Elsevier

Autoimmunity Reviews

Volume 9, Issue 1, September 2009, Pages 62-66
Autoimmunity Reviews

Autoimmune neutropenia in adults

https://doi.org/10.1016/j.autrev.2009.03.006Get rights and content

Abstract

Autoimmune neutropenias (AIN) in adults are a heterogeneous group of diseases with clinical manifestations varying from being asymptomatic to having infectious complications with considerable morbidity and mortality. They are characterized by autoantibodies directed against neutrophils, resulting in destruction of neutrophils. AIN can be divided into two forms. In primary AIN, neutropenia is usually the sole hematologic abnormality and it is more common in children. Secondary AIN, which is more prevalent in adults, is associated with underlying autoimmune diseases, malignancies, infections, particularly viral, neurological diseases or drug exposure. This article is an overview of these conditions with emphasis on secondary AIN; it also discusses the available serological methods for antibody detection and recent therapeutic developments including colony stimulating factors, rituximab and Campath-1H.

Introduction

Autoimmune neutropenias (AIN) in adults can be divided into primary and secondary forms. Primary AIN is not a common condition in adults. But, secondary AINs are probably as common as autoimmune disorders of red blood cells and platelets; and often go undetected because symptoms are less overt, and there are no reliable markers for in vivo neutrophil lysis in contrast with plasma hemoglobin in hemolytic anemia. They are usually associated with autoimmune disorders, hematological and non-hematological malignancies and drug exposure (Table 1). Neutropenia is associated with an increased risk of infection, particularly if ANC falls below 500/ µL. Bacterial infections, particularly intermittent stomatitis and gingivitis, perirectal abscess and cellulitis are more common than pneumonia and septicemia. Fungal infections are unusual, but oral candidiasis is common; and there is usually no increased risk for viral or parasitic infections.

Section snippets

Pathophysiology and mechanisms of immune neutrophil destruction

Our current knowledge about mechanisms of neutrophil destruction is mostly based on in vitro observations. Agglutination is the major form of neutrophils response to antineutrophil antibodies. Complement-induced neutrophil agglutination due to antineutrophil autoantibodies is another suggested mechanism for neutrophil destruction. Activated complement system can cause neutrophil aggregation and adherence of neutrophils to endothelial cells. Phagocytosis of the neutrophils, which are coated with

Primary autoimmune neutropenia

Primary AIN in adults is often a chronic disease with higher prevalence in females. There is a wide range in clinical manifestations; however, it is usually a benign condition [8]. Spontaneous remission is not common. It can be associated with anemia and thrombocytopenia. Karlström et al. [9] described association between AIN and IgG3 deficiency in a cohort of patients with mild to moderate neutropenia. None of the patients showed increased susceptibility to infection. It has been shown that

Secondary autoimmune neutropenia

The etiology of neutropenia in secondary AIN is usually multifactorial. In secondary AIN the antineutrophil antibodies have pan-FcγRIIIb activity. High incidence of antineutrophil autoantibodies has been reported in X-linked autoimmune lymphoproliferative syndrome (ALPS), which is an inherited chronic, non-malignant lymphadenopathy and hepatosplenomegaly together with hypergammaglobulinemia and autoantimmunity. ALPS is usually diagnosed in the first months of life, however it can also present

Neutrophil antigens

Neutrophils, like red cells and platelets, have their own specific antigens, which are expressed on plasma membrane glycoproteins. To date, 5 neutrophil-specific antigens carried on 2 different glycoproteins have been completely or partially characterized [34]. The NA antigens are expressed on the FcγRIIIb (CD16) glycoprotein, which is the low-affinity receptor for IgG1 and IgG3. The alleles of FcγRIIIb are NA1, NA2 and SH [35]. FcγRIIIb is expressed on mature myeloid cells from metamyelocyte

Diagnosis and laboratory detection of neutrophil antibodies

Diagnosis of AIN is based on the presence of neutropenia and demonstration of anti-neutrophil antibodies. The granulocyte immunofluorescence test (GIFT) is a method, which requires few cells, and can be used to test for antibodies in both the patient's serum and directly on autologous cells [1]. GIFT is currently the most sensitive method for detection and identification of neutrophil auto- and allo-antibodies most commonly by using fluorescent-labeled antiglobulin reagents and flow cytometry.

Management and treatment

Management of primary AIN is usually supportive with antibiotics only for the management of infectious episodes, and the condition is usually self-limited. Secondary AIN in adults requires more extensive management including the use of G-CSF and prophylactic antibiotics. Treatment with G-CSF with a starting dose of 5 µg/kg/day subcutaneously is reasonable, and the majority of patients show response days of starting G-CSF therapy; however, the duration of neutrophil count normalization does not

Conclusion and perspectives

The diagnosis of autoimmune neutropenia is based on the demonstration of neutropenia and antineutrophil antibodies. Clinicians should be aware of different etiologies of congenital and acquired neutropenia, particularly secondary autoimmune neutropenia and drug-induced immune neutropenia in adult patients with incidental neutropenia. It is of interest that neutrophil specific antigens are the target of autoimmune neutropenia in most cases. So far only 5 neutrophil-specific antigens have been

Take-home messages

  • Secondary AINs are probably as common as autoimmune disorders of red blood cells and platelets.

  • Many drugs can cause immune neutropenia.

  • Diagnosis of AIN is based on the demonstration of anti-neutrophil antibodies.

  • Treatment with G-CSF is currently the first line treatment in patients with primary and secondary AIN.

  • Corticosteroid therapy gives unpredictable results and is often unsuccessful.

  • Results of rituximab therapy in adult AIN have not been encouraging.

Acknowledgement

The authors are very thankful to Prof. Parviz Lalezari, Albert Einstein College of Medicine, New York, for critical discussion and review of the manuscript.

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