal pH and specific gravity; urine culture is negative.
Figure 1. Admission plain films: Medial left-upper-lobe consolidation
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Radiographs of the chest taken at admission reveal volume loss in the left hemithorax with elevation of the left diaphragm
(Figure 1). There is medial left-upper-lobe consolidation that you believe is most likely caused by Streptococcus pneumoniae, as it is the most common cause of bacterial pneumonia in children the patient's age.
Figure 2. CT confirms pneumonia, reveals more
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You prescribe ceftriaxone until the patient can tolerate oral antibiotics, and expect to see his condition improve over the
next one or two days. You're disappointed to learn, however, that, a few days later, he remains febrile, diaphoretic, and
tachypneic and continues to favor his left side. You order a computed tomography (CT) scan of the chest to define the opacity
in the left-upper lobe and look for other causes of the symptoms. The scan (Figure 2) shows not only left-upper-lobe pneumonia
with extension into the posterobasilar and superior segments of the left lower lobe but also—a surprise—multiple pulmonary
nodules that were not visualized on the plain films of the chest. No lymphadenopathy is seen.
What could cause the small nodules not seen on plain films? What to do next? Possible causes of pulmonary nodules in children
his age include tuberculosis, septic emboli, arteriovenous malformations, fungal infection, lymphoma and other neoplasms,
round pneumonias associated with early pneumococcal infection, infection with atypical mycobacteria, Mycoplasma infection, sarcoidosis, and chronic granulomatous disease.1
Earlier blood cultures are negative at 48 hours. You prescribe vancomycin for possible resistant pneumococcus and azithromycin
to treat atypical organisms (Mycoplasma, Legionella). A purified protein derivative test is placed; 48 hours later, it is read as nonreactive.
After three days, the boy still has not improved. Bronchoscopy with lavage is performed to evaluate the process that underlies
the pulmonary nodules. Lavage fluid at the time of bronchoscopy is clear. The examination is significant only for a small
submucosal mass in the bronchus intermedius. Bronchial washings are sent for culture for aerobic and anaerobic bacteria, Legionella, Mycoplasma, fungi, and acid-fast bacilli. He continues to have an intermittent fever as high as 102 F and periods of tachypnea. After
three days, no growth is seen in the cultures.
A "B" in microbiology
You're considering a recommendation for lung biopsy when a call from the microbiology lab informs you that gram-negative bacteria
are growing on a culture of the bronchial washing. You examine the culture plates with the microbiologist and concur that
the growth pattern of the colonies is similar to that of Pseudomonas. Subsequently, the lab identifies the organism as Burkholderia cepacia.
You learn that B cepacia is a gram-negative, catalase-positive, non-fermenting bacillus that can cause serious pulmonary infections in persons with
cystic fibrosis. The pathogen causes bacteremia in premature infants and nosocomial wound, urinary tract, and lung infections,2 and can infect children afflicted by a hemoglobinopathy, malignancy, or chronic granulomatous disease.
The B cepacia complex comprises at least seven species, all of which are pathogens in an immunocompromised human host. The organism is
water- and soil-borne and able to survive for a long period in a moist environment.3 Speculation at this point? The family's dehumidifier could be the source of his infection.
Trimethoprim-sulfamethoxazole (TMP-SMX) and piperacillin-tazobactam are effective in the treatment of B cepacia.4 Therapy is begun, and the boy begins to improve. He becomes afebrile within 48 hours and the tachypnea resolves. A percutaneous
intravenous catheter is placed for four weeks of IV antibiotics. At discharge, you schedule the patient for an outpatient
sweat chloride test, with follow-up by the pediatric pulmonary service.
Through the revolving ED door
But two days later, he returns again with fever, rash, and cervical lymphadenopathy. You order another chest radiograph, which
shows slight improvement of the left-upper-lobe pneumonia. What should you do next?
TMP-SMX can cause a rash, and so you decide to discontinue it. Nebulized tobramycin aerosol is added, as well as clindamycin
for the cervical lymphadenopathy. The boy is again discharged, five days later. At discharge, the piperacillin-tazobactam
and the nebulized tobramycin are continued and ceftazidine is added. Third-generation cephalosporins have also been shown
to be effective in the treatment of B cepacia.4
Three days later, the patient returns with a new rash, although he has not had a recurrence of fever and the cervical lymphadenopathy
has resolved. A sweat chloride test is negative. You stop the piperacillin-tazobactam and ceftazidine and add oral ciprofloxacin.
Nebulized tobramycin is continued for one month, after which a CT scan shows that the size of the nodules has decreased.
How can a previously healthy 5-year-old who does not have cystic fibrosis develop B cepacia pneumonia? From what you have learned about B cepacia, it is usually pathogenic in the immunocompromised. This patient's immunoglobulin levels and T cell panels are normal. Could
the pulmonary nodules be a malignancy? That's unlikely, in the absence of adenopathy and abnormal laboratory results.
