Autoimmune Neutropenia Of Infancy Research Articles

Association between human leukocyte antigens (HLAs) and human neutrophil antigens (HNAs) and autoimmune neutropenia of infancy in Danish patients.

BackgroundAutoimmune neutropenia of infancy (AIN) is a frequent cause of neutropenia in children. The disease is caused by antibodies against epitopes on the immunoglobulin G (IgG) Fc receptor type 3b (FcγIIIb). We investigated the possible association of human neutrophil antigens (HNA), human leukocyte antigen (HLA)‐DR, and HLA‐DQ alleles with AIN and the association of these genotypes with the presence of autoantibodies.MethodsEighty AIN cases with a median age of 13.5 months were included. Controls were healthy unrelated Danish blood donors. Anti‐HNA‐1a autoantibodies were detected using a flow cytometric granulocyte immunofluorescence test (Flow‐GIFT) with phenotyped donor cells for detection of antibody specificity. Molecular determination of HNA genotypes was determined using real‐time polymerase chain reaction (q‐PCR). High‐resolution HLA‐DRB1 and HLA‐DQB1 were determined by next‐generation sequencing.ResultsAntibodies against HNA‐1a were detected in 51% (n = 41) of AIN patients, and anti‐HNA‐1b was detected in 3% (n = 2) of cases. In 46% of cases, the antibodies were anti‐FcγIIIb‐reactive. FCGR3B*01+,*02‐,*03‐ was more common (odds ratio, 6.70; P < .0001), and FCGR3B*01‐,*02+,*03‐ was less common (odds ratio, 0.30; P < .0001) among AIN cases. HNA‐1a antibodies were significantly more frequent among AIN cases with the FCGR3B*01+,*02‐,*03‐ genotype (odds ratio, 3.86; P < .007). The HLA‐DRB1*14 ‐ HLA‐DQB1*05:03 haplotype was significantly more common (odds ratio, 7.44; P < .0001) in AIN patients.ConclusionThe HLA haplotype HLA‐DRB1*14 ‐ DQB1*05:03 is associated with Danish AIN cases. Among Danish AIN patients, anti‐HNA‐1a is the most common autoantibody, and the antibody is more common in cases with the FCGR3B*01+,*02‐,*03‐ genotype.

Antibody-Associated Autoimmune Disease (AAD) in Children with Cancer in Immune Recovery Phase Following Cessation of Chemotherapy

(Introduction) Outcome of pediatric cancer has improved dramatically by intensive chemotherapy, surgical treatment, radiotherapy, and stem cell transplantation (SCT). In children with cancer, immune system is damaged during treatment. Autoimmune diseases such as autoimmune hemolytic anemia (AIHA) during immune reconstitution were observed as complication after intensive chemotherapy in our institute. Although most of them recovered with supportive treatment, immunosuppressive agents including steroid were needed in some patients. Thus, we defined this complication as antibody-associated autoimmune disease (AAD), and we examined AAD in pediatric patients following cessation of treatment. (Patients and Methods) We reviewed medical records of patients who received intensive chemotherapy in Department of Pediatrics, Hokkaido University Hospital. Between January 2010 and December 2018, 130 patients with hematological malignancies, 127 patients with malignant solid tumor, 120 patients with brain tumor were treated in our institute. All of these patients were included in this study. The diagnoses of AAD were made by clinical criteria, combined with laboratory evidence of a definitive antibody in the serum of patients such as positive Coombs test, antineutrophil antibodies, antiplatelet antibodies, and thyroid-stimulating antibodies. In this study, apparent clinical GVHD and AAD associated with SCT were excluded. (Results) Among the 377 patients, 10 patients (2.7%) developed AAD. AAD was observed as ITP in 5 patients, AIHA in 2 patients, Hashimoto's diseases, multiple sclerosis, and neutropenia with antineutrophil antibody in one patient each. AAD developed a median of 4.0 months (range 2-27months) after cessation of treatment. At onset of AAD, the mean CD4 positive cell counts was 397 /ul and the mean serum IgG was 789 mg/dl. Prednisolone was administered in 3 patients (AIHA and ITP) to treat AAD. The clinical symptoms of AAD regressed with supportive therapy only in the other patients. In 3 out of 5 patients who developed AAD with CD4 positive cell count over 500 /ul, autoimmune antibody in serum of the patients was detected continuously. On the other hand, in 5 patients who developed AAD with CD4 positive cell count below 500 /ul, both clinical symptoms and laboratory examinations regressed, synchronizing with the immune recovery. The mean duration of CD4 positive cell count &lt;500/ul was significantly longer in patients with AAD (n=10) compared with that in patients without AAD (n=45) (p=0.013, 11.0±7.2 months vs 5.6±5.3 months), and the mean duration of serum IgG &lt;500mg/dl was significantly longer in patients with AAD, compared to patients without AAD (p=0.002, 11.0±6.3 months vs 4.3±4.4 months). (Discussion and Conclusion) AAD was observed in immune recovery phase following cessation of chemotherapy, which mimicked immune reconstitution syndrome (IRS) after antiretroviral therapy in patients with HIV infection. It was reported that IRS was also observed in HIV-negative patients who were administered alemtuzumab, and in those who received stem cell transplantation. It was interesting that patients who had smaller number of CD4-positive cells at diagnosis of AAD had a faster recovery of the diseases in our study. We also speculate that AAD mimic autoimmune cytopenia such as ITP, AIHA, and autoimmune neutropenia in infancy because the diseases are caused by autoantibodies, occurring in immune-naive age, and they naturally recover in most cases although some patients need immunosuppressive treatment. Further studies are needed to clarify the pathogenesis of AAD in children. Disclosures No relevant conflicts of interest to declare.

