Rethinking Autoimmune Neutropenia in Children

Authors of a registry analysis published in Blood Advances have identified two distinct autoimmune neutropenia entities in children who present with apparent primary autoimmune neutropenia (pAN): long-lasting neutropenia and late-onset neutropenia. Each condition had separate clinical and immunohematologic features, the knowledge of which could help better tailor treatment and monitoring plans, the authors, led by Francesca Fioredda, MD, from the IRCCS–Istituto Giannina Gaslini in Genoa, Italy, wrote.

“Children with apparent pAN but whose neutropenia lasts longer or appears later in life, have other important differences,” the researchers explained, suggesting that “cases that present after 3 years of age, with low/no tendency to resolution, require close monitoring and extensive immune investigations [to identify early] underlying immunologic disease that might develop.”

Dr. Fioredda and colleagues reviewed data from children enrolled in the Italian Neutropenia Registry who had clinical features resembling pAN, but who did not fully match criteria for pAN because neutropenia either appeared late or lasted longer than 3 years. Autoimmune neutropenia (AN) was defined by the presence of an absolute neutrophil count below the threshold for age, lasting longer than 3 months, and associated with positive indirect anti–neutrophil antibody testing (antibodies found in the patient’s serum).

“Cases that present after 3 years of age, with low/no tendency to resolution, require close monitoring.”

—Francesca Fioredda, MD

Two categories of patients were eligible:

  • children diagnosed between the ages of 5 and 18 who were defined as late-onset neutropenia
  • children diagnosed before age 3, whose neutropenia lasted >3 years and was defined as long-lasting neutropenia

Neutropenia resolution occurred when absolute neutrophil count (ANC) was stably >1.5×109/L in at least three samples within three months.

From 2002 to 2019, 214 cases of AN were identified and categorized as:

  • pAN: 135 cases (63%)
  • late-onset neutropenia: 31 cases (15%)
  • long-lasting neutropenia: 48 cases (22%)

When the investigators compared patients in the three groups, they found significant differences in almost all variables, with the exception of monocytosis, CD8+ cell depletion, deficiency of ≥1 class of immunoglobulin, and severity of infections.

For example, median ANC values were significantly higher with late-onset neutropenia (0.649×109/L) and in long-lasting neutropenia (0.552×109/L) compared with pAN (0.43×109/L). Severe neutropenia (defined as 0.5×109/L) was more frequent in pAN (58%) than in long-lasting or late-onset (37% and 32%, respectively) neutropenia (p=0.03).

Lymphocytes also were lower in late-onset neutropenia (1.68×109/L) and long-lasting neutropenia (2.37×109/L), compared with pAN (4.74×109/L; p<0.001). This finding might account for the higher frequency of leukopenia observed in patients with late-onset and long-lasting neutropenia (73% and 26% vs. 11%; p=0.01).

Lymphocyte subset analysis revealed that patients with late-onset and long-lasting neutropenia also had low CD19+ cells, compared with patients with pAN (48% and 35% vs. 9%; p<0.001).

Rate of severe infections (such as meningitis, sepsis, or pneumonia) were similar among the three groups. However, those with long-lasting and late-onset neutropenia more frequently used granulocyte colony stimulating factor (G-CSF) than those with pAN (17% and14% vs. 5%; p=0.04). This could be explained by national guidelines that recommend on-demand G-CSF in patients with otherwise unmanageable infections or as prophylaxis before surgery.

Lastly, the occurrence of autoimmune diseases also differed among the three groups, with autoimmune markers and diseases occurring more frequently in late-onset and long-lasting neutropenia (55% and 17%, respectively), compared with pAN (1%; p=0.01).

The authors found no significant differences in sex, monocytosis, severity of neutropenia, overall severe infection rate, need for G-CSF, and lymphocyte subsets between late-onset and long-lasting neutropenia. However, comparing patients with late-onset neutropenia with those with long-lasting neutropenia, late-onset cases had:

  • lower rate of resolution (13% vs. 58%; p<0.001)
  • lower white blood cell count (3.18 vs. 5.03×109/L; p<0.001)
  • lower lymphocyte count (1.68 vs. 2.37×109/L; p<0.001)
  • a stronger association with autoimmune diseases/markers (55% vs. 17%; p=0.001)

“Overall, this comparison indicates that, in our cohort, on immunohematologic and clinical ground, patients with pAN, late-onset neutropenia, and long-lasting neutropenia differ not only because of late-onset or longer duration, but also because of rate of resolution, leukopenia, severity of neutropenia, lymphopenia with low B+ and natural killers cells, increased need of G-CSF, and increased frequency of associated autoimmunity,” the researchers concluded.

The implications of the study are limited by its retrospective nature, “which implies some selection bias and some incomplete data,” the authors wrote. “In addition, the relatively short follow-up does not allow [us] to capture those patients who present in childhood with isolated neutropenia and [who] might become immunodeficient in adult age. In this respect, a joint study with adult neutropenia registry/groups would be advisable to fill this age gap.”

The authors report no relevant conflicts of interest.


Fioredda F, Rotulo GA, Farruggia P, et al. Late-onset and long-lasting autoimmune neutropenia: an analysis from the Italian Neutropenia Registry. Blood Adv. 2020;4(22):5644-5649.