Autoimmune neutropenia in pregnant women causing neonatal neutropenia

Autoimmune neutropenia (AIN) can occur during pregnancy. However, neonatal neutropenia occurring in an infant born to a mother with AIN has only rarely been documented. Recently, we have experienced two cases of AIN during pregnancy, both of which caused severe yet transient neonatal neutropenia (< 0.3 x 10(9)/l), probably as a result of transplacental maternal anti-neutrophil autoantibodies. The anti-neutrophil antibodies seemed to be against antigens other than NA1/NA2 because the autoantibodies did not bind to neutrophils of specific NA types selectively in the granulocyte indirect immunofluorescence test. Although AIN is a relatively uncommon disease, neonatal neutropenia caused by maternal AIN may not be quite as rare.     

Lack of clinical efficacy of rituximab in the treatment of autoimmune neutropenia and pure red cell aplasia: implications for their pathophysiology

We describe 11 patients with severe refractory autoimmune cytopenias treated with the anti-CD20 monoclonal antibody rituximab. Six patients had autoimmune neutropenia (AIN), two had pure red cell aplasia (PRCA), one had AIN and autoimmune haemolytic anaemia, one had AIN and immune thrombocytopaenia purpura (ITP) and one had PRCA and ITP. Rituximab was administered at a dose of 375 mg/m² as an intravenous infusion weekly for 4 weeks. Six of eight patients with AIN and all three patients with PRCA did not respond. Two patients died: one with resistant AIN and autoimmune haemolytic anaemia died of pneumocytis pneumonia infection, and one with PRCA and ITP died of an acute exacerbation of bronchiectasis. Rituximab in AIN and PRCA appears to be less effective than Campath-1H when compared to historical data from our group. This supports the hypothesis that T cells may be important in the pathophysiology of AIN and PRCA.     

Primary autoimmune neutropenia in children: a study of neutrophil antibodies and clinical course

BACKGROUND AND OBJECTIVES: Primary autoimmune neutropenia (AIN) in children is characterized by severe neutropenia, but mild bacterial infections and a spontaneous resolution. Neutrophil autoantibodies are involved in the disease. The precise relationship between the specificity and level of reactivity of the antibodies with the absolute neutrophil count and frequency of infections is not known. To obtain a better insight into this relationship, we performed a follow-up study in 15 patients with primary AIN. In addition, we performed two different neutrophil antibody tests to evaluate their sensitivity and specificity. MATERIALS AND METHODS: Blood samples from 15 children were tested for neutrophil antibodies, at different time-points during the disease, by using the indirect granulocyte immunofluorescence test (GIFT) and the monoclonal antibody-specific immobilization of granulocyte antigens (MAIGA) assay. Clinical data related to the occurrence of bacterial infections and treatment, and neutrophil counts were collected. RESULTS: Early in the disease, antibodies with pan-FcRIIIb specificity were detected, and HNA-1a or HNA-1b specificity of the antibodies developed over time. The sensitivity and specificity of neutrophil antibody detection tests were higher in the GIFT than in the MAIGA assay. Variables predicting time of recovery from neutropenia were not found. Prophylactic antibiotics led to the almost complete disappearance of infections. CONCLUSIONS: In patients with primary neutropenia, neutrophil antibody specificity changes over time. Prophylactic antibiotics do benefit the patients.     

Neutrophil antibody specificity in different types of childhood autoimmune neutropenia.

