Idiopathic neutropenia refers to distinct diseases characterized by low counts of neutrophil granulocytes that render the affected individual prone to infections, e.g., chronic idiopathic neutropenia and primary autoimmune neutropenia. The patients' age at symptom onset, the severity of neutropenia and ensuing clinical presentations vary considerably.
The clinical consequences of isolated neutropenia largely depend on the severity of the condition. In this context, the following general observations can be made [1]:
IN may be associated with mild to severe neutropenia, while agranulocytosis is very rare. A considerable share of patients does not present any clinical symptoms and neutropenia is incidentally detected while analyzing blood samples for non-related reasons. Even in case of severely reduced neutrophil counts, IN patients merely present with gingivitis, oral sores, or recurrent, febrile infection of the upper respiratory tract or skin, whereas pneumonia, invasive skin infection, sepsis or meningitis are uncommon.
Laboratory analyses of blood specimens don't only allow for detecting neutropenia, but may also reveal additional hematological alterations that imply or rule out differential diagnoses, e.g., lymphocytosis, anemia and thrombocytopenia. In order to monitor the course of the disease and to assess its severity, complete blood counts with differential should be conducted monthly over at least four months. More frequent measurements of neutrophil counts may be required to rule out cyclic neutropenia. Transient neutropenia may merely be associated with a recent history of infection and may not warrant any additional measures except for treatment of this infection.
CIN remains a diagnosis of exclusion. The following criteria have been established to this end [7]:
Diagnosis of PAN may be based on the presence of anti-neutrophil autoantibodies, but repeated testing may be necessary to obtain positive results. Immunofluorescence tests and leukoagglutination assays are usually carried out to this end. If neither analysis yields conclusive findings, a bone marrow biopsy specimen should be obtained. In both CIN and PAN, myeloid arrest may result in a reduced ratio of metamyelocytes and mature granulocytes. As for PAN, overall hypercellularity is more frequently observed than normo- or hypocellularity; in about a third of patients, no alterations are noted at all [9].
Of note, routine examination of bone marrow biopsy samples at the time of diagnosis of chronic neutropenia and upon exacerbation of neutropenia or appearance of additional hematological alterations has been recommended in the light of a possible transformation to malignant diseases [11].
While acute infections may indicate antimicrobial therapy, most patients diagnosed with IN don't require any special treatment. Otherwise, long-term administration of human recombinant granulocyte colony-stimulating factor (G-CSF) may be recommended. In this context, CIN patients may receive daily doses of 6 μg/kg, while an application of 1.5 μg/kg three times a week is usually sufficient to treat infants suffering from symptomatic PAN [2]. Neutrophil counts should be monitored to assess the response to G-CSF administration, to adjust doses and to decide on continuation or cessation of therapy. In case of persistent neutropenia, corticosteroids may be used to increase neutrophil counts. Corticosteroids stimulate the mobilization of neutrophils from the bone marrow reserve pool to the circulating and marginal pool. High-dose intravenous immunoglobulin G has also been applied. In any case, therapeutic guidelines have not yet been established and an individualized approach is required.
In general, patients suffering from chronic neutropenia should be advised on appropriate measures to prevent infection. Besides mouth hygiene, skin care, and general hygiene measures, vaccination against bacterial pathogens may lower the individual risk of severe infections. Because of the low incidence of severe infections, prophylactic administration of antibiotics is not generally recommended.
Due to their predisposition for osteopenia and osteoporosis, CIN patients should undergo regular measurements of bone density.
IN is a usually considered a benign condition, although this assumption has been questioned [11].
As its name implies, CIN is a chronic disorder and generally persists throughout life without major complications [2]. The single most important risk factor for infections is the severity of neutropenia. Moreover, CIN patients are at higher risks of osteopenia and osteoporosis than the general population [12].
Spontaneous remission is observed in about 95% of children diagnosed with PAN and can usually be expected within a maximum of two years [9].
Neutrophils arise from hematopoietic stem cells and precursors, and neutropenia may either be provoked by reduced neutropoiesis, or by excess sequestration or consumption of mature cells. CIN is an immune disease characterized by a T cell- and cytokine-mediated reduction of neutropoiesis, and PAN results from the production of autoantibodies directed against precursors or mature neutrophils [2].
With regards to the former, excess release of tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) by immune cells in the bone marrow has been suggested to trigger premature apoptosis of CD34+ neutrophil precursor cells [3]. The aforementioned cytokines may induce an upregulation of Fas receptor expression and may thus render CD34+ cells susceptible to Fas ligand-mediated apoptosis. Lymphocytes are known to produce IFN-γ and Fas ligand and indeed, in CIN, those cytokines appear to originate from activated, myelosuppressive T lymphocytes [4]. Subpopulations of immune cells accountable for excess production of TNF-α could not yet be identified. Presumably, complex signaling cascades involving more than one cell type lead to pathological reductions of neutropoiesis prior to the onset of CIN.
