What every physician needs to know about autoimmune neutropenia:
Autoimmune neutropenia (AIN) is a heterogeneous disorder that is characterized by a decreased neutrophil count in the setting of defects in cell-mediated or humoral immunity. The neutropenia can be an isolated clinical finding, or can be associated with defects in other hematopoietic lineages. There are no well-established tests to confirm the diagnosis of immune neutropenia, and it remains largely a diagnosis of exclusion.
Primary AIN is primarily seen in children, with an age of onset of 6 to 12 months. It is almost uniformly associated with antibodies against common neutrophil antigens, including human neutrophil antigen 1 (HNA1), human neutrophil antigen 2 (HNA2), CD11b, and FCγRIIIb. It is a self-limited condition, with more than 95% of children recovering normal neutrophil counts within 2 years. Patients can be managed with prophylactic antibiotics and rarely need further intervention.
Secondary AIN is more common in adults, and frequently occurs in the setting of systemic autoimmune disease. Its etiology is much more heterogeneous, and treatment is focused on minimizing the morbidity and mortality associated with serious infections and treatment of the underlying autoimmune condition.
Drug-induced agranulocytosis is an acute form of immune neutropenia that is an idiosyncratic immune response that results in profound neutropenia.
What features of the presentation will guide me toward possible causes and next treatment steps:
The evaluation and therapy of patients with immune neutropenia will depend on several aspects of the clinical presentation:
– The presence of fever in the setting of an absolute neutrophil count (ANC) of less than 500 can be life-threatening. Patients should be admitted to hospital for urgent diagnostic evaluation and treatment with broad spectrum antibiotics.
Thrombocytopenia or hemolytic anemia
– Accompanying thrombocytopenia or hemolytic anemia in the setting of new onset neutropenia should raise the question of a hematologic malignancy rather than a primary immune phenomenon, although combined cytopenias can occur in the setting of autoimmune disease.
– Neutropenia in the setting of known autoimmune disease is often mild and more a reflection of the activity of the underlying immune disease than a distinct hematologic problem that needs specific directed therapy.
– Splenomegaly in the setting of neutropenia in a patient with rheumatoid arthritis should suggest a diagnosis of Felty syndrome.
– Agranulocytosis that develops acutely is almost always drug-induced immune neutropenia. All potentially offending drugs must be stopped and antibiotics administered as needed. The role of granulocyte colony-stimulating factor (G-CSF) in this setting is discussed below. Drugs inducing agranulocytosis should not be restarted.
– Drugs can also cause a milder, often dose-related neutropenia. Patients usually manifest stable though reduced ANC. This more benign side effect of drug therapy does not always require discontinuation of therapy.
What laboratory studies should you order to help make the diagnosis and how should you interpret the results?
Laboratory studies for the evaluation of neutropenia include:
– Complete blood count (CBC) with manual differential. A CBC should be repeated at least twice, at 2 week intervals to confirm bona fide neutropenia.
Folate and B12
– Folate and B12 determination to confirm that the patient does not have a nutritional neutropenia caused by deficiencies of these essential vitamins.
Bone marrow examination with aspirate and core biopsy
– Although the findings in autoimmune neutropenia are not diagnostic, marrow examination is mainly important to rule out other causes of neutropenia such as lymphoproliferative neoplasm, myelodysplastic syndrome, or leukemia. Cytogenetics and flow cytometry should be included in the evaluation. The exception is drug-induced agranulocytosis, where if the patient presents with normal platelet count and hematocrit in the setting of profound acute neutropenia, the diagnosis is quite clear. In these cases marrow examination can be omitted unless the patient has a prolonged period of neutropenia with no response.
– Flow cytometry for large granular lymphocytes (LGL). LGL related neutropenia can be either sporadic or associated with autoimmune disease, most commonly rheumatoid arthritis.
Antineutrophil antibody studies
– Testing for antineutrophil antibodies is difficult and there is no gold standard by which to validate the information the studies provide. In primary autoimmune neutropenia, assay for anti-FcγRIII antibodies may confirm the diagnosis in the appropriate clinical setting. Testing for anti-neutrophil antibodies in the setting of autoimmune disease is not recommended, since antibodies are often detected in patients but correlate poorly with the presence of neutropenia.
What conditions can underlie autoimmune neutropenia:
Large granular lymphocyte leukemia
LGL is a chronic lymphoproliferative disease caused by clonal proliferation of lymphocytes with cell-surface makers suggestive of natural killer (NK) or cytotoxic T-cell (CTL) lineage, including CD52 and CD57. LGL can be sporadic, or may arise as a complication of underlying autoimmune disease. Patients with LGL respond to modest doses of cytotoxic therapy with cyclosporine or methotrexate. This entity is discussed in detail elsewhere.