Autoimmune neutropenia (AIN) in children can be divided into 2 forms. In primary AIN, neutropenia is the sole abnormality, and although neutrophil counts are generally below 500 microL(-1), mild bacterial infections occur. Primary AIN is mostly seen in young children and shows a self-limited course. AIN occurring in association with autoimmune diseases (secondary AIN) often shows more severe infectious complications. We analyzed clinical and serological data from 28 pediatric patients with AIN to evaluate whether there is a possible relationship between specificity of the neutrophil autoantibodies and the clinical course of the disease. Specificity of the circulating antibodies was determined with the indirect granulocyte immunofluorescence test (GIFT) and a panel of phenotyped donor neutrophils. The samples were further analyzed in the monoclonal antibody immobilization of granulocyte antigens assay (MAIGA) for neutrophil antigen (NA)1, NA2, CD11a, and CD11b specificity. With the indirect GIFT, an antibody specificity was deduced in 26 of the 28 analyzed samples. In all but 3 sera from patients with primary AIN, NA1-(76%) or NA2-(10%) specific antibodies were detected with the indirect GIFT. In 2 samples, the reactivity in the indirect GIFT was too weak to draw conclusions, but the MAIGA showed NA1 and/or NA2 specificity of the antibodies. One serum, from a patient with primary AIN with a persistent neutropenia for more than 6 years, contained NA1, possibly pan-FcgammaRIIIb, and CD11a antibodies. In 4 sera from patients with primary AIN, weak antibodies with CD11a or CD11b specificity were detected with the MAIGA. Sera from 7 patients with secondary AIN contained in all cases antibodies with pan-FcgammaRIIIb specificity, as deduced from the indirect GIFT results and absorbance/elution experiments performed with 2 sera. The MAIGA confirmed this for only 1 of the 5 tested sera. Furthermore, CD11a antibodies were detected in 1 of the 5 tested sera. In conclusion, our results indicate that primary AIN is usually associated with NA-specific antibodies, whereas secondary AIN seems to be associated with pan-FcgammaRIIIb antibodies. Thus, characterization of the antibodies in sera from children with AIN discriminates patients with primary AIN from those with secondary AIN.     

Autoimmune neutropenia of childhood

Autoimmune neutropenia (AIN) of infancy is an underreported disease because of its benign nature. In addition, the relative unavailability of neutrophil antibody testing prevents confirmation of suspected diagnoses. Small children do not have life-threatening infections, do not have associated diseases, respond to i.v. gamma globulin with increased neutrophil counts, and tend to improve on their own. Older children with AIN have associated diseases such as hepatitis or Hodgkin's disease, often have other immune cytopenias, and respond poorly to any therapy. Immune deficiency states, especially those of the humoral arms, are associated with development of AIN.     

Autoimmune neutropenia due to antineutrophil antibodies in a patient with primary sclerosing cholangitis

Autoimmune neutropenia (AIN) is defined as a decrease in the circulating absolute neutrophil count (ANC) to less than 1500/μl caused by serum antineutrophil antibodies. Secondary AIN is associated with various autoimmune diseases. Herein we present the case of a patient with primary sclerosing cholangitis (PSC) who developed secondary AIN. A 19-year-old man was admitted due to liver injury, and a diagnosis of PSC was established by cholangiogram and liver biopsy. Severe neutropenia, with the ANC down to 130/μl, developed during his hospital course. No medications had been given at that time and bone marrow aspiration revealed no abnormality. Therefore we suspected secondary AIN as a causative etiology and examined whether antineutrophil antibodies were detectable in the patient’s sera by flow cytometric analysis of the granulocyte indirect immunofluorescence test. We found that antineutrophil antibody was strongly positive on admission, and the titer decreased along with recovery from neutropenia. This is the first reported case of a patient with PSC who developed AIN, with detection of serum antineutrophil antibodies.     

Characterization of the bone marrow immunofluorescence test in childhood autoimmune neutropenia

The bone marrow immunofluorescenece test (BMIFT) demonstrates autoantibodies to granulocytes and their precursors on fresh-frozen bone marrow slides. It may be used to differentiate childhood autoimmune neutropenia (AIN) from other causes of childhood neutropenia, even when circulating neutrophil counts are low. We sought to characterize the diagnostic utility of the BMIFT in childhood AIN. All BMIFT requests for investigation of children with neutropenia between January 1998 and May 2007 were reviewed. Patients were classified as AIN or nonautoimmune causes. Baseline demographic data, results of BMIFT, granulocyte immunofluorescence testing and bone marrow findings were collected from clinical records and the institutional laboratory database. Seventy-six children had BMIFT performed for investigation of neutropenia. There were 45 patients diagnosed with AIN, 28 with nonimmune neutropenia and three failed tests. The median age of children with AIN was 1.2 years (range 0.3-15.3), compared with 3.6 years (range 0.1-15.7) in the nonautoimmune group. The median neutrophil count in AIN was 0.3 x 10(9)/l (0.9 x 10(9)/l in nonautoimmune). BMIFT was positive in 24 of 45 patients with AIN and 0 of 28 with nonautoimmune neutropenia (sensitivity 53%, specificity 100%, positive predictive value (PPV) 100%, negative predictive value 57%). Ten patients had other autoimmune diatheses at diagnosis. The BMIFT is a simple, highly specific test with excellent PPV and thus is a clinically useful test to confirm AIN in children.     

