Perinatal/Neonatal ...... Case Presentation Persistent Perianal in Early Infancy as a Presentation of Autoimmune

Marisa Lejkowski, DO CASE REPORTS Akhil Maheshwari, MD Case 1 Darlene A. Calhoun, DO A 3-week-old male infant was admitted to the hospital with a Robert D. Christensen, MD spontaneously draining perianal abscess. He was born following an Suzanne Skoda-Smith, MD unremarkable antenatal and early neonatal period and was otherwise in good health, without any history of , decrease in Sharon Dabrow, MD appetite, or loss of weight. Upon hospitalization, he was found to be neutropenic with an absolute neutrophil count (ANC) of 387/ml. A bone marrow biopsy showed abundant and markedly left Autoimmune neutropenia of infancy is a primary, usually self-limiting, shifted myeloid elements, with a relative paucity of the more antineutrophil autoimmune phenomenon seen in infancy and early mature stages of granulocyte development. Granulocyte typing, childhood. These infants are at a higher risk of infection, and early granulocyte cross matching, and serum assays to detect neutrophil- detection, particularly with the availability of newer therapeutic options specific were performed at the Neutrophil Serology such as hematopoietic growth factors, can allow close follow-up and, if Reference Laboratory of the American Red Cross, St. Paul, MN. The needed, treatment. We report two infants with autoimmune neutropenia granulocyte immunofluorescence assay (GIF) was positive for who presented with a persistent perianal abscess, which has not been neutrophil-specific antibodies. The maternal serum was negative, documented previously in this population. suggesting an autoimmune etiology for the infant’s neutropenia. Journal of Perinatology (2003) 23, 428–430. doi:10.1038/sj.jp.7210952 Despite extended testing in the monoclonal antibody immobilization of granulocyte antigen (MAIGA) assay, the exact antigenic specificity of the antineutrophil antibodies was not determined. INTRODUCTION He was treated with oral augmentin for 7 days. The ANC increased over the first 5 days to 1600/ml, and rose further to 2178/ Autoimmune neutropenia of infancy (AINI) is a rare disorder ml when tested at a clinic visit in 2 weeks time. However, at 9 weeks characterized by neutrophil destruction secondary to antineutrophil 1 of age, he was noted to be neutropenic again with an ANC of 200/ autoantibodies. Infants with AINI are at a high risk of infection; ml. The perianal abscess had improved only partially, with a small up to 12% develop serious bacterial infections such as pneumonia, 1 amount of drainage still persisting at that time. He was started on meningitis, or sepsis. Early recognition, therefore, can facilitate recombinant human granulocyte colony-stimulating factor (rhG- closer observation and, if needed, treatment with recombinant CSF) at 10 mcg/kg/day three times per week, and had a prompt hematopoietic growth factors. We report two infants with immune- neutrophil response. He received only intermittent doses after mediated neutropenia who presented with a perianal abscess. 4 months of age, and his perianal lesions healed well. The Although anorectal are a common presentation in neutrophil counts have stayed above 1000/ml without rhG-CSF neutropenia due to various non-immune causes, these have not since 5 months of age. He is currently 8 months old with no been documented with immune-mediated neutropenias in infants. further evidence of infection or neutropenia.

Case 2 Division of Neonatal-Perinatal Medicine (A.M., D.A.C., R.D.C.), Department of Pediatrics, A 5-month-old male infant was admitted to the hospital for a University of South Florida College of Medicine and All Children’s Hospital, St. Petersburg, FL, USA; Divison of General Academic Pediatrics & Adolescent Medicine, (M.L., S.D.), Department nonhealing perianal abscess. He was first seen at his physician’s of Pediatrics, University of South Florida College of Medicine and All Children’s Hospital, office for a persistently draining perianal abscess at 8 weeks of age, St. Petersburg, FL, USA; and Division of Immunology (S.S.-S.), Department of Pediatrics, University of Florida, Gainesville, FL, USA. and was treated with oral and surgical drainage. However, after partial improvement lasting for about 1 week, there Address correspondence and reprint requests to Sharon Dabrow, MD, Department of Pediatrics at University of South Florida and All Children’s Hospital, 801 6th St South, POB 31020, was reappearance of blood-tinged purulent discharge. He was St. Petersburg, FL, 33731, USA. treated with oral antibiotics at least on three occasions as an

Journal of Perinatology 2003; 23:428–430 r 2003 Nature Publishing Group All rights reserved. 0743-8346/03 $25 428 www.nature.com/jp Autoimmune Neutropenia Presenting as a Perianal Abscess Lejkowski et al.