Idiopathic neutropenia of infancy: Data from the Italian Neutropenia Registry.

Autoimmune neutropenia of infancy (AIN) is characterized by low risk of severe infection, tendency to spontaneously resolve and typically onset at ≤4-5 years of age; it is due to auto-antibodies whose detection is often difficult. In case of negativity of 4 antineutrophils autoantibody tests, after having excluded ethnic, postinfection, drug induced, or congenital neutropenia, according to the Italian guidelines the patients will be defined as affected by "idiopathic neutropenia" (IN). We describe the characteristics of 85 IN patients enrolled in the Italian neutropenia registry: they were compared with 336 children affected by AIN. The 2 groups were clinically very similar and the main differences were detection age (later in IN), length of disease (longer in IN) and, among recovered patients, age of spontaneous recovery: the median age at resolution was 2.13 years in AINs and 3.03 years in INs (P = .00002). At bivariate analysis among AIN patients earlier detection age (P = .00013), male sex (P = .000748), absence of leucopenia (P = .0045), and absence of monocytosis (P = .0419) were significantly associated with earlier recovery; in the IN group only detection age (P = .013) and absence of monocytosis (P = .0333) were significant. At multivariate analysis detection age and absence of monocytosis were independently significant (P = 6.7e-05 and 4.4e-03, respectively) in the AIN group, whereas in the IN group only detection age stayed significant (P = .013).

Autoimmune Neutropenia of Infancy- Unexpected Prevalence of Pseudomonas Skin Infections