Acquired cyclic neutropenia: Successful treatment with prednisone

A previously healthy woman developed severe, periodic neutropenia after ingestion of phenylbutazone. Oscillations in the monocyte count and hemoglobin concentrations also occurred. The neutropenic episodes were associated with severe bacterial infections requiring hospitalization. Lithium induced a transient interruption in the neutropenia, but continued use was ineffective. Prednisone in a dosage of 100 mg daily successfully interrupted the neutrophil cycling and prevented infection. The patient has remained in remission on 10 mg of prednisone on alternate days.     

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).     

Case report: granulocyte colony-stimulating factor overcomes severe neutropenia of large granular lymphocytosis.

Large granular lymphocytosis (LGL) is characterized by enhanced proliferation of T lymphocytes that have antibody-dependent cell-mediated cytotoxicity or natural killer cell activity and that often produce severe cytopenias, including neutropenia. When a 68-year-old man with seropositive rheumatoid arthritis and severe neutropenia was examined, he was found to have LGL with a T cell gene rearrangement, indicating the presence of a clonal population of T lymphocytes. The patient was admitted with a fever of 102 degrees F and a nonhealing ulcer over the right tibia. When the infection did not respond to intravenous antibiotics, granulocyte colony-stimulating factor (GCSF) therapy was started at 5 micrograms/kg subcutaneously each day. The neutrophil count promptly increased and the patient subsequently defervesced and was able to have a skin graft placed, which healed without difficulty. GCSF, which is known to be an effective therapeutic agent for neutropenia associated with chemotherapy and bone marrow transplantation, also was a very valuable treatment for the life-threatening neutropenia of LGL.     

Exacerbation of autoimmune neutropenia to agranulocytosis in association with severe autoimmune thrombocytopenia and hemolytic anemia in a patient with Sjögren's syndrome

A 73-year-old woman with Sj?gren's syndrome and autoimmune neutropenia (AIN) associated with large granular lymphocytosis of the polyclonal T cell type, demonstrated autoimmune thrombocytopenia (AIT) at diagnosis of sigmoid colon cancer. Ten months later, both AIN and AIT had exacerbated to agranulocytosis and severe thrombocytopenia below 10×10(9)/L, respectively. There were no dysplastic features of bone marrow hematopoietic cells. Furthermore, an in vitro assay of hematopoietic progenitors showed normal granuloid and erythroid colony formation. Although we serially treated her with prednisolone (oral), filgrastim, intravenous high-dose immunoglobulin infusion, cyclophosphamide (oral), danazol, cyclosporine A (oral), and rituximab, number of neutrophils and platelets elevated only temporarily. During the course of agranulocytosis and severe thrombocytopenia, the patient also developed autoimmune hemolytic anemia (AIHA). She died of pneumonia 5 months after the onset of agranulocytosis. This case is very unique and novel in terms of autoimmune phenomena simultaneously directed to granulocytes, platelets, and red blood cells under the background of Sj?gren's syndrome.     

The successful treatment of G-CSF in autoimmune neutropenia with liver cirrhosis complicated by esophageal varices]

A 72 year-old woman was admitted to our hospital for hematoemesis. After admission, endoscopic examination showed esophageal varices with a red color sign which indicated endoscopic injection sclerotherapy (EIS). Concurrently, however, laboratory findings revealed severe neutropenia in peripheral blood, while bone marrow examination showed marked reduction of mature granulocytes with mild myeloid hyperplasia. As a result of those hematological abnormalities, EIS was halted. Concerning the pathogenesis of this neutropenia, immunofluorescence technique using flow cytometry disclosed the presence of anti-neutrophil autoantibody in the serum, giving a clinical diagnosis of autoimmune neutropenia (AIN). Thereafter, a conventional regimen of corticosteroids as an initial therapy and steroid pulse therapy as a succeeding maneuver were instituted, but in vain. As a last resort, 125 micrograms/body of rhG-CSF was given daily subcutaneously. As a consequence, significant increase in granulocyte count, though transient, was attained, which made EIS possible without any episodes of infections. It seems most likely that a high dose of rhG-CSF exerts beneficial effects as a prophylactic and therapeutic regimen against infections in patients with AIN.     