outpatient, but as symptoms persisted, was admitted at 5 months of A wide variety of neutrophil-specific antigenic targets have been age for evaluation. No laboratory studies were conducted prior to identified, including HNA-1a, HNA-1b, HNA-2a, and in the past, this admission. Similar to Case 1, he had no history of systemic ND1 and NE1.8 HNA-1a (NA1) is the most frequently implicated symptoms, such as fever or decrease in appetite, and had antigen, with reports varying between 10 and 55% of all AINI sera.8 maintained normal growth. A 1-cm nodular abscess was noted in The other antigens include the FcRgIIb, leukocyte the perianal area, which on surgical exploration was found molecule b (CD11b/CD18), and the C3b complement receptor CR1. connected to a fistula-in-ano. During hospitalization, and upon Neutrophil destruction in AINI is mainly through review of his first CBC, he was noted to be neutropenic with an ANC reticuloendothelial phagocytosis of opsonized cells. Numerous of 825/ml. Over the next 3 days, the ANC decreased progressively to defects have been documented in neutrophil function in the zero. As there were no prior CBCs documented, we cannot state presence of autoantibodies, even in patients with normal with certainty the sequence of the neutropenia and the neutrophil counts.9 development of the abscess. He was treated with intravenous The incidence of AINI is estimated to be about 1 in 100,000 in cefazolin and gentamicin for 2 days, followed by a 10-day children between the ages of infancy and 10 years.8 It is most outpatient course of augmentin. commonly seen in the age range 3 to 30 months, but has been well Neutrophil serology was carried out at the same laboratory, and described in the neonatal period.10 It is likely that in many cases antineutrophil antibodies against HNA-1a (NA1) antigen were the neutropenia begins early, and comes to clinical attention only detected. Maternal serum was negative for such antibodies. Since when symptoms appear with infectious events.10 In their 5 months had elapsed since delivery, maternal neutrophil antigen retrospective analysis of 240 cases, Bux et al.,1 reported that 12% typing was also performed to exclude a possibility of maternal of the children presented with severe infections including serum testing negative for antineutrophil antibodies because of pneumonia, sepsis, or meningitis.1 However, these children usually postnatal decline in titers (with the loss of antigenic stimulation present with minor infections like , respiratory tract from fetal neutrophils). The maternal neutrophils were also infections, , or . Often, the diagnosis is HNA-1a positive, suggesting that the infant’s antineutrophil considered only after a blood count reveals neutropenia. As most antibodies could not have been of maternal origin. Other tests of these infants lack characteristic clinical manifestations, there performed on the patient, including those for T-cell subsets and is reason to believe that many of them may remain undiagnosed serum immunoglobulin concentrations, were normal. and the disorder may actually be more common than is suggested The patient was started on rhG-CSF on hospital day 5 at by the literature. 10 mcg/kg/day and had a prompt response with rise in neutrophil Owing to technical difficulties, antineutrophil antibody testing is concentrations within 48 hours. He was discharged home on weekly usually performed using a combination of tests. A combination of injections that were maintained for the next month. Over the next GIF with the granulocyte agglutination test, as the two have several months, he maintained ANCs >1000/ml with treatment, different individual sensitivities for different antigens, is the best and by 4 months after presentation, his perianal abscess had currently available means of antibody detection.1,10 The MAIGA is healed completely. 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 DISCUSSION be determined through MAIGA. Autoimmune neutropenia is the neutrophil analog of autoimmune It is surprising that anorectal infections, which are known to be hemolytic anemia and thrombocytopenia. The presence of common in the neutropenic host, have not been reported as antineutrophil antibodies in AINI is usually an isolated frequently in patients with immune-mediated neutropenias. They autoantibody phenomenon, unlike the ‘secondary’ disorder of older (anorectal abscesses) have not been documented previously in AINI children and adults that is associated with systemic autoimmune or secondary autoimmune neutropenia. There is only one report of diseases.1 Suggested etiologic mechanisms include molecular gluteal cellulitis in a neonate with alloimmune neutropenia mimicry by environmental triggers (e.g., parvovirus B19, b-lactam secondary to antibodies against HNA-1a (NA1).11 This is in contrast antibiotics), alterations in endogenous antigens, enhanced to multiple reports of perianal infection in neutropenia of other expression of the major histocompatibility complex molecules, or causes: secondary to chemotherapy in leukemia and other loss of suppression of autoreacting lymphocyte clones.2–4 Genetic malignancies,12 chronic severe neutropenia,13 cyclic neutropenia,13 susceptibility related to HLA-DR2 immune response genes,5 or hyper-IgM syndrome,14 Schwachman–Diamond syndrome,15 and certain Fc receptor type (FcR) gIIIb and FcRgIIa polymorphisms glycogen storage disease type 1b.16 Since infancy, overall, is a may be important in the pathophysiology of AINI,6 but reports of relatively common age group for anorectal infections,17 it is the disease occurring in only one of identical twin pairs suggest unlikely that the apparently low frequency of anorectal infections that environmental factors may be equally important.7 in immune-mediated neutropenias could be an artifact of small