Background: Autoimmune neutropenia of infancy (AIN), the most frequent type of severe neutropenia in young children, occurs due to recognition of membrane antigens by anti-neutrophil antibodies, resulting in peripheral neutrophil destruction. Despite the often severe and prolonged neutropenia, serious infectious complications are less frequent in AIN compared with other etiologies of severe neutropenia.Objectives and methods: The purpose of this historical prospective study was to describe the demographics and clinical course of AIN with a focus on the incidence of infectious events, the pathogens involved and assessment of contributing factors. Data was extracted from the medical records of AIN patients treated at the pediatric hematology clinic in Schneider Children's Medical Center of Israel between 2001-2016.Results: One hundred and one patients diagnosed with AIN were included in the study, representing a total of 175 patient-years of follow-up, with a mean of 1.9 years per patient. Mean age at presentation was 0.8 years and at resolution 2.8 years; 90% were healthy by the age 3.8 years. The reason for performing a blood count was febrile infection in 56.3% while nearly 20% were diagnosed by the routine blood count performed between ages 9-12 months in the well-baby clinic. Prophylactic antibiotic use did not correlate with the number of infectious events or days of fever. At least one microbiologically proven bacterial infection was identified in 26% of the patients including acute otitis, urinary tract infections, skin lesions and bacteremia. Bacterial isolates were mostly gram negative, predominantly Pseudomonas species (13/32, 40.6% of isolates) (Figure 1). Prevalence of significant skin infections, especially in the genital region, was very high (20% of infections). There were only 3 episodes of bacteremia out of 559 total febrile illnesses (0.5%).Discussion and conclusions: A standard treatment protocol for AIN is lacking, possibly due to a paucity of data in the literature. Severe bacterial infections in AIN are less common than in severe congenital neutropenia or chemotherapy induced neutropenia. The prevalence of bacteremia in AIN is not well defined in the post-pneumococcal vaccine era. In our cohort bacteremia was uncommon, while bacterial skin infections were much more prevalent, especially involving the genital area, with a high isolation rate of gram negative bacteria, especially Pseudomonas sp. This finding was surprising as ecthymal lesions are more commonly associated with hypoproductive neutropenias. The common practice of treating febrile illnesses in AIN with broad spectrum antibiotics may be unnecessary for a proportion of patients, while a subset of patients seems to be susceptible to gram negative skin infections and should be covered with anti-pseudomonal antibiotics. We recommend that patients with AIN and a febrile illness undergo a careful daily physical examination in addition to laboratory studies including blood counts and cultures of blood, urine and any other suspected sites of infection. Antibiotic therapy should be prescribed according to the clinical picture and the laboratory results. DisclosuresNo relevant conflicts of interest to declare.

CD16b: Primary Structure of Human Neutrophil Antigen Epitopes and Their Functional Consequences

Neutrophil specific Fcg receptor IIIb (CD16b) is a glycosylphosphatidylinositol-anchored low-affinity glycoprotein that plays a significant role in phagocytosis and the clearance of immune complexes. CD16b has numerous polymorphic variants; the most relevant variants are associated with human neutrophil antigens (HNA) -1a, -1b, and -1c. HNA-1a and HNA-1b differ in four amino acids (aa) (positions 36, 65, 82 and 106). One additional aa mutation on HNA-1b at position 78 results in HNA-1c.Immunization against CD16b variants can lead to the production of alloantibodies (aabs) responsible for neonatal alloimmune neutropenia (NIN), autoimmune neutropenia of infancy (AIN) and transfusion-related acute lung injury (TRALI). The exact contribution of five aa mutations for the formation of HNA-1a, -1b and -1c and function of CD16b is currently unknown.In this study, permutation of each polymorphic aa from wild-type CD16b cDNA constructs was performed and stably expressed on HEK293 cells. In total, 3 cell lines expressing wild-type (HNA-1a, -1b and -1c) and 18 cell lines expressing mutant variants were produced; 14 derived from HNA-1a or HNA-1b (panel 1) and 4 derived from HNA-1c (panel 2). When panel 1 was tested with well-defined aabs by antigen capture assay, 4 cell lines reacted with anti-HNA-1a only, 4 with anti-HNA-1b only, 4 with both aabs, and 4 did not react with both aabs. These results indicate that aa36 and aa65 are responsible for the formation of the HNA-1a and HPA-1b epitope(s), respectively. Analysis of panel 2 showed that 2/4 mutant variants reacted with anti-HNA-1c exclusively, suggesting that the HNA-1c epitope is formed by Ala78Asp irrespective of the other polymorphic aa.To analyze the binding affinity of CD16b variants, adhesion assay onto immobilized IgG was performed. In comparison to HNA-1a, HNA-1b cells bound slightly weaker to IgG (p<0.002). In contrast, HNA-1c cells interacted significantly stronger with IgG in comparison to both, HNA-1a and -1b cells (p<0.0001). Similar results were obtained with HNA-1a, -1b and -1c recombinant proteins by direct protein-binding analysis (solid phase ELISA and Surface Plasmon Resonance). Interestingly, all mutant variants carrying HNA-1c bound also stronger to IgG than HNA-1a and -1b transfected cells. Similar results were observed with HNA-1c phenotyped neutrophils.In conclusion, although HNA-1a and HNA-1b differ in four aa positions, only two (aa36, aa65) are necessary for the complete formation of the respective epitopes. In contrast, the HNA-1c epitope is created by only one aa mutation (Ala78Asp). Furthermore, our results show that HNA-1c exhibits higher affinity to IgG compared to HNA-1a and HNA-1b forms. Accordingly, the Ala78Asp mutation is not only responsible for epitope formation, but is also involved in the regulation of CD16 affinity. Characterization of HNA-1 epitopes by tailored recombinant tools will help us to improve our diagnostic work-up in patients with suspected NIN, AIN and TRALI and our understanding on the role of CD16 polymorphism in other diseases such as, immune complex-mediated disorders. DisclosuresNo relevant conflicts of interest to declare.

