Neonatal Neutropenia
INTRODUCTION: NEUTROPENIA
The neutrophil is a myeloid-derived white blood cell important in combating bacterial and fungal infections. For a more detailed discussion of neutrophil development and immunologic function, refer to chapters 49 and 51. Most neutrophil abnormalities in the neonate involve quantitative disorders of the neutrophil, with the vast majority of clinical issues involving decreased neutrophil counts or neutropenia. Neutropenia is defined as an absolute neutrophil count (ANC) less than 1500/mm3. In a newborn, there can be many causes, some acquired with expected resolution, such as increased utilization of neutrophils with low marrow reserve or failures of production or release from the bone marrow, or there can be congenital causes, which are expected to be lifelong. The patient may have different clinical presentations depending on the etiology. Because of the low neutrophil reserve (capacity to produce neutrophils) in the bone marrow, the neonate is especially prone to development of neutropenia. Differentiating the etiology of neutropenia in an infant is therefore dependent on thorough knowledge of the maternal (both pregnancy and delivery) and neonatal history, as well as the physical examination of the infant, in conjunction with appropriate laboratory tests.
INITIAL CLINICAL APPROACH
Because the severity and the cause of neutropenia may often be fatal in this patient population and because of the limitations of blood volume available for laboratory testing, a prompt but logical approach to the workup is essential. A thorough history can indicate if immediate assessment is necessary. Information, such as appropriate prenatal care, maternal medications, difficulties during pregnancy, fetal vital signs, complications during delivery, and Apgar scores should be included in the initial assessment. The past medical histories of parents and family members, in particular infections, early childhood deaths, or specific diagnoses, may suggest a congenital cause of neutropenia. In addition to assessment of the infant for possible sepsis, particular attention should be made to specific physical findings related to the different causes of neutropenia, such as splenomegaly, skin lesions, and physical anomalies. For example, infants with neonatal lupus may have neutropenia but often will have a rash and splenomegaly. Patients with congenital bone marrow failure syndromes may exhibit abnormal thumbs, be small for gestational age or have a low birth weight, or exhibit a classical facies/congenital abnormalities. Thus, the family history and the appearance of the infant, toxic vs nontoxic, will help narrow the differential diagnosis and thus guide the diagnostic tests and management.
Initial baseline diagnostic tests recommended include a complete blood cell count (CBC) with differential, calculation of the ANC (see Figure 110-1), chemistry, blood cultures, and chest x-ray. Abnormalities detected during physical examination, such as skeletal anomalies and enlarged spleen, warrant further imaging. If the degree of acuity has been thoroughly considered, management may occur depending on the differential diagnosis.
FIGURE 110-1
Sepsis
In general, a newborn who is neutropenic should be always assessed and empirically treated for sepsis. A nontoxic infant with normal vital signs and physical examination, however, does not exclude the diagnosis of sepsis. Thus, all neutropenic patients should be considered septic initially.
Toxic Infants
For ill-appearing infants, a full course of antibiotics and workup for fever in the neonate should be performed (see chapters 51 and 52). Granulocyte colony-stimulating factor (G-CSF), a hormone involved in neutrophil development, may be given to boost the neutrophil count if clinically indicated. With appropriate management, the neutropenia should improve over time if caused by infection. If the clinical situation improves and the neutropenia persists, then further workup is indicated. Initially, it is often impossible to determine if a patient who presents with sepsis and neutropenia developed the infection as a result of neutropenia or if the neutropenia is caused by the sepsis. Thus, treatment and observation of the ANC are required. There is no consensus regarding the period of observation. Because newborns have a low neutrophil reserve, the period of neutropenia recovery after an infection may be longer than in older patients. We suggest beginning a workup if there is no resolution after a 3- to 4-week period.
Nontoxic Infants
If the infant is nontoxic appearing, after a short period of empiric antibiotics and the infant is deemed nonseptic, then consideration of other causes of neutropenia should be considered. It is appropriate to repeat the CBC with differential to confirm persistence of neutropenia and to document the ANC trend. It is not unusual for neutrophil count to decrease in the second or third week of life when lymphocyte maturation predominates.1 In addition, 50% of premature infants with birth weights less than 2 kg possess ANC below 1500 at birth, and pregnancies complicated by preeclampsia are at risk for neutropenic newborns.2,3 The neutrophil count gradually normalizes in the majority of premature patients. Ethnicity is another factor to consider. Individuals of African and Jewish decent tend to have lower neutrophil counts at birth.4 For example, the ANC of Africa American children on average5 is between 1000 and 1400.
PERSISTENT NEUTROPENIA
If the neutropenia persists or if the neutrophil count is severe (less than 500), then a workup is indicated. The differential diagnosis can be divided into acquired and congenital causes. Reviewing the maternal and family history and determining if previous children or the mother developed neutropenia during pregnancy are initially important, as they may help to suggest an etiology. For example, if there is any suggestion of premature rupture of membranes or maternal fevers, this history may suggest an infectious cause. A maternal history of autoimmune neutropenia, or autoimmune disease, may suggest an alloimmune process in the infant. Finally, if a known family history of chronic neutropenia or severe recurrent infections is obtained, especially if the affected members are children, this may suggest a genetic etiology. Thus, a special effort to take a careful and relevant history should be made.
Acquired Neutropenia
Infections
Infection should always be first on the differential of a neonate with persistent neutropenia. More specifically, congenital infections (namely, toxoplasmosis, rubella, cytomegalovirus, herpes simplex virus, as well as syphilis, hepatitis B, and human immunodeficiency virus [HIV]) should be considered. To our knowledge, there are no published data indicating a particular organism is more commonly associated with isolated neutropenia. Thus, the more likely scenario is neutropenia preceding an infection; however, it is often difficult to discern whether neutropenia led to the infection or is the result of a response to an infection because of low reserves in the neonate. Nonetheless, the patient should be broadly protected with antibiotics based on the patient’s level of neutropenia and the institution’s guidelines until an infection is empirically treated.
Neonatal Isoimmune/Alloimmune Neutropenia
Neonatal isoimmune/alloimmune neutropenia (NAIN) is an acquired cause of isolated neutropenia and is unique to the neonate. NAIN is a rare condition mediated by transplacental maternal immunoglobulin (Ig) G granulocyte-specific antibodies developed against paternally inherited fetal neutrophil antigens.6,7 This may also occur if the mother carries the diagnosis of autoimmune neutropenia, in which the mother’s autoantibodies cross the placenta. The clinical picture for both of these processes is similar. The incidence of NAIN is approximately less than 1% of all births, and the clinical features of NAIN are varied, mostly presenting incidentally without symptoms or as isolated skin infections. Only on rare occasions this may be associated with life-threatening sepsis.
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