What Causes Neutropenia?

Patient Presentation
A 4-month-old female came to the emergency room with fever, poor feeding, fussiness and strong smelling urine. She had not been feeding well for 36 hours, with a decreasing number of diapers and increasing foul-smelling urine. The fever began about 18 hours previously and had ranged from 99.8°F to 102.3°F. Acetaminophen helped but the fever returned. She was crying more, and could be consoled but she appeared overall ill. She had 2 episodes of emesis just before coming to the emergency room but no diarrhea. Her parents denied any cough, rhinorrhea, or rashes other than her eczema.

The past medical history showed a term-infant born without complications who had received appropriate preventative care including vaccinations. She had been diagnosed with atopic dermatitis 2 week previously. The family history was positive for heart disease and diarrhea. They denied any kidney disease or immune problems. The review of systems was otherwise negative.

The pertinent physical exam revealed a tired and fussy infant who would calm with some effort. Her vital signs had a fever of 102.6° with tachycardia to 114 beats/min, respiratory rate of 26/min and an oxygen saturation of 100%. Her weight was down 250 grams from her visit 2 weeks ago, which was at the 50%. Her capillary refill was 2-3 seconds, with slightly dry mucous membranes. Her fontanelle was normal. Her skin showed dry reddened areas in the flexural areas and behind her ears, and general xerosis of her trunk and cheeks. Her examination was otherwise well. Her diaper smelled foul.

The laboratory evaluation showed a catheterized urinalysis of 1.025 specific gravity, many white blood cells, some red blood cells with positive nitrites and leukocyte esterase. Her complete blood count showed a hemoglobin of 10.6 x 1000/mm2, white blood cell count of 5.2 x 1000/mm2 with only 1350 neutrophils. Her platelets were 360 x 1000/mm2. The rest of her complete blood count was normal as a complete metabolic profile. Her C-reactive protein was elevated at 2.7 mg/dl.

The diagnosis of a urinary tract infection and potential bacteremia was made. She was admitted for intravenous fluids, antibiotics and monitoring. The patient’s clinical course showed that she improved with treatment and was discharged at 48 hours. The blood culture was negative. Her urine culture grew Escherichia coli that was pansensitive to antibiotics and she was sent home on oral antibiotics. An ultrasound of her kidneys was normal before discharge. Her complete blood count still showed mild neutropenia at 1475 at discharge. Her C-reactive protein had decreased to 1.8 mg/dl. At her one week followup appointment her neutropenia and complete blood count were normal. At her one year well-child examination, her complete blood count was normal and she had not had any other urinary tract infections.

Neuropenia is defined as a neutrophil count < 1500/µL. It is classified as mild from 1000-1500/µL, moderate from 500-1000/µL, and severe if < 500/µL.

It is not uncommonly seen in the setting of acute self-limited infections, and with re-testing returns to normal. It is also not uncommon at certain ages, such as perinatally, especially in premature infants (up to 6%) . It is also common in certain ethnic groups particularly African American or Arabic populations where up to 10% of the children may have mild neutropenia which does not cause clinical disease. The overall prevalence and incidence are not known but some studies estimate it at 2 per million persons.

Neutropenia can be thought of as an acute problem due to rapid neutrophil use or destruction, or decreased production of neutrophils. Chronic neutropenia is due to decreased production or splenic sequestration.

Neutropenia can also be thought of as a primary or intrinsic problem due to primary myeloid cell production or an intrinsic defects. Secondary or acquired causes of neutropenia are usually due to infections, immune response, bone marrow infiltration or drugs.

Clinical signs or symptoms of potential neutropenia include fever, oral ulcers, upper airway infections (e.g. otitis media, pharyngitis, sinusitis), respiratory (e.g. pneumonias) or perianal infections. Skin infections like cellulitis, paronychia, or furunculosis may also indicate neutropenia. Bacteremia or sepsis are also potential clinical indications. Recurrent or complicated infections or infections with unusual organisms may indicate neutropenia. Other systems can also be affected.

Treatment depends on the underlying cause with antibiotics, general support, discontinuation of potential iatrogenic causes, and granulocyte stimulating medications if appropriate.

Learning Point
The differential diagnosis of neutropenia includes:

  • Age or ethnic-related
    • Premature infant
    • Newborn infant
    • African American or Arabic ethnicity
  • Infection
  • Congenital or hereditary neutropenia
    • ELANE mutations
      • Cyclic neutropenia – generally 21 day cycles between normal and abnormal neutrophil counts
      • Severe congenital neutropenia
    • Non-syndromic
      • Autosomal dominant severe congenital neutropenia
        • Kostman syndrome
      • Autosomal recessive severe congential neutropenia
        • Wiskott Aldrich syndrome
      • X-linked neutropenia
    • Other syndromic
      • G6PC3 deficiency
      • Barth syndrome
      • Cohen syndrome
    • Bone marrow insufficiency
      • Dyskeratosis congenital
      • GATA2 deficiency
      • Fanconi anemia
    • Combined immunodeficiency
      • XHIGMS
      • WHIM syndrome
      • Reticular dysgenesis
    • Metabolic disease
      • Glycogen storage disease 1b
      • Isovaleric acidemia
      • Methylmalonic acidemia
      • Propionic acidemia
    • Oculocutaneous hypopigmentation
      • Chediak-Higashi syndrome
      • Griscell syndrome type 2
      • Hermansky Pudlak syndrome type 2
      • p14 deficiency
    • Pancreatic insufficiency
      • Schwachman-Diamond syndrome
      • Pearson marrow syndrome
  • Drug related
    • Antibiotics
    • Alcohol
    • Chemotherapy
  • Immune mediated
    • Neonatal alloimmune – transplacental transfer of maternal antibodies to paternal antigen
    • Neonatal isoimmune neutropenia – transplacental transfer of existing maternal IgG antibodies
    • Autoimmune – probably triggered by viral infections or environmental antigens
    • AIDS
  • Myelodysplasia
    • Bone marrow infiltration or replacement
      • Leukemias
      • Dysgammaglobulinemia
  • Other
    • Folate or Vitamin B12 deficiency
    • Hypersplenism or splenic sequestration

Questions for Further Discussion
1. What are common presentations for primary immunodeficiencies? A review can be found here

2. What are different fever patterns and what are their potential problems? A review can be found here

3. What is in the differential diagnosis of lymphocytosis? A review can be found here
4. What are potential complications of acute pyelonephritis? A review can be found here
5. How do you treat fever and neutropenia due to chemotherapy?

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for these topics: Urinary Tract Infections, Blood Disorders and Immune System and Disorders.

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

Neutropenia – Hematology and Oncology. Merck Manuals Professional Edition. https://www.merckmanuals.com/professional/hematology-and-oncology/leukopenias/neutropenia?query=neutropenia. Accessed December 3, 2019.

Dale DC. How I manage children with neutropenia. Br J Haematol. 2017;178(3):351-363. doi:10.1111/bjh.14677

Kebudi R, Kizilocak H. Febrile Neutropenia in Children with Cancer: Approach to Diagnosis and Treatment. Curr Pediatr Rev. 2018;14:204-209.

Spoor J, Farajifard H, Rezaei N. Congenital neutropenia and primary immunodeficiency diseases. Crit Rev Oncol Hematol. 2019;133:149-162. doi:10.1016/j.critrevonc.2018.10.003

Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa