Workup of Neutropenia in a 10-mo-old Infant: A Case Presentation

Educational Objectives

The goal of this program is to improve diagnosis and management of autoimmune neutropenia. After hearing and assimilating this program, the clinician will be better able to:

1. Perform a differential diagnosis for children with low neutrophil counts.
2. Manage patients with autoimmune neutropenia.

Summary

Presentation: a 10-mo-old girl was referred to the speaker’s institution from an outside emergency department (ED) for dehydration; the patient reportedly had several days of nonbloody, nonbilious emesis and diarrhea; the absolute neutrophil count (ANC) was 0, and she was referred for outpatient follow-up

Workup: history — before the acute onset of diarrhea and emesis, the patient had a history of poor oral intake and decreased energy but no fever, cough, congestion, or altered breathing; physical examination — no lymphadenopathy or signs of bleeding or bruising are present; medical history — the patient was born at 36 wk gestation and stayed for ≈24 hr in the neonatal intensive care unit (NICU) to monitor oxygen desaturations; the patient is not on any medication and has no allergies to food or drugs; immunizations are up to date; family history — is positive for maternal alpha thalassemia and sickle cell trait; no history of pediatric cancers, sudden death, or other hematologic disorders was reported; other information — the patient was growing symmetrically, meeting milestones, and had no history of infection, hospitalization, oral ulcers, anal lesions or abscesses, paronychia, or cyclic fevers; laboratory results — white blood cell (WBC) count, hemoglobin (Hb), red blood cell (RBC) indices (mean corpuscular volume, red cell distribution width, mean corpuscular hemoglobin concentration), and platelet counts are normal; the WBC differential shows a normal but elevated absolute lymphocyte count with variant (atypical) lymphocytes of 10%, consistent with infection

Differential diagnosis: viral myelosuppression with neutropenia is most likely, especially in the setting of gastroenteritis; bone marrow suppression is unlikely because of reduction of only one cell line in a well-appearing infant; autoimmune neutropenia (AIN) is possible, but further test results and history are needed; cyclic neutropenia may be possible but more information is needed, eg, history or future blood counts; drug-induced neutropenia is unlikely given the medication history; acute infantile leukemia is also unlikely because it involves pancytopenia and an unwell-appearing infant; diagnosing benign familial neutropenia requires additional information

Additional information at the speaker’s office: ≈2 wk after the ED visit, the child had completely recovered and was well appearing; physical examination — her temperature was normal; her weight was in the 14th percentile and height in the ninth percentile (consistent with the patient’s baseline); the oral mucosa is normal without ulcers or thrush; her abdomen is nontender with no masses; she has no significant lymphadenopathy, hepatosplenomegaly, rashes, erythema, or induration; she has no signs of rectal abscess or genitourinary infection; patient had no signs of paronychia; laboratory results — her newborn screen was notable for fetal Hb, HbA, and HbS (consistent with family history of sickle cell trait); at birth, she had a normal WBC count, Hb, platelet count, and a slightly low ANC (inconsistent with congenital neutropenia); complete blood cell count (CBC) at the office visit reveals a normal WBC, slightly low Hb, low-normal RBC indices, and slightly elevated platelet count; the ANC was 1440/μL, the absolute lymphocyte count was normal, and variant lymphocytes were 5%; on peripheral blood smear, the average number of lobes in each neutrophil is 3 to 4; the neutrophils have minimal granulations and vacuoles (consistent with activated neutrophils during infection)

Revised differential diagnosis: viral myelosuppression neutropenia is still likely, as neutropenia is improving and the patient appears healthy; additional findings are not consistent with inherited bone marrow suppression; AIN is still possible because of her age and mild neutropenia on repeat CBC; cyclic neutropenia is still possible; drug-induced neutropenia is highly unlikely; acute infantile leukemia is unlikely because the patient appears healthy and has a relatively normal CBC and smear; additional family history is required to support a diagnosis of benign familial neutropenia

Repeat testing: 4 wk later, the ANC decreased to 590/μL, and anti-neutrophil antibody testing was sent off; repeat CBC after another 4 wk revealed an ANC of ≈1000/μL with antibody results pending; after another 4 wk, the ANC was 760/μL, and the anti-neutrophil antibody test was positive; the most recent ANC at 23 mo was 990/μL with normal Hb

Revised differential diagnosis: AIN is most likely because of the positive anti-neutrophil antibody test; cyclic neutropenia is also possible because of the fluctuating neutrophil counts