Rheumatoid arthritis (RA) associated neutropenia may be severe and associated with significant morbidity. The triad of RA, splenomegaly, and neutropenia, termed “Felty syndrome” and LGL both occur in this setting. There has been considerable effort to separate these two entities, with Felty syndrome considered primarily as a polyclonal disease and LGL as a clonal proliferation. However, with the increasing ability to detect small clonal populations of lymphocytes, this distinction has become blurred. Furthermore, 90% of patients with either syndrome are HLA DR4 positive, suggesting that they lie in a spectrum of a single disease. Of note, LGL in the absence of RA does not have this strong association with HLA DR4.
Systemic lupus erythematosis
Neutropenia is extremely common in systemic lupus erythematosis (SLE). However, unlike in the setting of Felty syndrome or LGL, the neutropenia is usually mild and reflects the level of disease activity. Neutropenia requiring direct intervention is rare, and infectious complications usually reflect the effects of the immunosuppressive agents used to treat the SLE, more than the impact of the modestly decreased ANC.
When do you need to get more aggressive tests:
Patients with persistent neutropenia that lasts for more than 2 to 4 weeks, those who have severe infections or fever accompanying neutropenia, and those with impairment of other hematopoietic lineages should undergo additional testing.
Work-up will typically include serologic testing for systemic autoimmune disease (ANA, rheumatoid factor, anti-cyclic citrullinated peptide [anti-CCP]). As noted above, flow cytometry for LGL and bone marrow examination are a standard part of the evaluation for immune neutropenia.
What imaging studies (if any) will be helpful?
Imaging studies are not typically a part of the evaluation for autoimmune neutropenia. However, if a lymphoma is suspected, imaging with computed tomography (CT) scan and/or magnetic resonance imaging (MRI) scan may be indicated. Splenomegaly can be assessed by imaging as well, although the finding of isolated splenomegaly does not suggest a particular diagnosis.
What therapies should you initiate immediately and under what circumstances – even if root cause is unidentified?
In the setting of severe neutropenia and fever, broad spectrum antibiotics such as a third generation cephalosporin should be initiated to cover gram negative organisms, including Pseudomonas. Coverage for gram positive cocci should be included in the appropriate clinical setting. Recommended antibiotic coverage for febrile neutropenia is discussed in detail under the general discussion of leukopenia.
In the setting of severe neutropenia and fever, G-CSF is recommended to increase the neutrophil count. Pegylated G-CSF (Neulasta) is not recommended in this setting. A daily CBC (complete blood count) with manual differential should be followed, and the G-CSF can be discontinued when the ANC has exceeded 1000/μl for 2 successive days if the infection is controlled. Patients with recurrent fever and chronic profound neutropenia should be treated with G-CSF more chronically. G-CSF is again favored over pegylated G-CSF. Patients should be treated with intermittent G-CSF to keep their ANC around 500/μl, and often can be managed with dosing once or twice weekly. Potential complications of therapy include bone pain, gastrointestinal distress, and splenomegaly.
An appropriate evaluation for an underlying source of infection should be undertaken in any febrile neutropenic patient. This can include blood cultures, urine culture, chest X-ray and other testing, as deemed clinically appropriate.
Infants and toddlers with primary autoimmune neutropenia are best managed with prophylactic antibiotics. G-CSF is usually reserved only for acute infectious episodes unless they become recurrent.
Drug-induced agranulocytosis has a mortality of up to 10% from acute sepsis. Patients should be treated promptly with full supportive care, broad-spectrum antibiotics, and G-CSF.
What other therapies are helpful for reducing complications?
As noted above, the timely administration of antibiotics, G-CSF, and a thorough search for an underlying source of infection is imperative in the setting of fever associated with severe neutropenia.
An appropriate evaluation for underlying autoimmune disease amenable to therapy may improve the neutropenia.
Patients with chronic autoimmune neutropenia should be instructed to seek immediate medical attention in the event of an episode of fever. In addition, it is prudent to supply them with a broad spectrum antibiotic (such as a fluoroquinolone) to have at home to take immediately upon developing a fever while they seek appropriate medical attention.
What should you tell the patient and the family about prognosis?
Parents of infants and toddlers with primary autoimmune neutropenia should be reassured that over 95% of patients will have an uneventful resolution of their neutropenia within 2 years.
Adults with autoimmune neutropenia are more likely to experience chronic neutropenia. However, many cases will improve with successful treatment of the underlying autoimmune disease. The prognosis depends largely on the degree of infectious complications that the patient experiences. Chronic neutropenia is generally well-tolerated and has a benign course. If the patient has recurrent infections, chronic G-CSF administration is usually very effective in controlling the ANC and eradicating infections.
Drug-induced agranulocytosis can be associated with acute mortality from sepsis in up to 10% of patients. However, if the drug is stopped and the infection treated, the patient should recover uneventfully.
“What if” scenarios.
The patient presents with profound neutropenia (absolute neutrophil count of less than 500) and a fever
As described above, such patients should be admitted to the hospital and given intravenous antibiotics and G-CSF.
