Autoimmune neutropenia of infancy is a primary, usually self-limiting, antineutrophil autoimmune phenomenon seen in infancy and early childhood. These infants are at a higher risk of infection, and early detection, particularly with the availability of newer therapeutic options such as hematopoietic growth factors, can allow close follow-up and, if needed, treatment. We report two infants with autoimmune neutropenia who presented with a persistent perianal abscess, which has not been documented previously in this population.
Autoimmune neutropenia of infancy (AINI) is a rare disorder characterized by neutrophil destruction secondary to antineutrophil autoantibodies.1 Infants with AINI are at a high risk of infection; up to 12% develop serious bacterial infections such as pneumonia, meningitis, or sepsis.1 Early recognition, therefore, can facilitate closer observation and, if needed, treatment with recombinant hematopoietic growth factors. We report two infants with immune-mediated neutropenia who presented with a perianal abscess. Although anorectal abscesses are a common presentation in neutropenia due to various non-immune causes, these have not been documented with immune-mediated neutropenias in infants.
A 3-week-old male infant was admitted to the hospital with a spontaneously draining perianal abscess. He was born following an unremarkable antenatal and early neonatal period and was otherwise in good health, without any history of fever, decrease in appetite, or loss of weight. Upon hospitalization, he was found to be neutropenic with an absolute neutrophil count (ANC) of 387/μl.
A bone marrow biopsy showed abundant and markedly left shifted myeloid elements, with a relative paucity of the more mature stages of granulocyte development. Granulocyte typing, granulocyte cross matching, and serum assays to detect neutrophil-specific antibodies were performed at the Neutrophil Serology Reference Laboratory of the American Red Cross, St. Paul, MN. The granulocyte immunofluorescence assay (GIF) was positive for neutrophil-specific antibodies. The maternal serum was negative, suggesting an autoimmune etiology for the infant's neutropenia. Despite extended antibody testing in the monoclonal antibody immobilization of granulocyte antigen (MAIGA) assay, the exact antigenic specificity of the antineutrophil antibodies was not determined.
He was treated with oral augmentin for 7 days. The ANC increased over the first 5 days to 1600/μl, and rose further to 2178/μl when tested at a clinic visit in 2 weeks time. However, at 9 weeks of age, he was noted to be neutropenic again with an ANC of 200/μl. The perianal abscess had improved only partially, with a small amount of drainage still persisting at that time. He was started on recombinant human granulocyte colony-stimulating factor (rhG-CSF) at 10 mcg/kg/day three times per week, and had a prompt neutrophil response. He received only intermittent doses after 4 months of age, and his perianal lesions healed well. The neutrophil counts have stayed above 1000/μl without rhG-CSF since 5 months of age. He is currently 8 months old with no further evidence of infection or neutropenia.
A 5-month-old male infant was admitted to the hospital for a nonhealing perianal abscess. He was first seen at his physician's office for a persistently draining perianal abscess at 8 weeks of age, and was treated with oral antibiotics and surgical drainage. However, after partial improvement lasting for about 1 week, there was reappearance of blood-tinged purulent discharge. He was treated with oral antibiotics at least on three occasions as an outpatient, but as symptoms persisted, was admitted at 5 months of age for evaluation. No laboratory studies were conducted prior to this admission. Similar to Case 1, he had no history of systemic symptoms, such as fever or decrease in appetite, and had maintained normal growth. A 1-cm nodular abscess was noted in the perianal area, which on surgical exploration was found connected to a fistula-in-ano. During hospitalization, and upon review of his first CBC, he was noted to be neutropenic with an ANC of 825/μl. Over the next 3 days, the ANC decreased progressively to zero. As there were no prior CBCs documented, we cannot state with certainty the sequence of the neutropenia and the development of the abscess. He was treated with intravenous cefazolin and gentamicin for 2 days, followed by a 10-day outpatient course of augmentin.
Neutrophil serology was carried out at the same laboratory, and antineutrophil antibodies against HNA-1a (NA1) antigen were detected. Maternal serum was negative for such antibodies. Since 5 months had elapsed since delivery, maternal neutrophil antigen typing was also performed to exclude a possibility of maternal serum testing negative for antineutrophil antibodies because of postnatal decline in titers (with the loss of antigenic stimulation from fetal neutrophils). The maternal neutrophils were also HNA-1a positive, suggesting that the infant's antineutrophil antibodies could not have been of maternal origin. Other tests performed on the patient, including those for T-cell subsets and serum immunoglobulin concentrations, were normal.
The patient was started on rhG-CSF on hospital day 5 at 10 mcg/kg/day and had a prompt response with rise in neutrophil concentrations within 48 hours. He was discharged home on weekly injections that were maintained for the next month. Over the next several months, he maintained ANCs >1000/μl with treatment, and by 4 months after presentation, his perianal abscess had healed completely.
