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Autoimmune Neutropenia of Infancy

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Autoimmune Neutropenia of Infancy J Clin Pathol 1992;45:431-434 431 Autoimmune neutropenia of infancy E G H Lyall, G F Lucas, 0 B Eden J Clin Pathol: first published as 10.1136/jcp.45.5.431 on 1 May 1992. Downloaded from Abstract from 0-10 years, we have seen five children Aim: Assessment of the clinical and with serologically confirmed ANI, suggest- haematological course of autoimmune ing an annual incidence of approximately neutropenia ofinfancy (ANI) in a defined 1/1000 000 in this population. All ofthese cases childhood population in the south east of have so far followed the classic benign course of Scotland. the condition. Methods: From January 1986 to February 1991 all children presenting with persis- Methods tent neutropenia were examined From January 1986 to February 1991 all chil- serologically for evidence of anti- dren presenting outside the neonatal period granulocyte antibodies. The clinical with isolated neutropenia (absolute neutrophil course of those children found to have count (ANC) <1-5 x 109/1), were seen by anti-granulocyte antibodies was then OBE. A full history and examination were closely monitored. carried out and particular attention was paid to Results: During the study period five previous illnesses, medications administered, children had serologically confirmed and family history. ANI, giving an annual incidence of Screening investigations to ascertain the approximately 1/100 000 in this popula- cause ofthe neutropenia were carried out when tion. All ofthese cases followed the classic the ANC had not returned to normal within 2- benign course of the condition. The 3 weeks. These included: serial full blood presenting illnesses were mild, often with counts; bone marrow aspiration; serum superficial skin sepsis and the initial immunoglobulin (G, A, M) and complement absolute neutrophil count (ANC) ranged concentrations; lymphocyte subsets; auto- from 0-00-0-87 x 10'/I. All have remained antibodies; viral serology; B12 and folate con- well with no serious infections. Two chil- centrations; chromosomal analysis; blood and dren attained a normal ANC after 14 and urine amino acid screening; and anti- 24 months respectively, the others granulocyte antibodies. The children found to http://jcp.bmj.com/ currently remain neutropenic. have anti-granulocyte antibodies and other Conclusions: Autoimmune neutropenia features consistent with the diagnosis of ANI of infancy is a condition which rests on a form the basis of this study. serological diagnosis. It follows a chronic Two techniques were used to detect gran- benign course and all children eventually ulocyte reactive antibodies; a microplate attain a normal ANC. The level of anti- modification of the granulocyte immuno- granulocyte antibody in the serum often fluorescence test (GIFT)'0 and the granulocyte on October 2, 2021 by guest. Protected copyright. begins to wane prior to improvement in chemiluminescence test (GCLT)."' A micro- the ANC and can give an indication of plate modification of the lymphocyte im- when recovery will begin to occur. munofluorescence test (LIFT)'2 was used to detect lymphocyte reactive (anti-HLA) anti- Autoimmune neutropenia of infancy (ANI), bodies. Results of the immunofluorescence first described by Lalezari in 1975,' is a benign tests were scored as negative (0) or as graded condition which has become increasingly positives ranging from W + (weak +) to 4+. characterised as reliable techniques for detect- The GCLT is a functional assay which Department of ing anti-granulocyte antibodies have become measures the response of human monocytes to Haematology, Royal more available. In Lalezari et al2 The results of the Hospital for Sick widely 1986, opsonised granulocytes. Children, Sciennes reported 121 infants with this disorder, 119 of GCLT were expressed as a ratio (the opsonic Rd, Edinburgh EH9 whom were demonstrated to have anti- index) between the response of monocytes to 1LF granulocyte antibodies. Smaller studies'7 have granulocytes incubated with test serum and the E G H Lyall and 0 B Eden confirmed both the clinical serological response of monocytes to granulocytes International Blood features of the condition and it seems likely incubated with serum from untransfused male Group Reference that the condition previously termed chronic (group AB) donors. The normal range of the Laboratory, South benign neutropenia is equivalent to ANI.289 GCLT is 1-0 +0 3 (3 SD). Western Regional Transfusion Centre, The exact incidence of ANI is unknown but The techniques were performed as Southmead Rd, because of its benign nature, the disorder may previously described except for the following Bristol BS10 SND be more common than is suggested by the modifications: granulocytes and mononuclear