PAN is increasingly recognized as an autoimmune disease. Autoantibodies directed against different epitopes on neutrophil precursors and mature neutrophils may not only cause an absolute reduction of neutrophil counts, they may also provoke functional impairment of those immune cells. In this line, it has been shown that determined autoantibodies may hinder chemotaxis, adherence to the vascular endothelium, and phagocytosis, among others [2]. The precise causes of this autoimmune response are still unknown, but molecular mimicry of microbial pathogens and drug-induced modifications of endogenous epitopes may contribute to autoreactivity.
Because milder forms of IN don't usually interfere with host defense mechanisms, the disease is most likely underdiagnosed. Thus, provided epidemiological data should be interpreted with care.
While the prevalence of neutropenia in the general population may be up to 4.5% [5], neither incidence nor prevalence of CIN are known. With regards to CIN, strong predilection for females has been observed [6]. The patients' age at symptom onset varies largely and may be 15 to 29 years (20%), 30 to 59 years (65%), 60 to 79 years (15%) [7].
For PAN, annual incidence rates of about 1 per 100,000 children aged less than 10 years have been reported in the 1990s [8]. Most commonly, infants are diagnosed with PAN when aged 7 to 9 months. Occasionally, symptom onset occurs much earlier or during the following years of life. Incidence rates don't differ between boys and girls [9].
As per definition, mild, moderate and severe neutropenia may be distinguished and correspond to neutrophil counts below 1,500, 1,000, and 500 per µl, respectively. Patients presenting with neutrophil counts of less than 200 neutrophils/µl are usually diagnosed with agranulocytosis [6]. However, these values should merely serve as an orientation since reference ranges may differ for patients of distinct races, genders and age. In detail, children aged less than one year and patients of African descent are more likely to present with physiological mild neutropenia, i.e., with neutrophil counts below 1,000 per µl [10].
Neutrophils form part of the innate immune system; they are professional phagocytes and effectively control bacterial and fungal infections. Consequently, neutropenic individuals are predisposed to infectious diseases triggered by such agents. Their individual propensity for infection directly correlates with the severity of neutropenia as described above.
No specific measures can be recommended to prevent IN.
Considering the broader sense of the word, the term idiopathic neutropenia (IN) may be used to refer to low counts of neutrophil granulocytes that cannot be ascribed to an underlying pathology. In this context, different, poorly understood entities may be designated IN. Neutropenia may manifest at any age, follow an acute, intermittent or chronic course, and may or may not provoke clinical symptoms. Here, neutropenia may be the result of gene or developmental defects, may be autoimmune-mediated, occur as a complication of infectious diseases or malignancies, may be induced by drugs or radiotherapy - few cases remain "idiopathic" after a thorough workup, though.
Pathologies possibly associated with neutropenia comprise but are not limited to the following [1]:
Of the aforegiven entities, only two are still considered idiopathic, namely chronic idiopathic neutropenia (CIN) or primary autoimmune neutropenia (PAN). In 2008, Papadaki et al. proposed to limit the scope of IN to those diseases [2] and thus, this article will focus on CIN and PAN.
Patients affected by either disease present with similar clinical features, but while CIN is most frequently diagnosed in adult women, PAN typically affects infants and young children.
The medical term idiopathic is used to refer to diseases of unknown origin, whereas neutropenia describes the condition of reduced counts of neutrophil granulocytes, which are cells that fulfill important functions in the immune system. Primarily, neutrophils eliminate bacterial and fungal pathogens. A wide variety of entities is related with reduced neutrophil counts, and as long as neutropenia and additional symptoms cannot be related to any of those diseases, they may be deemed idiopathic. Nevertheless, a thorough workup usually reveals these pathologies to result from gene defects, viral or bacterial infections, medication or radiotherapy, and others. Nowadays, two entities are considered as truly idiopathic neutropenia: chronic idiopathic neutropenia (CIN) and primary autoimmune neutropenia (PAN).
While CIN may affect adolescents and adults, PAN is typically diagnosed in infants and young children. Both CIN and PAN predispose for infections with bacteria and fungi, but most patients show only mild reductions of neutrophil counts and don't experience any symptoms. If so, gingivitis, mouths sores and febrile infections of the skin and upper respiratory tract are most commonly observed. They may be treated with antimicrobials. Few patients diagnosed with idiopathic neutropenia require long-term treatment, which may comprise the administration of human recombinant granulocyte colony-stimulating factor, corticosteroids or intravenous immunoglobulin G.
While CIN generally persists throughout life without major complications, spontaneous remission is observed in the vast majority of PAN patients. Nevertheless, individuals suffering from neutropenia are strongly advised to take general hygiene measures to prevent infections and to discuss vaccination schedules with their physicians.