Autoimmune neutropenia of infancy: Data from the Italian neutropenia registry

Autoimmune neutropenia of infancy: Data from the <scp>I</scp>talian neutropenia registry

Severe congenital neutropenia caused by the ELANE gene mutation in a Vietnamese boy with misdiagnosis of tuberculosis and autoimmune neutropenia: a case report.

BackgroundSevere congenital neutropenia (SCN) is an immunodeficiency disease characterized low blood neutrophil counts, early bacterial infections, and risk of leukaemia development. Heterozygous mutations in the ELANE gene coding neutrophil elastase are associated with SCN. Patients with SCN suffer from recurrent bacterial infections and often succumb them. To our knowledge, this is the first report of SCN from Vietnam.Case presentationA 6-year-old boy was admitted due to severe bacterial infection and severe neutropenia. He had recurrent infections from 8 months of age, and was misdiagnosed with tuberculosis and and autoimmune neutropenia in infancy at 21 and 41 months of age, respectively. His medical report has showed severe neutropenia for many times. In direct DNA sequencing analysis, we found an ELANE gene mutation (R81P), which had been confirmed to cause SCN.ConclusionThe missed and delayed diagnosis may be attributable to insufficient awareness of this rare disease on the background of frequent infections even in the immunocompetent pediatric population in Vietnam. Our results indicate further evidence for the role of ELANE in SCN.

Diagnosis and management of primary autoimmune neutropenia in children: insights for clinicians.

Autoimmune neutropenia of infancy (AIN), also called primary autoimmune neutropenia, is a disease in which antibodies recognize membrane antigens of neutrophils, mostly located on immunoglobulin G (IgG) Fc receptor type 3b (FcγIIIb receptor), causing their peripheral destruction. It is the most frequent type of neutropenia in children under 3-4 years of age and in most cases shows a benign, self-limited course. The diagnosis is based on evidence of indirect antineutrophil antibodies, whose detection frequently remains difficult. In this review we have analyzed the literature regarding AIN and present our personal experience in diagnosis and management.