Treatment of large granular lymphocyte leukemia with oral low-dose methotrexate

Morbidity and mortality in patients with T large granular lymphocyte (T- LGL) leukemia result from infections acquired during severe neutropenia. Optimum treatment for severe neutropenia remains undefined. We conducted an uncontrolled but prospective study of low- dose oral methotrexate, up to 10 mg/m2 weekly, in 10 patients with this disease. Therapeutic response was assessed by serial clinical evaluations and laboratory determinations including complete blood counts, lymphocyte phenotyping, and T-cell receptor gene rearrangement studies. A partial response was defined as a sustained increase in neutrophil count greater than 500/microL. A complete clinical remission was defined as achievement of a normal complete blood count and CD3+ LGL count. Previous prednisone treatment in eight of these patients had produced one clinical remission and four partial responses; tapering of prednisone in each of these patients resulted in recurrence of severe neutropenia. Five patients in this study received both methotrexate and tapering doses of prednisone. Complete clinical remissions on methotrexate were observed in five patients; an additional patient had a partial response. Molecular analyses of T-cell receptor gene rearrangement could not detect the abnormal clone in three of five patients achieving a complete clinical remission. Two weeks to 4 months of therapy were needed before attaining a neutrophil count greater than 500/microL. Complete and partial responses have been maintained on therapy, with a follow-up period ranging from 1.3 to 9.6 years. Low- dose oral methotrexate therapy is an effective treatment for some patients with LGL leukemia.     

Neutropenic enterocolitis: An unusual complication of HCV combination therapy with PEG-IFN and ribavirin

Drug induced neutropenia as a consequence of intensive chemotherapy for hematological malignancies and solid tumors is known to be associated with severe, life-threatening infections such as neutropenic enterocolitis. However, the neutropenia associated with HCV combination therapy with Pegylated Interferon [PEG-IFN] and ribavirin is considered to be well tolerated in patients without other co-morbidities. We present a case of a severe gastrointestinal complication in a patient receiving HCV combination therapy and advocate caution in continuing therapy in patients with neutropenia, especially in the presence of underlying co-morbidities such as cirrhosis.     

Severe neutropenia associated with large granular lymphocyte lymphocytosis: Successful control with cyclosporin A

Summary Lymphocytosis of large granular lymphocytes (LGL) with severe neutropenia was diagnosed in a 42-years old patient. After prednisone yielded only a transistory effect, long lasting improvement was achieved by treatment with cyclosporin A.     

Autoimmune neutropenia: clinical and laboratory studies in 143 patients

Summary Clinical and laboratory data of 143 patients with primary or secondary autoimmune neutropenia (AIN) were evaluated. Primary AIN was found predominantly in children below 3 years, whereas secondary AIN was more frequent in patients 40–60 years of age. Female patients with primary AIN were slightly more prevalent (54%) than male patients (46%). The peripheral blood count showed normal or diminished leukocyte counts with median absolute neutrophil counts of 250 cells/l. In 38% of the patients neutropenia was accompanied by monocytosis. Bone marrow examination revealed in 95% a normo- or hypercellular marrow with a marked reduction of mature neutrophils in 56% of the specimens. Twenty-three percent of the sera showed specificity for the NA1 antigen. Patients were usually affected by benign bacterial infections of the skin and of the upper respiratory tract, as well as by recurrent otitis media. Infections were treated symptomatically, and only six patients required continuous administration of antibiotics. Remission of neutropenia during treatment occurred in three of six patients treated with intravenous immunoglobulin G and in three of four patients who received steroid therapy. Except for one patient neutropenia relapsed after discontinuation of therapy. During a follow-up of 6–36 months, spontaneous remission has been observed in four patients.This work was supported by theDeutsche Forschungsgemeinschaft (Mu 277/9-7)     

Anal intraepithelial neoplasia in the highly active antiretroviral therapy era among HIV-positive men who have sex with men

