A guide to neutropenia: diagnosing and treating a perplexing problem

March 2002

MIAMI BEACH, Fla. – Preventing infections is a serious concern if a child has neutropenia. But the most pressing problem is why the child has a low neutrophil count in the first place.

There can be many reasons, including drug reaction, infections, immune system disorder, or bone marrow failure, said George R. Buchanan, MD, during the 37th Annual Miami Children’s Hospital Postgraduate Course held here.

The fact that some children have naturally low absolute neutrophil counts (ANC) adds to the diagnostic dilemma. “The normal ANC for adults and older children is >1,500/mm³. On the other hand, toddlers can have neutrophil counts as low as 1,000/mm³ and black children can have neutrophil counts of <600/mm³. One study showed that normal, healthy black children can have neutrophil counts as low as 200-300/mm³,” said Buchanan, director of pediatric hematology-oncology at The University of Texas Southwestern Medical Center and Children’s Medical Center, Dallas. “One has to keep that in mind when considering an African-American child with a seemingly low leukocyte count.”

Children with ANC values between 500/mm³ and 1,000/mm³ have minimal risk of infection, he said. Serious infection most often occurs in those with ANCs <100/mm³. An important risk determinant is the bone marrow. “If the bone marrow is making neutrophils effectively, even very low neutrophil counts can be tolerated with few problems,” said Buchanan, who is also professor of pediatrics at UT Southwestern.

“How does the pediatrician approach the child with acute neutropenia? Well, assuming that the child has a normal hemoglobin value and normal platelet count, the best strategy is to observe that child, repeat the blood count every one to two weeks, and you’ll find most of the time the neutrophil count will recover to normal,” he said.

If the hemoglobin and the platelet count are also low, however, the children should be referred to a hematologist for a bone marrow aspirate for diagnosis and treatment.

Persistent neutropenia

A child with persistent neutropenia demands a detailed evaluation, he said. The most common disorders are congenital, cyclic and autoimmune neutropenias. The problems faced by children with any chronic neutropenic disorder include intermittent low-grade fever, malaise, mouth sores or gingivitis, lymphadenopathy, recurrent upper respiratory infections, pneumonia and skin rashes like impetigo, recurrent boils and cellulitis.

The causative organisms tend to be Staphylococcus aureus, Pseudomonas, Escherichia coli, Proteus, Klebsiella, Enterococcus, group A streptococcus, Candida and Aspergillus. “Notably missing from this list are the encapsulated microorganisms, Streptococcus pneumoniae and Haemophilus influenzae type b. Neutrophils are not important in the immune defense against these organisms,” he explained.

Most children with chronic neutropenia are otherwise well, he explained. Their physical findings are limited to acute or chronic infection.

Severe congenital neutropenia is an autosomal recessive disorder that presents shortly after birth with recurrent and often severe bacterial infection. The neutrophil count is usually <100.

“It is a rare disease. Prior to the advent of granulocyte colony-stimulating factor (G-CSF), these children died by 3 to 4 years of age,” said Buchanan. In the late 1980s, G-CSF replaced bone marrow transplantation as the treatment. Now, almost all children respond. Their neutrophil counts normalize, their infections go away and their quality of life improves.

“Now that these children survive, we have observed that there is an increased risk of leukemia that approaches 10%, confirming that this is a preleukemic disorder,” he said.

“So, G-CSF therapy — this is the same hormonal therapy that one uses for cancer patients to stimulate the recovery of the bone marrow following chemotherapy — was found in the late 1980s to be a wonderful therapy for these youngsters. The dosage is quite large, as high as 100 µg/kg/day, given subcutaneously.”

The child should receive daily G-CSF. Bone marrow should be monitored for myelodysplasia or leukemia. If the child develops leukemia or fails to respond to G-CSF, stem cell transplantation is the only option left. Antibiotics should be used aggressively, he added.

Cyclic neutropenia

Cyclic neutropenia is characterized by a predictable fluctuation in neutrophil count. The count varies from near normal to zero in predictable 19- to 21-day cycles. “Interestingly, in this disease, not only do the neutrophils cycle, but other elements of the blood count, the monocytes, also the platelets and the reticulocytes. Now, if one does a bone marrow examination on these patients, the bone marrow varies depending on when in the cycle you do the procedure. This is usually an inherited disorder, either dominant or recessive inheritance,” he explained.

To make the diagnosis, blood counts are taken two or three times a week for up to eight weeks. “You wouldn’t want to embark on that kind of a work-up unless you’ve got a fairly significant, convincing history from the parents that every 21 days the child develops fevers, mouth sores, malaise, gingivitis, for four or five days and then gets better,” he said.

“This disease tends to be over diagnosed. Many pediatricians and hematologists will call it cyclic neutropenia simply because the blood count fluctuates, as neutrophil counts normally do, but the 21-day cycle really is necessary for diagnosis,” he added.

This disorder does not predispose to leukemia.

Autoimmune neutropenia

The most common type of neutropenia that pediatricians will encounter is autoimmune neutropenia. Children typically present with infections between 6 months and 12 months of age. Usually a child has recurrent, minor bacterial infections, and happens to get a blood count and profound neutropenia is found that persists for more than six weeks.

“One particular kind of infection in little girls is a labial infection with cellulitis or abscess due to Pseudomonas,” said Buchanan. “So, anytime you see a little girl with an infection around her genitalia, you really need to do a blood count.”

The neutrophil count, although low, is not usually zero. During an infection, the neutrophil count actually rises. “So, the bone marrow reserve here is quite good and that probably accounts for the fact that this disorder is less severe,” Buchanan explained.

Luckily, children outgrow this condition. After about 12 to 24 months, the neutrophil count slowly rises to normal and, by age 4 or 5, they are fine. This is an immune-mediated disease, and children do not develop leukemia as a result of this condition.

The condition is due to an antibody directed against antigens on the neutrophil surface. The neutrophils that are coated with antibodies are ingested by macrophages of the spleen and, therefore, don’t survive. If there is an infection, however, the children can mount a neutrophil response.

These children should be treated symptomatically with liberal use of antibiotics during febrile illness. If the child looks sick, a short-term hospitalization may be needed. Good oral hygiene is important.

G-CSF therapy is not necessary for most, but some children with autoimmune neutropenia and recurrent infections benefit from G-CSF. “About 20% of children in my experience have recurrent infections that are problematic enough” to receive G-CSF if the child has repeat visits to the pediatrician every couple of weeks for infections. “If you treat them with G-CSF, these children will have a dramatic normalization of their blood count. And, what’s interesting is the doses of G-CSF are much lower than what you need for congenital neutropenia or children with cancer receiving chemotherapy,” he said.

One to three doses per week at 2 µg/kg to 5 µg/kg subcutaneously, usually raises the neutrophil count enough that the child is having fewer infections. Discontinue therapy periodically because children do outgrow the condition, he suggested.

For more information:

• Buchanan G. Child with neutropenia. Presented at the Miami Children’s Hospital Postgraduate Course. Jan. 25-Jan. 31, 2002. Miami Beach, Fla.

• Dr. Buchanan has no direct financial interest in the products mentioned in this article, nor is he a paid consultant for any companies mentioned.