Anti-Granulocyte Antibodies in Transfusion Medicine

Granulocyte antibodies, in contrast to antibodies recognizing red blood cells and platelets, have been widely neglected in transfusion medicine for several decades, although their clinical relevance is well-described. Autoimmune neutropenia of infancy and neonatal alloimmune neutropenia are probably the most well-known granulocyte antibody-induced disorders. The facts that antibody-induced neutropenias are rare disorders with a favorable prognosis and that sophisticated, labor-intensive in-house techniques are required for granulocyte antibody detection may both have contributed to this negligence. When transfusion-related acute lung injury (TRALI) was delineated as the leading cause of transfusion-associated mortality and, subsequently, granulocytes were identified as key players in TRALI, granulocyte antibodies received progressively higher attention. It took only a short period of time to unravel that transfusion of granulocyte antibodies can lead to activation of the transfusion recipient’s own granulocytes with subsequent breakdown of the pulmonary endothelial barrier and lung edema. Clinical and regulatory pressure has prompted the identification of new target antigens on granulocytes, the development of better diagnostic approaches for antibody identification, and drastic changes in blood component production in order to reduce the risk of TRALI. There were two major fields of controversy in this rather straight-forward process. First, there are two groups of antibodies associated with TRALI: 1) granulocyte antibodies in sensu strictu, i.e., those which recognize human neutrophil antigens (HNA); and 2) human leukocyte antigen (HLA) antibodies which can bind to granulocytes, but also to other cells. These observations led to a debate on whether granulocytes are primary target cells or, at least in some cases, “auxiliary” cells in TRALI. Evidence from animal studies supports the idea that HLA class I antibodies may bind to endothelial cells and recruit granulocytes to the vessel wall, where they get activated; and that HLA class II antibodies, since their target antigen is not expressed on quiescent granulocytes, may bind to monocytes which then activate granulocytes. Recent data on HNA antibodies which cause TRALI by direct binding to pulmonary endothelium in the absence of granulocytes have added to the complexity, as has the observation from prospective clinical trials that HLA class I antibodies are of less relevance than previously anticipated. Today, there is consensus that different antibodies can cause TRALI by different pathways which do partially overlap. Second, the presence of granulocyte antibodies in blood components as the only causative factor for TRALI appeared partially doubtful: a minority of components produced from the same donor and transfused to different recipients led to TRALI. These doubts were further substantiated by the fact that in some TRALI cases, no antibodies whatsoever could be identified. Other substances often referred to as biological response modifiers (BMR) were demonstrated causative for TRALI, but only in animals pre-exposed to priming agents. This observation was crucial in understanding that not only factors present in a blood component (antibody or BMR) need to be considered, but also factors present in the recipient; this led to the “two-hit model” or “threshold model” of TRALI. Nowadays, there is consensus that antibody-mediated TRALI and non-antibody-mediated TRALI exist, with the latter one posing new challenges for transfusion medicine. This overview will start from pre-TRALI knowledge of granulocyte antibodies, consider antibody-mediated TRALI in detail, and will finally return to non-TRALI disorders in the light of relevant new findings in the field. DisclosuresNo relevant conflicts of interest to declare.

Immune-mediated Neutropenia in the Neonate

Neutropenia is a relatively common finding in ill neonates, occurring in approximately 32,000 infants each year in the United States. In this patient population, immune-mediated neutropenia results from the antibody-mediated destruction of neutrophils and is associated with such disorders as alloimmune neonatal neutropenia, neonatal autoimmune neutropenia, and autoimmune neutropenia of infancy. Such conditions only recently have begun to be understood and often are problematic in terms of clinical identification and laboratory confirmation. This article reviews the clinical presentation, laboratory diagnosis, and treatment options for these three disorders.

Pyoderma Gangrenosum in Association with Autoimmune Neutropenia of Infancy

We report the case of a 10-month-old girl who presented with a spontaneous ulcer on the left buttock which failed to heal despite antibiotic therapy. Histology showed changes consistent with pyoderma gangrenosum and the ulcer resolved rapidly with super-potent topical steroids under occlusion. Blood tests revealed a persistent neutropenia. Immunoglobulin G (IgG) antineutrophil antibodies were detected in the serum, directed against human neutrophil antigen (HNA)-1a. Bone marrow studies showed normocellular marrow with no evidence of dysplasia. T and B cell subsets and karyotype analysis were normal. Autoimmune neutropenia is an uncommon self-limiting condition in young children. Pyoderma gangrenosum is rare in infants, although the buttocks are a common site of involvement in this age group. Pyoderma gangrenosum in infancy can be associated with systemic disease as in adults, particularly myelodysplasia and leukemia, arthritis and inflammatory bowel disease. However, the association of pyoderma gangrenosum and autoimmune neutropenia of infancy has not previously been reported.

