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Autoimmune Neutropenia in Early Infancy: a Review PREMA R

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Autoimmune Neutropenia in Early Infancy: a Review PREMA R ANNALS OF CLINICAL AND LABORATORY SCIENCE, Vol. 12, No. 5 Copyright © 1982, Institute for Clinical Science, Inc. Autoimmune Neutropenia in Early Infancy: A Review PREMA R. MADYASTHA, Ph .D.,* H. HUGH FUDENBERG, M.D.,f ARMAND B. GLASSMAN, M.D.,* K. RAMANANDA MADYASTHA, PH.D.,f and CHARLES L. SMITH, B.A.f *Department of Laboratory Medicine, f Department of Basic and Clinical Immunology and Microbiology, Medical University of South Carolina, Charleston, SC 29425 ABSTRACT Fourteen infants with autoimmune neutropenia reported in the literature have been reviewed. Autoantibodies directed against their own neutrophils were demonstrated in the sera of these infants by agglutination, comple- ment-dependent cytotoxicity, and immunofluorescence techniques. These antibodies were highly specific and were directed against antigens present on neutrophils. Among the currently known neutrophil antigens (NA1, NA2, NB1, NCI, NE1, ND1,9A), antibodies reacting with either NA1 or NA2have been identified frequently in the sera of infants with autoimmune neutro­ penia. Good correlation was demonstrated between the presence or absence of autoantibodies and the episodes of neutropenia in many cases. Antibodies from the patients also reacted with neutrophils from their parents and from normal unrelated volunteers when they shared the neutrophil-specific anti­ gen against which the antibody was directed. Antibodies demonstrable by complement-dependent cytotoxicity appeared to detect different antigens which may also cause autoimmune neutropenia. Infants with this disorder were healthy at birth and for a few months afterwards, then became chron­ ically ill with such symptoms as intermittent fever, diarrhea, and infections. Their hemoglobin levels, lymphocyte and platelet counts, and other immu­ nological studies were normal except for severe to moderate neutropenia. Introduction and platelets (autoimmune thrombocy­ topenia) are well-recognized entities. Autoimmune destruction of erythro­ Neutropenia is classified as autoimmune cytes (autoimmune hemolytic anemia) when neutrophils are eliminated from the Publication no. 527 from the Department of Basic circulation by the host’s autologous im- and Clinical Immunology and Microbiology, Medi­ une mechanisms, usually by humoral cal University of South Carolina, Charleston, SC. antibodies. Neutropenia is considered 356 0091-7370/82/0900-0356 $01.80 © Institute for Clinical Science, Inc. REVIEW OF AUTOIMMUNE NEUTROPENIA IN INFANCY 357 mild in patients with absolute neutrophil et al27 were the first to report a well- counts (ANC) between 1000 and 1500 per documented example of isolated chronic fil), moderate (ANC 300 to 1000 per /utl), or AIN (in an infant). Since then, further severe (ANC less than 300 per ¡j,I).6 Pa­ cases have been documented, and the tients with severe neutropenia generally disease seems to be more common than have increased susceptibility to life- originally anticipated.10,21,27,28,30,32,33,34,38, threatening infections.2 Although devel­ 41,51,53 usjng sera from mothers of in­ opment of autoimmunity against neutro­ fants with isoimmune neonatal neutrope­ phils in early childhood is rare, several nia, Lalezari et al characterized several cases of chronic benign neutropenia in antigens specific to human neutro­ infants were reported in earlier literature phils,4,24,25,26 and in detailed investiga­ and reviewed in 1956 by Stahlie.46 In tions of AIN27 demonstrated that the 1964, Zuelzer and Bajoghli56 described neutrophil antigens detectable by isoanti­ five cases and reviewed those previously bodies can also become targets for de­ reported; they suggested that the selec­ struction by autologous antibodies. This tive lack of segmented neutrophils was is similar to autoimmune hemolytic dis­ perhaps caused by increased destruction ease, in which erythrocyte autoantibodies of the mature forms, possibly by antibody. are directed against antigens defined by The existence of autoimmune neutro­ alloantibodies. penia (AIN) similar to autoimmune hemo­ lytic anemia or thrombocytopenia was Disease Manifestations in Infants with anticipated in some earlier reports. How­ Autoimmune Neutropenia ever, reliable immunological assays were Infants with isoimmune neonatal neu­ not available to document the immune de­ tropenia are born with neutropenia and struction of neutrophils, and other find­ infection. The neutropenia is transient, ings were either conflicting or negative. however, and the infants usually recover In vitro granulocyte antibody assays, al­ by five to 12 weeks, coinciding with the though described 20 years ago,9,13 were disappearance of circulating maternal not reproducible or reliable. Develop­ antibodies. In contrast, infants with AIN ment of techniques with greater repro­ are normal and healthy in the first few ducibility and sensitivity for the study of months of life, then become chronically ill immune reactions involving granulocytes with such symptoms as fever, diarrhea, was slow, and the available assays were vomiting, failure to gain weight, etc. In somewhat difficult to standardize. The table I are described the clinical manifes­ major drawbacks were the difficulty in tations observed in 14 cases of AIN re­ isolating pure granulocyte cell suspen­ ported in the literature. Respiratory tract sion and the need to keep them alive for infections, otitis, and skin rash were very the assays. The tendency of granulocytes common among these patients. Broncho­ to aggregate spontaneously further com­ pneumonia also was observed in many in­ plicated interpretation of the results. fants. On physical examination, the pa­ However, with the advent of the tech­ tients showed no abnormalities, except niques of microagglutination20’23 and iso­ that lymphadenopathy and hepatospleno- lation of granulocytes by Ficoll-Hypaque megaly were noted in two patients.51,53 All density gradient centrifugation,7,17,31 an­ the infants were the result of uncompli­ tineutrophil antibodies have been suc­ cated, full-term pregnancies. cessfully demonstrated in the sera of mothers of infants with neonatal neu­ Hematology tropenia22,24,36 and in patients with Bone marrow samples obtained from in­ chronic neutropenia.21,27,30,34,44 Lalezari fants with AIN showed either hypercellu- 3 5 8 MADYASTHA, FUDENBERG, GLASSMAN, MADYASTHA, AND SMITH T A B L E I Disease Manifestations Observed in Infants with Autoimmune Neutropenia* Patients Ref. Age No. Month Sex Disease Manifestations Bone Marrow Multiple mild and transient episodes of Hypercellular with normal red cells and fever, respiratory infection, otitis megakaryocytes. The myeloid cells and skin rash. No organomegaly or showed normal maturation with paucity growth abnormality on physical of mature neutrophils. examination. 21 18 Diarrhea, transient respiratory Normal cellularity, erythropoiesis, and infections. megakaryocytes, maturation arrest. 34 8 Several episodes of fever, bilateral Normal cellularity, normal myeloid otitis and pharyngitis, developed precursors with a relative deficit of furuncles, rhinorrhea, mild cervical segmented neutrophils. lymphadenopathy. 53 24 Chronically ill with intermittent fever, Lymphocytosis and an active granulo­ otitis, bronchopneumonia, pyoderma, poiesis with a maturation arrest at associated with hepatosplenomegaly and the myelocyte level. mild generalized lymphadenopathy and anemia. 10,41 5 Chronically ill, otitis media and Maturation arrest at the myelocytic mastoiditis, upper respiratory tract stage. infections, fever. Infection, mastoiditis, skin rash, Shift to the left. fever. None. Normal. Fever, otitis, conjunctivitis, mild Normal with complete absence of upper respiratory tract infections. neutrophils. Shift to the left. Chronically ill with intermittent fever, Maturation arrest of the granulocyte otitis, bronchopneumonia and pyoderma, compartment at the myelocyte level. pharyngitis, anemia, hepatosplenomegaly and mild generalized lymphadenopathy. Recurrent vomiting, fever, diarrhea, Hypercellular with no maturation arrest. mild pneumonitis, and acute otitis media. No lymphadenopathy or hepato­ megaly. Failure to gain weight. 33 18 Recurrent otitis and severe neutropenia. Maturation arrest at the band stage. 32 14 Diarrhea, recurrent fever, upper Normal maturation with decreased number respiratory tract infection, viral of granulocytes. gastroenteritis. 28 6 Details not reported. - t 15 Diarrhea, recurrent fever, vomiting, Details not available. skin rash. *A11 these infants had severe neutropenia fUnpublished (Madyastha et al., 1982). larity27,38,53 or normal cellularity.21,34 Mat­ cytes,11 also contribute to the body’s de­ uration arrest at the myelocyte level was fense. All the infants were less than two seen in bone marrow of a few of the in­ years of age; in one infant, disease mani­ fants,21,33,51,53 with deficits of mature neu­ festations had been observed as early as trophils. Peripheral examination revealed one month of age.27 normal Hb, RBC, platelet, and lympho­ cyte levels, with moderate to severe neu­ Association with Sex tropenia (table II). Monocytosis was a common feature in the majority of the pa­ Dale et al12 have emphasized that tients. In neutropenia, it is important to chronic neutropenia is encountered most take into account the monocytes which, frequently in women, reflecting the age although not as phagocytic as granulo­ and sex patterns of other well-defined REVIEW OF AUTOIMMUNE NEUTROPENIA IN INFANCY 3 5 9 TABLE II Hematological Examination of the Peripheral Blood to identify autoantibodies against
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