The patient requires therapy with immunosuppressive therapy for underlying autoimmune disease
The presence of neutropenia should not prevent patients from being treated appropriately for underlying autoimmune disease. Even if the agents are cytotoxic, it is likely that the neutrophil count will improve with appropriate therapy of the underlying disease. However, empiric administration of immunosuppressive agents to treat the neutropenia per se is not recommended.
The patient has an inadequate response to granulocyte colony-stimulating factor
Most patients with autoimmune neutropenia respond to G-CSF, and it is the cornerstone of therapy. However, if G-CSF is ineffective in raising the ANC, consideration should be given to performing a bone marrow aspirate and biopsy to ascertain that there are adequate myeloid precursors in the bone marrow, and that there is not another bone marrow process present. Other immunosuppressive agents have been tried with limited success. Corticosteroids are not usually effective. There are case reports of responses to cyclosporine A, sirolimus, Campath-1H. Results with rituximab have not been encouraging, although in patients with SLE, response of the underlying disease to anti-CD20 therapy may also increase the ANC.
The mechanism of neutropenia in autoimmune neutropenia is varied and not well understood. Peripheral destruction of neutrophils is the hallmark of AIN, although there is often a component of reduced neutrophil production, presumably due to immune destruction of neutrophil precursors. Neutrophil destruction may be mediated by neutrophil-specific antibodies, immune complex binding, or cell-mediated cytotoxicity.
Primary AIN is antibody mediated, as described above. Antibodies are directed against common neutrophil antigens, including HNA1, HNA2, CD11b, and FCγRIIIb.
Secondary AIN in SLE is antibody-mediated, although the correlation between detectable antibody and the frequency and severity of neutropenia is poor. Increased neutrophil-associated immunoglobulin G (IgG) is detected in a large fraction of patients with SLE, but not all of the individuals with detectable antibody are neutropenic, and it is not clear whether the detected antibodies are neutrophil-specific or represent immune complex deposition.
Felty Syndrome, characterized by the association of RA, splenomegaly, and neutropenia, is associated with a proliferation of LGL. Neutropenia is thought to be mediated by cell-mediated cytotoxicity.
What other clinical manifestations may help me to diagnose immune neutropenia?
There are no specific clinical findings that distinguish immune neutropenia from neutropenia arising from other etiologies. As previously noted, patients with suspected immune neutropenia should be evaluated for evidence of underlying autoimmune disease. Evaluation of fever in the setting of neutropenia is of critical therapeutic importance and may dictate the necessity for intervention.
What other additional laboratory studies may be ordered?
Laboratory evaluation as outlined above will suffice.
What’s the evidence?
Akhtari, M, Curtis, B, Waller, E. “Autoimmune neutropenia in adults”. Autoimmune Reviews. vol. 9. 2009. pp. 62-66. [General review of immune neutropenia.]
Burks, E, Loughran, T. “Pathogenesis of neutropenia in large granular lymphocyte leukemia and Felty syndrome”. Blood Reviews. vol. 5. 2006. pp. 245-266. [Review of the pathophysiology of LGL and Felty syndrome and discussion of the link between the two syndromes.]
Bux, J, Kissel, K, Nowak, K, Spengel, U, Mueller-Eckhardt, C. “Autoimmune neutropenia: clinical and laboratory studies in 143 patients”. Ann Hematol. vol. 63. 1991. pp. 249-252. [Discussion of primary and secondary autoimmune neutropenia with reference to antineutrophil antibodies.]
Maciejewski, J, Tiu, R, Hoffman, Benz. ” Acquired disorders of red cell and white cell production”. Hematology, Basic Principles and Practice. 2009. pp. 395-410. [General review of acquired neutropenia.]
Mohan, S. “Diagnosis and therapy of neutropenia in large granular lymphocyte leukemia”. Current Opinion in Hematology. vol. 16. 2009. pp. 27-34. [Recent review of LGL leukemia and neutropenia, including LGL not associated with RA.]
Starkebaum, G. “Chronic neutropenia associated with autoimmune disease”. Semin Hematol. vol. 39. 2002. pp. 121-127. [Classic review of autoimmune neutropenia.]
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- Autoimmune neutropenia
- What every physician needs to know about autoimmune neutropenia:
- What features of the presentation will guide me toward possible causes and next treatment steps:
- What laboratory studies should you order to help make the diagnosis and how should you interpret the results?
- What conditions can underlie autoimmune neutropenia:
- When do you need to get more aggressive tests:
- What imaging studies (if any) will be helpful?
- What therapies should you initiate immediately and under what circumstances – even if root cause is unidentified?
- What other therapies are helpful for reducing complications?
- What should you tell the patient and the family about prognosis?
- “What if” scenarios.
- What other clinical manifestations may help me to diagnose immune neutropenia?
- What other additional laboratory studies may be ordered?