Oral 8, A case of pyoderma gangrenosum in association with autoimmune neutropenia of infancy

A 10-month-old girl presented in January 2006 with a 10-day history of a rapidly enlarging 2-cm ulcer on the left buttock which had not responded to antibiotic therapy. The ulcer had an indurated red border with mild surrounding erythema. Systemic examination was unremarkable. Skin swabs showed skin flora only and subsequent treatment with Trimovate® (GlaxoSmithKline, Uxbridge, U.K.) cream, mupirocin ointment and oral azithromycin had no effect. A skin biopsy taken 8 days after presentation showed active polymorph infiltration, granulation tissue formation and a heavy mixed inflammatory cell infiltrate within the ulcer. Tissue culture showed Enterococcus faecalis which was felt to represent colonization in the napkin area. A full blood count showed a neutropenia of 0·36 × 109 L–1 (normal 1·5–8·5 × 109) with a raised monocyte count of 1·36 × 109 L–1 (0·2–0·8 × 109). Renal and liver function tests, autoimmune screen, immunoglobulins, vitamin B12, folate and C-reactive protein were normal. A clinical diagnosis of pyoderma gangrenosum was made and the ulcer was treated with topical clobetasol propionate ointment under occlusion, resulting in dramatic improvement within 3 days followed by complete healing over in 2 weeks. The patient subsequently developed mild recurrent ear and upper respiratory tract infections and repeat full blood counts showed a persistent neutropenia < 0·3 × 109 L–1 associated with an intermittent monocytosis and thrombocythaemia. In view of the known association between pyoderma gangrenosum and myelodysplasia a bone marrow aspirate was performed which showed normocellular marrow with no cytogenetic abnormalities. Further blood tests showed an IgG granulocyte-specific antibody in the serum consistent with a diagnosis of autoimmune neutropenia of infancy. She is currently on prophylactic trimethoprim 2 mg kg–1 daily and nystatin suspension, and remains fit and healthy. Autoimmune neutropenia runs a benign clinical course associated with minor infections, and is normally self-limiting by 24 months of age.1 Pyoderma gangrenosum is rare in childhood but frequently involves the perianal and genital area in this age group.2 Recognized associations include inflammatory bowel disease and haematological malignancy, although an association with autoimmune neutropenia of infancy has to our knowledge not previously been described. References 1 Taniuchi S, Masuda M, Hasui M et al. Differential diagnosis and clinical course of autoimmune neutropenia in infancy; comparison with congenital neutropenia. Acta Paediatr 2002; 91:1179–82. 2 Graham JA, Hansen KK, Rabinowitz LG, Esterly NB. Pyoderma gangrenosum in infants and children. Pediatr Dermatol 1994; 11:10–17.

The Involvement of Regulatory T Cells in Immunopathophysiology of Autoimmune Neutropenia in Infancy.

CD4+25+ regulatory T cells (Treg) have been recognized to play a significant role in the immunopathogenesis of autoimmune disease, tumors, and organ transplantation. Several human autoimmune diseases in adulthood have been reported to associate with alternations in Treg. To date little is known about the standard value of Treg in infancy and childhood and its involvement in pediatric autoimmune disease. Autoimmune neutropenia (AIN) in infancy is a common disorder characterized by chronic neutropenia, the detection of antineutrophil antibodies in sera, and spontaneous resolution of neutropenia within several months to a few years. In this study, to elucidate the involvement of Treg in AIN known as a representative autoimmune disease in infancy and early childhood, we examined the frequencies of Treg in various normal age groups and AIN patient. Blood samples from normal neonates (n=22), infants (1 month through 3 years in age, n=21), adults (n=12) and AIN patients (1 month through 3 year in age, n=22) were obtained after informed consent. The frequency of Treg was assessed by the expression of CD4, CD25, and FOXP3 using flow cytometry. As shown in Table, the frequency of CD4+25high Treg known as pure Treg fraction was highest in neonates and decreased by aging. Notably CD4+25high Treg in AIN patients was fewer than age-matched control infants (P<0.01). Furthermore, the ratio of intracytosolic FOXP3 expression of each Treg fraction in AIN patients was fewer than age-matched control infants (P<0.05). The spontaneous disappearance of antineutrophil antibody and the restoration of the frequency of CD4+25high cells that preceded the normalization of the neutrophil count were found in two patients with AIN. These results suggest that Treg could contribute to the immunopathophysiology of AIN in infancy.Percentage of CD25+, CD25high, and CD25low in CD4+ cellsNeonatesInfantsAdultsPatients with AINCD25+11.9±2.610.1±2.018.5±3.99.5±1.9CD25high8.3±2.75.6±1.94.2±1.14.0±1.6CD25low3.6±1.24.5±1.914.3±3.65.5±1.5Date represent mean±SD.