Autoimmune neutropenia is the neutrophil analog of autoimmune hemolytic anemia and thrombocytopenia. The presence of antineutrophil antibodies in AINI is usually an isolated autoantibody phenomenon, unlike the ‘secondary’ disorder of older children and adults that is associated with systemic autoimmune diseases.1 Suggested etiologic mechanisms include molecular mimicry by environmental triggers (e.g., parvovirus B19, β-lactam antibiotics), alterations in endogenous antigens, enhanced expression of the major histocompatibility complex molecules, or loss of suppression of autoreacting lymphocyte clones.2,3,4 Genetic susceptibility related to HLA-DR2 immune response genes,5 or certain Fc receptor type (FcR) γIIIb and FcRγIIa polymorphisms may be important in the pathophysiology of AINI,6 but reports of the disease occurring in only one of identical twin pairs suggest that environmental factors may be equally important.7
A wide variety of neutrophil-specific antigenic targets have been identified, including HNA-1a, HNA-1b, HNA-2a, and in the past, ND1 and NE1.8 HNA-1a (NA1) is the most frequently implicated antigen, with reports varying between 10 and 55% of all AINI sera.8 The other antigens include the FcRγIIb, leukocyte adhesion molecule b (CD11b/CD18), and the C3b complement receptor CR1. Neutrophil destruction in AINI is mainly through reticuloendothelial phagocytosis of opsonized cells. Numerous defects have been documented in neutrophil function in the presence of autoantibodies, even in patients with normal neutrophil counts.9
The incidence of AINI is estimated to be about 1 in 100,000 in children between the ages of infancy and 10 years.8 It is most commonly seen in the age range 3 to 30 months, but has been well described in the neonatal period.10 It is likely that in many cases the neutropenia begins early, and comes to clinical attention only when symptoms appear with infectious events.10 In their retrospective analysis of 240 cases, Bux et al.,1 reported that 12% of the children presented with severe infections including pneumonia, sepsis, or meningitis.1 However, these children usually present with minor infections like otitis media, respiratory tract infections, gastroenteritis, or cellulitis. Often, the diagnosis is considered only after a blood count reveals neutropenia. As most of these infants lack characteristic clinical manifestations, there is reason to believe that many of them may remain undiagnosed and the disorder may actually be more common than is suggested by the literature.
Owing to technical difficulties, antineutrophil antibody testing is usually performed using a combination of tests. A combination of GIF with the granulocyte agglutination test, as the two have different individual sensitivities for different antigens, is the best currently available means of antibody detection.1,10 The MAIGA is highly specific for identification of affinities of the identified antibodies, but is often limited by a lower sensitivity.10 In Case 1, therefore, a positive result with GIF still remains a significant finding even though the specific affinity of this antibody could not be determined through MAIGA.
It is surprising that anorectal infections, which are known to be common in the neutropenic host, have not been reported as frequently in patients with immune-mediated neutropenias. They (anorectal abscesses) have not been documented previously in AINI or secondary autoimmune neutropenia. There is only one report of gluteal cellulitis in a neonate with alloimmune neutropenia secondary to antibodies against HNA-1a (NA1).11 This is in contrast to multiple reports of perianal infection in neutropenia of other causes: secondary to chemotherapy in leukemia and other malignancies,12 chronic severe neutropenia,13 cyclic neutropenia,13 hyper-IgM syndrome,14 Schwachman–Diamond syndrome,15 and glycogen storage disease type 1b.16 Since infancy, overall, is a relatively common age group for anorectal infections,17 it is unlikely that the apparently low frequency of anorectal infections in immune-mediated neutropenias could be an artifact of small numbers. It is more likely that since most of these patients appear well in the absence of serious infections (compared to those with chemotherapy-induced neutropenia or systemic metabolic disorders), neutropenia is often missed on presentation with an anorectal abscess because of a low index of suspicion. In both of our patients, a complete blood count was obtained only when the perianal abscess was considered refractory to usual treatment modalities.
In view of the morbidity and mortality risks of neutropenia, and also because of the fact that therapeutic use of recombinant hematopoietic growth factors like rhG-CSF can ameliorate the condition6,10 and may even shorten the course of autoimmune neutropenia,18 prompt clinical identification of this disorder can be helpful. A prospective study to estimate the incidence of neutropenia in all infants presenting with anorectal abscesses may be helpful to ascertain if a screening blood count should be routinely recommended for these patients.
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This work was supported by Grants HD-01180 and HD-42326 (Dr. Calhoun) and HL-61798 (Dr. Christensen) from the National Institutes of Health.
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Lejkowski, M., Maheshwari, A., Calhoun, D. et al. Persistent Perianal Abscess in Early Infancy as a Presentation of Autoimmune Neutropenia. J Perinatol 23, 428–430 (2003). https://doi.org/10.1038/sj.jp.7210952
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