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numbers. It is more likely that since most of these patients appear 5. Bux J, Mueller-Eckhardt G, Mueller-Eckhardt C. Autoimmunization against well in the absence of serious infections (compared to those with the neutrophil-specific NA1 antigen is associated with HLA-DR2. Hum chemotherapy-induced neutropenia or systemic metabolic Immunol 1991;30:18–21. disorders), neutropenia is often missed on presentation with an 6. Taniuchi S, Masuda M, Yamamoto A, et al. FcgammaRIII b and because of a low index of suspicion. In both of FcgammaRIIa polymorphism may affect the production of specific NA1 our patients, a complete blood count was obtained only when the autoantibody and clinical course of autoimmune neutropenia of infancy. Hum Immunol 2001;62:408–13. perianal abscess was considered refractory to usual treatment 7. Conway LT, Clay ME, Kline WE, Ramsay NK, Krivit W, McCullough J. modalities. Natural history of primary autoimmune neutropenia in infancy. Pediatrics In view of the morbidity and mortality risks of neutropenia, and 1987;79:728–33. also because of the fact that therapeutic use of recombinant 8. Bruin MC, von dem Borne AE, Tamminga RY, Kleijer M, Buddelmeijer L, hematopoietic growth factors like rhG-CSF can ameliorate the de Haas M. Neutrophil antibody specificity in different types of childhood condition6,10 and may even shorten the course of autoimmune autoimmune neutropenia. Blood 1999;94:1797–802. neutropenia,18 prompt clinical identification of this disorder can be 9. Shastri KA, Logue GL. Autoimmune neutropenia. Blood 1993;81:1984–95. helpful. A prospective study to estimate the incidence of 10. Calhoun DA, Rimsza LM, Burchfield DJ, et al. Congenital autoimmune neutropenia in all infants presenting with anorectal abscesses may neutropenia in two premature neonates. Pediatrics 2001;108:181–4. be helpful to ascertain if a screening blood count should be 11. Kummerle-Deschner J, Scheel-Walter HG, Speer CP. G-CSF therapy in a routinely recommended for these patients. neonate with alloimmune neutropenia. Z Geburtshilfe Neonatol 1997;201:273–6. 12. North Jr JH, Weber TK, Rodriguez-Bigas MA, Meropol NJ, Petrelli NJ. The management of infectious and noninfectious anorectal complications in Acknowledgements patients with leukemia. J Am Coll Surg 1996;183:322–8. This work was supported by Grants HD-01180 and HD-42326 (Dr. Calhoun) and 13. Welte K, Dale D. Pathophysiology and treatment of severe chronic HL-61798 (Dr. Christensen) from the National Institutes of Health. neutropenia. Ann Hematol 1996;72:158–65. 14. Uguz A, Yilmaz E, Ciftcioglu MA, Yegin O. An unusual presentation of immunodeficiency with hyper-IgM. Pediatr Dermatol 2001;18:48–50. References 15. Ventura A, Dragovich D, Luxardo P, Zanazzo G. Human granulocyte colony- 1. Bux J, Behrens G, Jaeger G, Welte K. Diagnosis and clinical course of stimulating factor (rHuG-CSF) for treatment of neutropenia in Shwachman autoimmune neutropenia in infancy: analysis of 240 cases. Blood syndrome. Haematologica 1995;80:227–9. 1998;91:181–6. 16. Visser G, Rake JP, Fernandes J, et al. Neutropenia, neutrophil dysfunction, 2. Taniuchi S, Masuda M, Yamamoto A, et al. Two cases of autoimmune and inflammatory bowel disease in glycogen storage disease type Ib: results neutropenia possibly induced by beta-lactam antibiotics in infants. J Pediatr of the European Study on Glycogen Storage Disease type I. J Pediatr Hematol Oncol 2000;22:533–8. 2000;137:187–91. 3. Murray JC, Morad AB. Childhood autoimmune neutropenia and human 17. Watanabe Y, Todani T, Yamamoto S. Conservative management of fistula in parvovirus B19. Am J Hematol 1994;47:336. ano in infants. Pediatr Surg Int 1998;13:274–6. 4. Dale DC. Immune and idiopathic neutropenia. Curr Opin Hematol 18. Carulli G. Treatment of autoimmune neutropenia with recombinant 1998;5:33–6. human granulocyte colony-stimulating factor. Ann Hematol 1998;76:93–4.

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