Autoimmune Neutropenia of Infancy with Multiple Brain Abscesses during the Course of Human Herpesvirus-6 Infection

Autoimmune neutropenia of infancy is characterized by recurrent infections such as pneumonia, otitis media, impetigo, purulent skin regions, gastritis, and upper respiratory infection. However, severe bacterial infection is uncommon. This report documents a 9-month-old boy presenting with autoimmune neutropenia in association with multiple brain abscesses during the course of human herpesvirus (HHV)-6 infection. HHV-6 has a tendency of neurovirulence, which can destroy the blood-brain barrier and facilitate the easy invasion of agents inside the brain. Although autoimmune neutropenia of infancy is benign and self limiting, it must be emphasized that severe bacterial infection will be induced by concurrent viral infection in this specific disorder.

Antineutrophil Antibodies Lead to Mistaken Identity in Severe Congenital Neutropenia.

Autoimmune Neutropenia of Infancy (ANI) is generally regarded as a benign condition diagnosed by finding neutropenia and a positive test for antineutrophil antibodies. To determine whether the presence of antineutrophil antibodies in infancy always predicts a benign disease, data were reviewed for young children with positive antineutrophil tests who are enrolled in the Severe Chronic Neutropenia International Registry (SCNIR). A set of identical twins presented with severe neutropenia at age 5 months. Twin A1 had a preceding history of aphthous ulcers, cellulitis, recurrent otitis media, pneumonitis, an episode of bacteremia and a positive test for antineutrophil antibodies<INS cite=mailto:%20 dateTime=2005-08-01T10:53>.</INS> Twin A2 had a preceding history of cellulitis, otitis media, and pneumonitis. The median absolute neutrophil count (ANC) of twin A1 and twin A2 was 0.280 x 109/L and 0.116 x 109/L, respectfully and bone marrow examination for twin A1 showed maturation arrest at the myelocyte-metamyelocyte level. With the diagnosis of ANI in one twin, both twins were placed on granulocyte-colony stimulating factor (G-CSF), because of frequent fever and recurrent infections. Fifty-one months after the diagnosis of immune neutropenia, twin A1 developed acute myelogenous leukemia. Further studies then revealed that both twins had a mutation in the neutrophil elastase gene (ELA2) at exon 5 resulting in a nucleotide substitution from TGC to TGA, which indicated a diagnosis of severe congenital neutropenia. Another set of fraternal twins were identified to have ANI at six months because of recurrent abscesses, mouth ulcers, otitis media and positive tests for antineutrophil antibodies. The ANC was 0.067 x 109/L in twin B1 and 0.166 x 109/L in twin B2. At age 31 months twin B1 developed a severe Clostridial infection, which led to the loss of his right leg and part of the anterior abdominal wall. Subsequently both twins were placed on G-CSF. Prior to G-CSF treatment, bone marrow studies revealed an arrest at the promyelocyte stage and an ELA2 mutation in exon 4 leading to a TCG to TTG substitution in both twins thereby indicating a diagnosis of severe congenital neutropenia. Upon further review of the SCNIR, eight other congenital patients were identified to have antineutrophil antibodies and bone marrow patterns consistent with severe congenital neutropenia. In conclusion, it is important to be aware that positive antineutrophil antibodies can occur associated with severe congenital neutropenia. Infants with severe neutropenia and repeated or severe bacterial infections should have a bone marrow examination and ELA2 evaluation to establish correctly the underlying pathogenesis of the neutropenia.

