Chronic benign neutropenia in adults: laboratory and clinical parameters of a 6-year follow-up

Background: Chronic benign neutropenia (CBN) is a rare hematological condition, characterized by an absolute neutrophil counts (ANCs) lower than 1800/µl in white and 1500/µl in black people for more than 3 months. This condition can be congenital or acquired, idiopathic or secondary and may be characterized by the presence of anti-neutrophils antibodies. While congenital and acquired forms of infancy and childhood are largely studied, with particular attention to the infective diathesis, less is known about adult neutropenia. Aims: To evaluate clinical and laboratory features of chronic benign neutropenia in adult patients, focusing on ANCs variations, on the positivity for anti-neutrophil auto-antibodies and on the incidence of infectious episodes. Methods: Complete blood counts and physical examination were performed every 3-4 months in the first 2 years, then at least once a year. Anti-neutrophil antibodies were determined by direct and indirect granulocyte immunofluorescence test (GIFT method). Infectious episodes were defined according to Common Terminology Criteria for Adverse Events (Version 4.0 http://evs.nci. nih.gov). Results: 47 patients (17 males and 30 females, median age 55 years, range 25- 86 years) were followed up for a median time of 47 months (range 6-240 months). As Figure 1 shows, mean ANCs at enrolment and over time displayed a great variability, both inter and intra-subject (>500/µl in 74% and >1000/µl in 25% of patients). Considering the severity of neutropenia, we observed 23 patients (49%) with neutrophils lower than 1000/µl in at least one observation (median number of 470/µl neutrophils, range 100-969/µl). Finally, the mean ANCs observed during the follow up was significantly lower in males than in females (610/µl, range 100-1380/µl versus 1070/µl, range 100-1750/µl, respectively; P=0,02). Anti-neutrophil antibodies were detected in 18/45 patients (40%), and mean ANCs were significantly lower in positive versus negative cases (P=0,021 for 6 and 12 months time). Bone marrow evaluation showed features of dismyelopoiesis in 14 cases (56%), hypocellularity in 3 (12%) and normal morphology in 8 (32%). Flow cytometry demonstrated increased Natural Killer cells in 13 patients (28%), Cytogenetic was normal 22 cases (88%), while in 3 male patients karyotype was 45, X0 (7,6 and 3 metaphases respectively). Finally, monocyte counts were higher than 600/µl in 8 patients (17%), and 5 of them (62%) showed an NK marrow infiltrate (P=0,015). Mild splenomegaly was present in 10 patients (21%) with a mean maximal diameter of11,4 cm by ultrasonography. These cases displayed lower ANCs compared with cases without splenomegaly (835/µl, 140-1400, versus 1380/µl, 200-3239, at 3 months; P=0,03). During the study 11 patients (23%) had an infection needing oral antibiotic or antiviral therapy (7 upper respiratory tract infections, 3 Herpes Zoster Virus infections and 1 urinary tract infection); no relationship was found between the occurrence of infections and the patient’s mean ANCs value, the nadir of ANCs, and the presence of anti-neutrophil antibodies Summary and Conclusions: In spite of the alarm that produces in the general practitioner, CBN in adults is a benign disease, often incidentally diagnosed, with an infectious rate comparable to that of general population and frequent spontaneous ANCs variations. Bone marrow evaluation shows abnormal findings in a half of patients, without reaching the criteria for clonal hematological diseases, but suggesting that this condition deserves clinical follow up.