G F Lucas available literature. cells used in both techniques were isolated Correspondence to: From 1986 to February 1991, within from EDTA anticoagulated blood from normal E G H Lyall January the Lothian of Scotland, which has a donors using a double density gradient tech- Accepted for publication region 30 October 1991 childhood population of just over 96 000 aged nique. Red cells contaminating the granulocyte 432 Lyall, Lucas, Eden Table 1 Cases of autoimmune neutropaenia of infancy in south east Scotland (1986-1991) Age Serum Bone marrow Increased Time to at Initial Lymphocyte IgG infections normal onset ANC TWC granulocyte subsets IgM M:E Maturation during ANC Cases (months) Sex Presenting illness TWC diff (%) serology T4:T8 IgA ratio arrest ANI (months) J Clin Pathol: first published as 10.1136/jcp.45.5.431 on 1 May 1992. Downloaded from 1 13 F Gastroenteritis 0Q N-0 01-10-0 9-83:1 N 6-5:1 NO NO 24 6-2 L-86 Antig IgG 3 + no specific target Ag identified 2 8 M Fever and skin 0-19 N-4 01-12-8 4-6:1 N 8 5:1 NO NO Not yet sepsis 4-8 L-68 Antig IgG 3 + recovered M-26 antig IgM W + after myelo-I no specific 19 months meta-1 target Ag identified 3 8 M Skin sepsis, Q-8 N-10 OI-8-6 4-3:1 N 9-4:1 NO NO Not yet lymphadenitis, 8-7 L-62 Antig IgG 3 + recovered upper respiratory M-27 antig IgM 0 after tract infection E-1 target Ag NAl 11 months 4 11 F Skin sepsis QJ01 N-3 01-15-9 2-7:1 N 2-5:1 NO NO Not yet 4-4 L-80 Antig IgG 2 + recovered M-12 Antig IgM 0 after E-4 target Ag NAb 7 months BI 5 7 F Fever, vomiting 0Q0 N-o OI-1-2 2-7:1 N 1-33:1 NO NO 14 oral/anal 10-9 L-91 Antig IgG 1+ candidiasis M-9 Antig IgM NEG target Ag NAb ANC = absolute neutrophil count x 10'/l; TWC = total white count x 109/l; TWC percentage differential: N = neutrophils; L = lymphocytes; M = monocytes; Myelo = myelocytes; Meta = metamyelocytes; E = eosinophils; B = basophils. 01 = opsonic index; Antig = antigranulocyte; Ag = antigen; N = normal. fraction were lysed using a hypo-osmolar solu- present. None of these children has suffered tion of ammonium oxalate. Granulocytes were any severe infections or any great increase in inactivated by incubation at 52°C for 2 minutes minor infections during the course of the prior to incubation with test serum and were neutropenia. Case 1 has been closely followed not treated with paraformaldehyde. through to complete recovery and the clinical Target granulocytes and lymphocytes were course of this patient demonstrates the typical obtained from normal donors typed for the features of this disorder (figure): neutrophil specific antigens NAI, NA2, and (1) The total white blood count always NB1, the tissue antigen 5b and HLA-A and B remained within normal limits. antigens. Granulocyte immunofluorescence (2) The ANC remained below 0 5 x 109/l for was used to determine NA1, NA2, NB1, and 5b the first 12 months. phenotype and lymphocytotoxicity was used to (3) The level of anti-granulocyte antibody http://jcp.bmj.com/ determine HLA-A and B phenotypes. activity slowly decreased during the course of the disease. (4) Temporary increases in peripheral Results neutrophil counts were observed with the During the study period, within the Lothian development of Campylobacter enteritis and an region of Scotland which has a childhood urticarial illness. population of just over 96 000 aged from 0-10 (5) The incidence of infections (five upper on October 2, 2021 by guest. Protected copyright. years, five children presented with serologically respiratory tract infections, two fevers, one confirmed ANI (table 1). Three were female episode of mouth ulcers and one episode of and the median age at diagnosis was 8 months diarrhoea, in addition to the two illnesses (range 7-13 months). They all presented with described above) during the 24 month period of minor illnesses, and in three there was skin neutropenia could not be considered excessive sepsis. All had absolute neutropenia with ANC for a child of this age. ranging from 0 00-0-87 x 109/1, case 4 also had iron deficiency anaemia. Bone marrow examin- Discussion ation of these patients confirmed an increased The five patients described in this report have M:E ratio with "left shift" ofthe myeloid series clinical and laboratory features (table 1) but no specific arrest patterns. In cases 1-3 entirely consistent with the previous reports of there appeared to be an initial elevated T4:T8 ANI.2-7 These five cases, from a defined geo- lymphocyte subset ratio which normalised with graphical area, suggest that the annual time. Serum immunoglobulin concentrations incidence ofANI is in the order of 1/100 000 of were normal. the childhood population, although, because of The anti-granulocyte antibodies detected the relatively benign course ofthe disorder this were of the IgG class but weakly reactive IgM figure is likely to be an underestimate.
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