Antineutrophil Antibodies and Autoimmune Neutropenia in Infancy and Early Childhood

Antineutrophil Antibodies and Autoimmune Neutropenia in Infancy and Early Childhood

Efficacy of prophylactic use of trimethoprim-sulfamethoxazole in autoimmune neutropenia in infancy.

Most children with autoimmune neutropenia (AIN) have a benign clinical course because of the spontaneous resolution of neutropenia. The authors observed the clinical course of AIN in infancy accompanied by the prophylactic use of trimethoprim-sulfamethoxazole (TMP-SMX) during neutropenia. Eight infants with AIN were followed by serial tests for antineutrophil antibodies and management of infectious complications. The spontaneous disappearance of antineutrophil antibodies that preceded the normalization of the neutrophil count was found in all patients. Until the resolution of neutropenia, TMP-SMX was administered in five patients, resulting in a reduction in the incidence of infection with no adverse effects. These observations demonstrate the possibility of the safety and usefulness of TMP-SMX treatment in patients with AIN.

Differential diagnosis and clinical course of autoimmune neutropenia in infancy: comparison with congenital neutropenia

Aim: Autoimmune neutropenia in infancy (AIN) is caused by granulocyte‐specific autoantibodies. Clinical presentation and diagnosis have not been well studied, resulting in cumbersome diagnostic investigations and unnecessary treatment such as granulocyte colony‐stimulating factor (G‐CSF) therapy. Methods: Clinical, laboratory and immunological data of 18 infants with AIN were evaluated. Granulocyte‐specific autoantibodies were detected by the direct granulocyte immuno‐fluorescence test (D‐GIFT), indirect granulocyte immunofluorescence test (I‐GIFT) and immuno‐blotting. Results: The average age of onset and resolution of neutropenia in AIN was 7.4 ± 3.4 mo (mean ± SD) and 20.4 ± 4.9 mo, respectively. Sixteen of the 18 patients presented with mild infectious symptoms; the other 2 patients were detected by chance and presented with no infectious symptoms. D‐GIFT was positive in all patients, and I‐GIFT was positive in 17 of these 18 patients. Most patients showed preferential binding to neutrophils from NA(1 + 2−)‐phenotyped donors by I‐GIFT and immunoblotting. An antibiotic (sulfamethoxazole‐trimethoprim) was given to 15 patients for prophylaxis. G‐CSF was given to only one infectious patient. Conclusion: A combination of diagnostic tests for the detection of granulocyte‐specific autoantibodies was useful in diagnosing AIN, thus avoiding unnecessary investigations. Continuous treatment with G‐CSF was not necessary for prophylaxis, even if neutrophil counts were extremely low.

Immune-mediated neutropenia in the neonate.

Alloimmune neonatal neutropenia, neonatal autoimmune neutropenia and autoimmune neutropenia of infancy have remained nebulous entities with difficulties in both clinical and laboratory identification. These disorders are reviewed in this article.

Detection of neutrophil-associated immunoglobulin using flow cytometry in autoimmune neutropenia of infancy.

Autoimmune neutropenia of infancy (ANI) is a common form of chronic childhood neutropenia, which is caused by antineutrophil antibodies. The syndrome is characterized by a severe selective neutropenia accompanied with recurrent bacterial infections. We investigated 10 ANI patients in our hospital. Neutropenia in ANI patients was found in patients aged between 9 and 19 months. They had no life-threatening infections and their infections episode could be controlled by the conventional antibiotic therapy in general. The correlation of absolute neutrophil counts (ANC) and neutrophil-associated immunoglobulin (NAIg) levels in each case was analyzed and their clinical courses followed. The NAIg levels were high in all cases at the diagnosis, however, they had no relationship with ANC. The severity of infection and the period of neutropenia in our patients have no correlation to NAIg levels either. In our four cases, neutropenia disappeared after a median of 26 months (range, 18-29 months). The periods of neutropenia were nearly similar to previous reports. After the NAIg level began to wane, neutrophil counts increased in four patients whose neutrophil counts had recovered finally. Detection of NAIg is useful for the diagnosis, and the observation of changes in NAIg may be helpful one by one for prediction of the prognosis.