Clinical Features of Alloimmune Neutropenia: Composite of 2 Case Series and 39 Case Reports
Authors: Kang Ramanjot S. , Bussel James B. 
Published: October 2019

Introduction: Alloimmune neutropenia (AIN) is a rare condition resulting from transplacental passage of maternal alloantibodies against paternal human neutrophil antigens (HNA). The resulting neutropenia may persist for months and predisposes neonates to bacterial and fungal infections, in particular sepsis. Despite the danger posed to neonates, little is known about the clinical features of AIN; no reviews incorporating more than 10 cases have comprehensive clinical information. The aim of this summary is to assess clinical data describing cases of AIN.

Methods: A Pubmed search was performed for cases of AIN. In addition, a search was performed from the reference lists of all identified articles. Only English language articles describing serologically confirmed cases of AIN were included in our review. Analysis was primarily descriptive. By including case reports, a bias is incorporated to more severe and unusual cases but this was the only approach to obtaining information on AIN cases.

Twenty-seven studies were identified - two case series[Tomicic Am J Reprod Immunol. 2014 (15 cases) and van den Tooren-de-Groot Acta Paediatr. 2014. (35 cases)] and 25 case reports that described 39 cases of AIN, a total of 89 cases (Table 1). The two case series relied on antibody testing to identify confirmed cases of AIN whereas the 25 articles described neutropenic neonates that were eventually diagnosed with AIN.

Results: Analysis revealed that AIN was first suspected due to an infection or as a part of routine blood work completed for preterm infants. Neonates either presented with no infection (29%), omphalitis (25%) or other infections; sepsis was identified in 14% (only 1 death). The mean gestational age was 35.6-36 weeks and mean birth weight was 2500-2700 grams. The HNA antibodies most commonly identified in AIN were anti-HNA-1b (25%), anti-HNA-1a (16%), and anti-HNA-1c (16%) with anti-HNA-2 (18%) and anti-FcgammaRIII (11%) next. Differences in course between different anti-HNA antibodies were not identified. Antibiotics were most commonly used in treatment (>65%), most of the time (52%) on their own; G-CSF was used in 11% of cases. Neutropenia resolved within 6 months. In very few cases was information provided on subsequent pregnancies.

Conclusions: Together, the studies provided information on why neonates were tested for AIN, HNA-antibody target, treatment of infections, weight and age of neonates and the average duration of neutropenia. In comparison to fetal and neonatal disorders hemolytic disease and alloimmune thrombocytopenia, there is still much to be learned about AIN. Analysis of the 89 cases suggests that AIN should be thought of earlier in infected neutropenic neonates, especially those with omphalitis and more consideration given to G-CSF and/or IVIG. The low incidence rate, self-limiting course, and current practice not to routinely obtain CBCs with differentials in neonates all contribute to the low rate of identifying AIN. Furthermore, serologic testing is not rapidly available in most clinical settings. To obtain a better understanding of the clinical features of AIN, a comprehensive prospective study evaluating full clinical data in real time of neonates serologically tested and found to have AIN should be conducted.

Table 1. Comparison of Cases of Alloimmune Neutropenia (AIN) van den Tooren-de Groot et al. 2014(n = 35) Tomicic et al. 2014 (n = 15) Case Reports (n = 39) Total (n = 89) Average Birth Weight (g) 2776 - 2556.6 Average Gestational Age (Weeks) 35.6 - 36.0 Average Absolute Neutrophil Count (/mm3) 430 631 197 HNA Antibodies anti-HNA-1a 7 1 4 12 (16%) anti-HNA-1b 12 - 7 19 (25%) anti-HNA-1c 2 1 9 12 (16%) anti-HNA-2 8 3 3 14 (18%) anti-HNA-3a 1 - - 1 (1%) anti-HNA-5a 1 - 2 3 (4%) anti-FcgammaRIIIb 4 2 3 9 (11%) anti-HLA - 4 2 6 (8%) Treatment No Treatment - 6 3 9 (12%) Antibiotics 25 7 7 39 (52%) Antibiotics and IVIG - 1 - 1 (1%) Antibiotics and G-CSF - 1 8 9 (12%) G-CSF 1 - - 1 (1%) Other - - 16 16 (21%) Clinical Data No Infection 14 - 9 23 (29%) UTI 1 - - 1 (1%) Omphalitis 6 7 7 20 (25%) Candida Mucositis 1 - - 1 (1%) FUO 6 - 1 7 (8%) Sepsis 7 2 5 14 (18%) Other - - 12 12 (15%) Death 0 0 1 1 (1%) Average Time for Neutropenia to Resolve (Weeks) - 7.7 9.8

Disclosures

No relevant conflicts of interest to declare.