Fever - Case 11-4: 7-Month-Old Girl
Fever - Case 11-4: 7-Month-Old Girl: Excerpt from Pediatric Complaints and Diagnostic Dilemmas
I. History of Present Illness
A 7-month-old Japanese girl developed fever to 38.9°C associated with cough, rhinorrhea, and loose stools. Over the next few days,
the respiratory symptoms and diarrhea resolved, but her fever persisted. Six
days before admission, she was evaluated by her primary pediatrician and
diagnosed with cellulitis involving the labia majora. She was treated with
cephalexin, an oral first-generation cephalosporin. She presented to the
emergency department because of continued fevers and worsening cellulitis and
was admitted for intravenous antibiotic therapy and additional evaluation.
II. Past Medical History
Her birth history was remarkable for unconjugated hyperbilirubinemia. Her
bilirubin level peaked at 16 mg/dL and returned to normal without phototherapy.
Two months before admission, she developed otitis media that resolved after
treatment with a 10-day course of amoxicillin. Cephalexin was her only
medication at the time of admission. She had received all of the appropriate
immunizations, including three doses of the heptavalent pneumococcal conjugate
vaccine. The family history was remarkable for hepatitis A in the maternal
grandmother approximately 2 months earlier.
III. Physical Examination
T, 40.3°C; RR, 50/min; HR, 160 bpm; BP, 104/60 mm Hg; SpO2, 98% in room air
Weight, 75th percentile
Examination revealed an ill but not toxic-appearing infant. The anterior
fontanel was open and flat. Tympanic membranes were mildly erythematous but had
normal mobility bilaterally. There were no oropharyngeal lesions. Capillary
refill was brisk. The heart and lung sounds were normal. The spleen was
palpable just below the left costal margin. Examination of the genitalia
revealed significant erythema and induration of the left labia majora with mild
fluctuance. There was no crepitus. There were no other skin lesions.
IV. Diagnostic Studies
The WBC count was 3,100/mm3, with 2% segmented neutrophils, 28% monocytes, and 70% lymphocytes. The
absolute neutrophil count (ANC) was 62 cells/mm
3. Hemoglobin was 12.3 mg/dL, and platelets were 337,000/mm3. A repeat complete blood count produced similar results. Lactate dehydrogenase
and uric acid concentrations were normal. Urinanalysis did not reveal pyuria or
hematuria. Blood and urine cultures were obtained.
V. Course of Illness
Gram staining after percutaneous drainage of the labial abscess demonstrated
many gram-negative rods. She received ticarcillin-clavulanate to provide
adequate coverage for
Staphylococcus aureus and gram-negative organisms, including Pseudomonas aeruginosa. Gentamicin was added to provide additional coverage against gram-negative
organisms. A bone marrow aspirate suggested the underlying diagnosis (Fig.
11-4).
Discussion: Case 11-4
I. Differential Diagnosis
Neutropenia, defined as an absolute decrease in the number of circulating
neutrophils in the blood, can be caused by decreased production, increased
peripheral utilization, or increased destruction. The ANC is calculated by
multiplying the total WBC count by the total percentage of band forms and
segmented neutrophils: ANC = total WBC
× (percent bands + percent segmented neutrophils). In general, patients may be
characterized as having mild (1,000 to 1,500 cells/mm
3), moderate (500 to 1,000 cells/mm3), or severe (fewer than 500 cells/mm3) neutropenia. Blacks tend to have lower neutrophils counts; therefore, in some
patients an ANC of 900 cells/mm
3 may be considered normal.
The differential diagnosis of neutropenia in infancy includes a wide range of
conditions (Table 11-4). In a child who was previously healthy, the most likely
causes are alloimmune neonatal neutropenia, cyclic neutropenia, autoimmune
neutropenia (AIN) in infancy, and Kostmann syndrome. Alloimmune neutropenia, a
condition occurring in neonates, is analogous to Rh hemolytic disease. Maternal
sensitization to fetal neutrophils results in maternal immunoglobulin G (IgG)
antibodies
' crossing the placenta and causing an immune-mediated destruction of fetal
neutrophils. The neutropenia lasts several weeks but rarely persists beyond 6
months of age, making it an unlikely diagnosis in this 7-month-old patient.
Cyclic neutropenia can be diagnosed by serial WBC counts.
Less likely causes include neutropenia related to infection. Neutropenia
associated with increased peripheral utilization is possible in the context of
a serious cellulitis. Infections such as Epstein-Barr virus and parvovirus B19
can also cause neutropenia, but the normal hemoglobin and platelet count in
this case make these infections less likely. The mother does not have AIN, a
finding that sometimes leads to transient secondary neutropenia in newborn
infants.
II. Diagnosis
Bone marrow aspiration revealed a hypercellular marrow (Fig. 11-4). There was an
increased number of granulocytes with maturation to the band stage, but there
were no mature neutrophils. Quantitative serum immunoglobulins (IgA, IgE, IgG,
and IgM) were normal.
These findings combined with the neutropenia suggest the diagnosis of autoimmune
neutropenia of infancy.
Antibodies to the neutrophil-specific cell surface antigen NA1 were detected,
confirming the diagnosis of AIN of childhood. Culture of the labial cellulitis
revealed
P. aeruginosa. The patient's infection resolved with a 10-day course of ticarcillin-clavulanate. Serial
absolute neutrophil counts over the next 6 weeks revealed persistent
neutropenia, effectively excluding the diagnosis of cyclic neutropenia. She
experienced no additional infections. Her neutropenia resolved by 20 months of
age. The episode of otitis media did not appear to be related to her
neutropenia.
