HISTORY OF PRESENT ILLNESS
A 7-month-old Japanese girl developed fever to 102°F associated with cough, rhinorrhea, and loose stools. During the next few days, the respiratory symptoms and diarrhea resolved; however, her fever persisted. Six days prior to 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 due to continued fevers and worsening cellulitis and was admitted for intravenous antibiotic therapy and additional evaluation.
The girl’s birth history was remarkable for unconjugated hyperbilirubinemia. Her bilirubin level peaked at 16 mg/dL and returned to normal without phototherapy. Two months ago, 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 ago.
T 40.3°C; HR 160 bpm; RR 50/min; BP 104/60 mmHg; SpO2 98% in room air
Weight, 75th percentile
Examination revealed an ill but nontoxic appearing infant. The anterior fontanelle 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.
The WBC count was 3100/mm3 with 2% segmented neutrophils, 28% monocytes, and 70% lymphocytes. The absolute neutrophil count (ANC) was 62 cells/mm3. Hemoglobin and platelets were 12.3 mg/dL and 337 000/mm3, respectively. A repeat complete blood count revealed similar results. Lactate dehydrogenase and uric acid were normal. Urinalysis did not reveal pyuria or hematuria. Blood and urine cultures were obtained.
COURSE OF ILLNESS
Gram-stain after percutaneous drainage of the labial abscess demonstrated many Gram-negative rods. She received vancomycin and piper-acillin-tazobactam to provide adequate coverage for Staphylcoccus aureus (including methicillin-resistant S. aureus isolates) and Gram-negative organisms, including Pseudomonas aeruginosa. A bone marrow aspirate suggested the underlying diagnosis (Figure 11-4).
FIGURE 11-4. Bone marrow aspirate.
DISCUSSION CASE 11-4
Neutropenia, defined as an absolute decrease in the number of circulating neutrophils in the blood, can be due to decreased production, increased peripheral utilization, or increased destruction. The absolute neutrophil count (ANC) is calculated by multiplying the total white blood cell (WBC) count by the percentage of band forms and segmented neutrophils [ANC = total WBC × (percent bands + percent segmented neutrophils)]. In general, patients may be characterized as having mild (1000-1500 cells/mm3), moderate (500-1000 cells/mm3), or severe (<500 cells/mm3) neutropenia. Blacks tend to have lower neutrophil counts, and therefore, in some patients an ANC equal to 900 cells/mm3 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 include alloimmune neonatal neutropenia, cyclic neutropenia, autoimmune neutropenia 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 IgG antibodies crossing the placenta and causing an immune-mediated destruction of fetal neutrophils. Neutropenia lasts several weeks but rarely persists beyond 6 months of age, making it an unlikely diagnosis in this 7-month-old infant. Cyclic neutropenia can be diagnosed by following serial white blood cell counts.
TABLE 11-4. Differential diagnosis of neutropenia in infancy.
Less likely cause includes 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 infection can also cause neutropenia but the normal hemoglobin and platelet count make these infections less likely. The mother does not have autoimmune neutropenia, a finding that sometimes leads to transient secondary neutropenia in newborn infants.
Bone marrow aspirate revealed a hypercellular marrow (Figure 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, 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 autoimmune neutropenia of childhood. Culture of the labial cellulitis revealed P. aeruginosa. The patient’s infection resolved with a 10-day course of piperacillin-tazobactam. Serial absolute neutrophil counts during 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.
EPIDEMIOLOGY AND INCIDENCE
Autoimmune neutropenia (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 autoimmune neutropenia in infancy (formerly chronic benign neutropenia). The average age at diagnosis of AIN in infancy is 8 months (range, 1-38 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.
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 the 26 girls developed cellulitis of the labia majora; 3 of these 6 infections were caused by P. aeruginosa. Approximately, 10%-15% suffer from serious infections including pneumonia, sepsis, or meningitis. In approximately 10% of children, the diagnosis will be suspected only after a routine complete blood count reveals neutropenia.
Complete blood count. The complete blood count reveals neutropenia (absolute neutrophil count <1000/mm3). Eosinophilia occasionally occurs. Patients with other causes of neutropenia may have anemia or thrombocytopenia (as occurs with Evan syndrome).
Neutrophil-specific antibodies. Anti-neutrophil antibodies are not consistently identified during the period of neutropenia. Therefore, such testing is not necessary in children with a normal hemoglobin and platelet count or with a bone marrow aspirate result consistent with the diagnosis of autoimmune neutropenia of infancy.
Coombs test. A Coombs test should be considered to evaluate for the presence of a concomitant red blood cell autoantibody.
Bone marrow aspirate. This test is not routinely required, particularly if the patient appears well and has a normal hemoglobin level and platelet count. When 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 immunoglobulins (IgA, IgG, IgE, IgM) should be sent if an underlying primary immunodeficiency associated with neutropenia is suspected. Examples include X-linked agammaglobulinemia, hyper-IgM syndrome, and common variable immunodeficiency. Serum vitamin B12 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; collagen vascular disease), serum copper level, and evaluation for metabolic diseases (e.g., glycogen storage disease type Ib, Shwachman-Diamond-Oski syndrome).
Most patients only require antibiotics to treat bacterial infections as they occur. Prophylactic antibiotics are not routinely used because the efficacy is not definite. Some patients benefit from antibacterial mouthwashes for occasional mouth sores and gingivitis. G-CSF, corticosteroids, and intravenous gamma globulin administration are not routinely required but they 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 gamma globulin. G-CSF is effective in almost all patients. The neutropenia resolves spontaneously in 95% of patients, usually in 7-24 months. Disappearance of autoantibodies precedes spontaneous normalization of the neutrophil count.
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