Is chronic granulomatous disease (CGD) a possibility? This rare condition is caused by the inability of neutrophils to effectively
kill catalase-positive microorganisms. Neutrophils of CGD patients demonstrate normal chemotaxis, phagocytosis, and degranulation
but cannot kill catalase-positive microbes such as Staphylococcus aureus and many gram-negative organisms, including B cepacia, Candida albicans, and Aspergillus and other fungi.5 How does this happen? Normally, oxygen is reduced by the oxidase complex (NADPH) superoxide anion, which is mutated to hydrogen
peroxide and hydroxy radicals that kill microbes intracellularly. The fundamental defect in CGD is the absence of hydrogen
peroxide. H influenzae and other catalase-negative organisms produce their own hydrogen peroxide, and are therefore killed with success by neutrophils,
even in CGD patients.6
CGD can manifest at any age and with various signs and symptoms. Certain features suggest the diagnosis, however, including
a history of severe, recurrent infections of the skin and lymph nodes; pneumonia; osteomyelitis; and hepatosplenomegaly—caused
by catalase-positive organisms such as S aureus, fungi, and many gram-negative organisms.7 Might your patient have CGD? You scramble to determine what test you can use to make the diagnosis.
Another turn to the laboratory
You learn from the clinical laboratory that, in fact, two tests are available to confirm the diagnosis of CGD:
- The older nitroblue tetrazolium (NBT) test is based on the principle that a normal neutrophil, when stimulated, will turn the colorless NBT dye to purple formazan,
which is visible within neutrophils under microscopy. Neutrophils that are unable to oxidize NBT lack colored inclusions.7
- That test is being replaced by a more accurate test, however: the dihydrorhodamine (DHR) 123-fluorescence test,8 in which an increase in fluorescence is noted when neutrophils exhibit normal oxidant production.5
You also learn that the answer won't come quickly: The DHR test is available only from a distant laboratory. A blood specimen
is sent. Results show that only 69% of neutrophils in the specimen are positive, indicative of markedly diminished oxidative
activity and supporting a diagnosis of CGD.
Coincidentally, the patient is readmitted the day the results of the DHR test become available, with left groin lymphadenopathy
and rectal pain. Sigmoidoscopy demonstrates fissures and granulomas. Crohn's disease and rectal granulomas are rare manifestations
of CGD.2 (This patient was not diagnosed with Crohn's.)
You discuss the diagnosis with the family and the need for DHR testing on the boy's brother, sister, and parents. You recall
from the family history that the patient's brother had an admission to the hospital one year earlier, for pneumonia and pleural
effusions that required decortication. DHR testing of the family reveals that the brother is affected and the mother is a
carrier, confirming that the patient has an X-linked form of CGD. The genetic testing also shows that the sister is not a
carrier.
What do you tell the family? There is encouraging news to offer them about treatment and the prognosis:
- Chronic prophylaxis with TMP-SMX, interferon-γ, and itraconazole will prevent many of the associated serious infections.
- Most abscesses that develop will require aggressive surgical therapy and prolonged antibiotic therapy.
- Trials of bone marrow transplantation are under way.
- Although the highest mortality from CGD is in young children, effective therapy and better understanding of the disease have
improved long-term prognosis.5
At this time, your patient and his brother are doing well on prophylactic therapy comprising itraconazole, interferon-γ, and,
after desensitization, TMP-SMX as well. The family is working with a clinical geneticist to weigh the possibility of bone
marrow transplantation for both boys someday.
DR. LAHTINEN-ALEY is a second-year pediatric resident at Albany Medical College, Albany, N.Y., where DR. LEPOW is a professor
in the department of pediatrics and chair of the section of infectious diseases.
The authors and section editor have nothing to disclose in regard to affiliations with, or financial interests in, any organization
that may have an interest in any part of this article.
REFERENCES
1. Kuhn J: Overview of imaging procedures in the pediatric neck and thorax, in Kuhn J, Slovis T, Haller J (eds): Caffey's Pediatric Diagnostic Imaging, ed 10. St. Louis, Mo., Mosby, 2004, p 771
2. Nauseff W, Clark R: Granulocytic phagocytes: Chronic granulomatous disease, in Mandell, Bennett, and Dolin (eds): Mandell, Douglas, and Bennett's Principles and Practice of Infectious Disease, ed 6. New York, N.Y., Churchill Livingstone, 2000, pp 106-108
3. Burkholderia infections, in Pickering LK (ed). Red Book: 2003 Report of the Committee on Infectious Diseases, ed 26. Elk Grove Village, Ill., American Academy of Pediatrics, 2003, pp 224,225
4. Maschmeyer G, Gobel U: Stenotrophomonous maltophilia and Burkholderia cepacia: Burkholderia cepacia, in Mandell, Bennett,
and Dolin (eds): Mandell, Douglas, and Bennett's Principles and Practices of Infectious Disease, ed 6. New York, N.Y., Churchill Livingstone, 2005, pp 2619
5. Boxer L: Disorders of phagocytic function, in Behrman R, Kliegaman R, Jenson H (eds): Nelson's Textbook of Pediatrics, ed 17. Philadelphia, Pa., W.B. Saunders, 2004, pp 715-717
6. Andrews T, Sullivan K: Infections in patients with inherited defects in phagocytic function. Clin Microbiol Rev 2003,16:597
7. Gentile D, Michaels M, Skoner D: Allergy and immunology, in Zitelli B, Davis H (eds): Atlas of Pediatric Physical Diagnoses, ed 4. St. Louis, Mo., Mosby, 2002, pp 112,125
8. Segal BH, Holland HM: Primary phagocytic disorders of childhood Pediatr Clin North Am 2000;47:1311
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