III. Epidemiology and Incidence
AIN can occur as an isolated phenomenon (primary AIN) or in association with a
known precipitating factor (secondary AIN), such as other autoimmune disorders,
infections, medications, and malignancies. In infants and young children, the
term
primary AIN usually refers to AIN in infancy (formerly known as chronic benign neutropenia).
The average age at diagnosis of AIN in infancy is 8 months (range, 1 to 38
months). Two thirds of patients are diagnosed between 5 and 15 months of age.
The estimated frequency is 1 per 100,000 children, making it more common than
the severe chronic neutropenias such as cyclic neutropenia.
IV. Clinical Presentation
Most patients with AIN in infancy suffer from mild infections such as otitis
media, gastroenteritis, lymphadenitis, superficial skin infections, or upper
respiratory tract infections. In one series, 6 (23%) of 26 girls developed
cellulitis of the labia majora, and 3 of these 6 infections were caused by
P. aeruginosa. Approximately 10% to 15% of patients have serious infections, including
pneumonia, sepsis, or meningitis. In approximately 10% of children, the
diagnosis is suspected only after a routine complete blood count reveals
neutropenia.
V. Diagnostic Approach
Complete blood count. At presentation, the ANC is less than 500 cells/mm3 in 70% of children (mean, 200/mm3). Most of the remaining children have an ANC between 500 and 1,000 cells/mm3. The hemoglobin level and platelet count are usually normal. The complete blood
count is repeated two or three times per week for a period of 1 month to
exclude the diagnosis of cyclic neutropenia.
Neutrophil-specific antibodies. Neutrophil-specific antibodies (usually to the NA1 antigen) are initially
detected in 70% of children with AIN in infancy. In the remaining 30%, antibody
titers are so low that antibody screening is negative initially; repeated
antibody testing on up to three additional blood samples at intervals of 2 to 4
weeks is sometimes necessary to make the diagnosis. The testing is hampered in
part by the need for a sufficient number of isolated neutrophils. Occasionally,
administering hydrocortisone before the test increases the peripheral
neutrophil count and facilitates antibody detection. Patients receiving
granulocyte colony-stimulating factor (G-CSF) may show a false-positive
antibody test result. Patients diagnosed shortly before spontaneous remission
may not have detectable antibodies.
Coombs test. A Coombs test should be considered to evaluate for the presence of a concomitant
red blood cell autoantibody.
Bone marrow aspiration. This test is not routinely required, particularly if the patient appears well
and has a normal hemoglobin level and normal platelet count. When the test is
performed, the bone marrow aspirate is usually normocellular to hypercellular.
The marrow contains a reduced number of mature neutrophils, and occasionally
there is maturation arrest at earlier stages. Bone marrow examination is normal
in 30% of cases and hypocellular in 3% of cases.
Other studies. Serum immunoglobulin determinations (IgA, IgG, IgE, and IgM) should be requested
if an underlying primary immunodeficiency associated with neutropenia is
suspected. Examples include X-linked agammaglobulinemia, hyper-IgM syndrome,
and common variable immunodeficiency. Serum vitamin B
12 and red blood cell folate levels are indicated in patients with suspected
nutritional deficiency. Other tests to consider in the patient with neutropenia
include antinuclear antibody (ANA) for collagen vascular disease, serum copper
level, and evaluation for metabolic diseases (e.g., glycogen storage disease
type Ib, Shwachman-Diamond syndrome).
VI. Treatment
Most patients require only appropriate antibiotic therapy to treat bacterial
infections as they occur. Prophylactic antibiotics are not routinely used,
because the efficacy of such prophylaxis is unclear. Some patients benefit from
antibacterial mouthwashes for occasional mouth sores and gingivitis. G-CSF,
corticosteroids, and intravenous gammaglobulin administration are not routinely
required but have been used to increase neutrophil counts in patients with
serious or recurrent infections (15% of patients with AIN in infancy). In such cases, approximately
50% of children respond to corticosteroids and 75% respond to gammaglobulin.
G-CSF is effective in almost all patients. The neutropenia resolves
spontaneously in 95% of patients, usually within 7 to 24 months. Disappearance
of autoantibodies precedes spontaneous normalization of the neutrophil count.
VII. References
1. Bux J, Behrens G, Jaeger G, et al. Diagnosis and clinical course of
autoimmune neutropenia in infancy: analysis of 240 cases.
Blood 1998;91:181–186.
2. Taniuchi S, Masuda M, Hasui M, et al. Differential diagnosis and clinical
course of autoimmune neutropenia: comparison with congenital neutropenia.
Acta Paediatr 2002;91:1179–1182.
3. Boxer LA. Neutrophil abnormalities. Pediatr Rev 2003;24:52–61.
4. Jonsson OG, Buchanan GR. Chronic neutropenia during childhood: a 13-year
experience in a single institution.
Am J Dis Child 1991;145:232–235.
5. Alario AJ, O'Shea JS. Risk of infectious complications in well-appearing children with
transient neutropenia.
Am J Dis Child 1989;143:973–976.
6. Dinauer MC. The phagocyte system and disorders of granulopoiesis and
granulocyte function. In: Nathan DG, Orkin SH, Ginsburg D, et al., eds.
Nathan and Oski's hematology of infancy and childhood, 6th ed. Philadelphia: WB Saunders, 2003:923–1010.
Pictures
Book Source Details
- Book Title: Pediatric Complaints and Diagnostic Dilemmas
- Author(s): Samir S Shah MD; Stephen Ludwig MD
- Year of Publication: 2003
- Copyright Details: Pediatric Complaints and Diagnostic Dilemmas, Copyright © 2003 Lippincott Williams & Wilkins.
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