OBJECTIVES: The incidence of anal cancer among men who have sex with men (MSM) has continued to increase since the introduction of highly active antiretroviral therapy (HAART). The prevalence of the putative anal cancer precursor, anal intraepithelial neoplasia (AIN) was high among HIV-positive MSM prior to the availability of HAART but little is known about AIN since HAART was introduced. We characterized the prevalence of AIN among HIV-positive MSM and examined the association between AIN and various factors including use of HAART. DESIGN AND METHODS: A baseline point-prevalence analyses in a prospective cohort study of AIN was performed at a university-based research clinic. A total of 357 HIV-positive MSM with no history of anal cancer completed a questionnaire detailing behaviors and medical history, anal cytology and human papillomavirus (HPV) testing, and high-resolution anoscopy with biopsy for detection of AIN. RESULTS: Eighty-one percent of participants with available CD4+ cell counts at baseline had AIN of any grade; 52% had AIN 2 or 3; and 95% had anal HPV infection. In multivariate analysis, detection of > or = 6 HPV types [odds ratio (OR), 36; 95% confidence interval (CI), 7.4-171) and use of HAART (OR, 10; 95% CI, 2.6-38) were associated with AIN after adjustment for length of time participants were HIV-positive, CD4+ cell count and HIV viral load. CONCLUSIONS: The prevalence of AIN has remained high among HIV-positive MSM after the introduction of HAART. Our data indicate that HAART is not associated with a reduced prevalence of AIN and support measures to prevent anal cancer among HIV-positive MSM whether or not they are using HAART.     

Response to granulocyte colony-stimulating factor in an autoimmune neutropenic adult.

Clinical value of granulocyte colony-stimulating factor (G-CSF) for autoimmune neutropenia (AIN) has not been well established. We experienced an adult case of AIN which showed an excellent response to G-CSF. A 75-year-old female was admitted with high-grade fever. Her neutrophil count was remarkably low (neutrophil 0.09 x 10(9)/l). Antigranulocyte autoantibody was demonstrated in her serum by an immunofluorescence method and she was diagnosed as AIN. Administration of G-CSF (filgrastim 5 microgram/kg) gave a rapid increase of neutrophils (from 0.11 x 10(9)/l to 2.10 x 10(9)/l on the second day), which has enabled us to preserve the use of G-CSF for emergency, that is, for overt serious infection.     

Monosomy 7 and activating RAS mutations accompany malignant transformation in patients with congenital neutropenia

Individuals with severe forms of congenital neutropenia suffer from recurrent infections. The therapeutic use of recombinant human granulocyte colony-stimulating factor (rhG-CSF) to increase the neutrophil count is associated with fewer infections and an improved quality of life. However, the long-term effects of this new therapy are largely unknown. In particular, it is unclear if myeloid leukemia, a known complication of some forms of congenital neutropenia, will occur with increased frequency among patients who receive long-term treatment with hematopoietic growth factors. We report 13 patients with congenital disorders of myelopoiesis who developed leukemic transformation with either myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML) and 1 who acquired a clonal cytogenetic abnormality without evidence of MDS or AML while receiving rhG-CSF. The bone marrows of 10 patients showed monosomy 7 and 5 had activating RAS mutations. These abnormalities were not detected in pretreatment bone marrows and cessation of rhG-CSF was not associated with either clinical improvement or cytogenetic remission. We conclude that patients with severe forms of congenital neutropenia are at relatively high risk of developing MDS and AML. The occurrence of monosomy 7 and RAS mutations in these cases suggests that the myeloid progenitors of some patients are genetically predisposed to malignant transformation. The relationship between therapeutic rhG-CSF and leukemogenesis in patients with severe chronic neutropenia is unclear.     

Incidence of neutropenia and use of granulocyte colony-stimulating factors in multiple myeloma: is current clinical practice adequate?

Although immunomodulatory drugs, alkylating agents, corticosteroids, protease inhibitors, and therapeutic monoclonal antibodies improve multiple myeloma outcomes, treatment burden is still an issue. Neutropenia is a known complication of cytotoxic cancer therapy and is often associated with infections; it is an important consideration in myeloma given the fact that patients often have a weakened immune system. The risk of febrile neutropenia increases with severe and persisting neutropenia. Recombinant granulocyte colony-stimulating factors (G-CSFs) are commonly used to reduce the incidence, duration, and severity of febrile neutropenia. Here, we review the risk and management of neutropenia associated with new and commonly used anti-myeloma agents. Few papers report the use of G-CSF in patients with multiple myeloma receiving anti-cancer treatments, and fewer describe whether G-CSF was beneficial. None of the identified studies reported G-CSF primary prophylaxis. Further studies are warranted to evaluate the need for G-CSF prophylaxis in multiple myeloma. Prophylaxis may be particularly useful in patients at high risk of prolonged severe neutropenia.