Autoimmune neutropenia: pathophysiology — involves peripheral destruction of neutrophils because of autoantibody binding to Fc receptors; the triggers are unclear; it may occur after viral exposure, but this is not necessary for diagnosis; when the patient develops immunoglobulin G (IgG) complexes in response to a trigger, the antibodies bind to Fc receptors and cause sensitization of neutrophils in the peripheral blood; peripheral destruction of neutrophils is the secondary process that causes neutropenia; epidemiology — AIN occurs in 1 of 100,000 children, but it may be underdiagnosed because it does not have clear triggers or related symptoms; it is most often diagnosed between 5 to 15 mo of age (median age, 7-9 mo); diagnosis — it is most commonly diagnosed incidentally; it typically resolves ≤2 yr of diagnosis or ≤5 yr of age; it is primarily a clinical diagnosis made using the patient history, birth history, and history of acute illness; anti-neutrophil antibody test is used to support diagnosis

Anti-neutrophil antibody test: is done by granulocyte immunofluorescence (GIF) or agglutination; an expert panel suggest using both; pitfalls of GIF testing include occasional false-positive results with direct testing because of high Fc receptor content on neutrophils and false-negative results on indirect testing because of low titers in the peripheral blood

Other features: include mild leukopenia; ≤25% of patients have monocytosis; serious infections are rare (occur in <20% of patients); closely follow patients

Immunofluorescence testing: direct method introduces patient neutrophils bound by IgG to an immunofluorescence IgG conjugate; indirect testing introduces pooled donor neutrophils to the patient’s serum; both use flow cytometry to identify fluorescence

Agglutination testing: introduces pooled donor neutrophils to the patient’s serum; binding (activation) causes aggregation, which is graded from 1 (limited) to 4 (high)

Management: most patients are followed with serial examination; CBC is obtained monthly or more frequently for atypical patterns; once results have stabilized, repeat CBCs every 3 to 6 mo; recommend routine vaccination; antibiotic prophylaxis is not recommended routinely; however, consider it for patients with mild to moderate infections; all patients with fever should be evaluated using neutropenic precautions (ie, CBC, blood culture, and clinical evaluation) because they are at increased risk for severe neutropenia and infection; for serious infection, consider administration of granulocyte colony stimulating factor (GCSF), starting at 1 to 2 μg/kg per day and uptitrating to the goal of ANC >1000/μL; consider prophylactic antibiotics on an individual basis; risks include delayed wound healing and immunocompromised status; preoperative use of GCSF is recommended; immunosuppression (eg, steroids) has no role

Further evaluation: is warranted if neutropenia is persistent for >3 yr or >5 yr of age; monitor individuals with severe clinical courses in other autoimmune conditions or suspicion of immunodeficiency; red flags include alterations in CBC, recurrent infections, or other syndromic features concerning for immunodeficiency; all patients should be referred to hematology; additional tests may include immunoglobulin assessment, lymphocyte subsets, bone marrow aspiration and biopsy, targeted autoimmune workup, immunology referral, or genetic evaluation

Readings

Căinap C, Cetean-Gheorghe S, Pop LA, et al. Continuous intravenous administration of granulocyte-colony-stimulating factors-a breakthrough in the treatment of cancer patients with febrile neutropenia. Medicina (Kaunas). 2021;57(7):675. Published 2021 Jun 30. doi:10.3390/medicina57070675; Celkan T, KoçBŞ. Approach to the patient with neutropenia in childhood. Turk Pediatri Ars. 2015;50(3):136-144. Published 2015 Sep 1. doi:10.5152/TurkPediatriArs.2015.2295; Khalid N, Aeddula NR. Antineutrophil cytoplasmic antibodies (ANCA) test. StatPearls Publishing. 2024 Aug 11. Available from: https://www.ncbi.nlm.nih.gov/books/NBK562339/; Park M. Overview of inherited bone marrow failure syndromes. Blood Res. 2022;57(S1):49-54. doi:10.5045/br.2022.2022012; Tsukui D, Kimura Y, Kono H. Pathogenesis and pathology of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis. J Transl Autoimmun. 2021;4:100094. Published 2021 Mar 3. doi:10.1016/j.jtauto.2021.100094.

Disclosures

For this program, members of the faculty and planning committee reported nothing relevant to disclose.

Acknowledgements

Dr. Goldenberg was recorded at the 50th Annual Pediatric Trends, held virtually on May 14-17, 2024, and presented by the Johns Hopkins University School of Medicine, Baltimore, MD, and Johns Hopkins Children's Center, Baltimore. For information on future CME activities from this presenter, please visit https://hopkinscme.cloud-cme.com. Audio Digest thanks the speakers and presenters for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0.75 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0.75 CE contact hours.

Lecture ID:

PD704602

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.