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]:

• Mild neutropenia does not interfere with host defense mechanisms, but repeated measurements of low neutrophil counts should prompt a workup as to their cause.
• Moderate neutropenia is well tolerated by otherwise healthy individuals, but may be associated with an increased susceptibility to infections in patients suffering from comorbidities of the immune system.
• Severe neutropenia is generally associated with recurrent infectious diseases.
• Agranulocytosis renders affected patients prone to life-threatening infections with opportunistic agents.

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.

• Fever

  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: Fever – The presence of fever [cancertherapyadvisor.com]

  In severe neutropenia, the patient is likely to develop periodontal disease, oral and rectal ulcers, fever, and bacterial pneumonia. Fever recurring every 19-30 days suggests cyclical neutropenia. [medical-dictionary.thefreedictionary.com]

  A girl with cystic fibrosis and cyclic neutropenia developed an erythematous papular eruption without fever or neutrophilia 7 months after commencing therapy with G-CSF. A skin biopsy specimen revealed microscopic, sterile, neutrophilic abscesses. [ncbi.nlm.nih.gov]

  Haemodialysis Idiopathic Decreased production and increased destruction Viral infection Infectious mononucleosis, CMV, Measles, Rubella HIV infection Dengue fever See Cytomegalovirus infection See Dengue Bacterial infections Septicaemia Typhoid fever [rcpa.edu.au]

• Recurrent Infection

  A 48-year-old woman who presented with chronic idiopathic neutropenia causing life-long recurrent infections, and postoperative suppurative wound infections, presented for elective coronary artery surgery. [ncbi.nlm.nih.gov]

  None had recurrent infections, leukemia, lupus erythematosus, or rheumatoid arthritis. [nejm.org]

  In addition to a laboratory assessment, neutropenia patients may have a history of frequent/recurrent infections, lung infections, chronic ear infections, skin infections, serious infections (e.g., meningitis, or bone infections) or chronic mouth ulcers [luriechildrens.org]

  In patients with recurrent infections, treatment with corticosteroids results in improved neutrophil counts in about half of patients. [neutropenia.ca]

  Patients may have recurrent infections, autoimmune diseases, a previously diagnosed haematological disease or solid tumour indicating an obvious disease-related state. [patient.info]

• Malaise

  The initial symptoms of neutropenia begin after 1-3 days with malaise, chills, sore throat, fever. Later easy fatigability and weakness are seen. Infection is the most serious consequence of neutropenia. [med-ed.virginia.edu]

  The most common adverse reactions in patients: with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs are anemia, constipation, diarrhea, oral pain, vomiting, asthenia, malaise, edema peripheral, hemoglobin decreased, decreased appetite [neupogenhcp.com]

  […] circulating blood by cell changes that trap them in the lungs and spleen. neutropenia [ noo″tro-pe´ne-ah ] diminished numbers of neutrophils in the blood. cyclic neutropenia a chronic form marked by regular, periodic episodic recurrences, associated with malaise [medical-dictionary.thefreedictionary.com]

  Cyclical neutropenia in children (rare - recurring episodes of severe neutropenia accompanied by malaise, fever, adenopathy, anorexia and ulceration of mucous membranes). [patient.info]

  The symptoms of infection are the usual ones: fever, malaise, and upper respiratory symptoms. A skin abscess or boil is also common. [hematologyandoncology.net]

• Weight Loss

  However, among those most often reported are bone pain, weight loss, fatigue, dyspnea, and anemia. [ncbi.nlm.nih.gov]

• Vietnamese

  Severe congenital neutropenia caused by the ELANE gene mutation in a Vietnamese boy with misdiagnosis of tuberculosis and autoimmune neutropenia: a case report. BMC Hematol. 2015;15:2. [ncbi.nlm.nih.gov]

• Oral Ulcers

  Life-threatening infections can follow neutropenic nadir of the cycle, with frequent aphthous gingivitis, periodontitis, oral ulcerations, fever and occasional sepsis. [news-medical.net]

  Oral Surg Oral Med Oral Pathol 1983;55:331-43. 7. Bortoluzzi MC, Passador-Santos F, Capella DL, Manfro G, Nodari RJ Jr., Presta AA. Eosinophilic ulcer of oral mucosa: A case report. Ann Stomatol (Roma) 2012;3:11-3. 8. [jisponline.com]

  They often complain of headaches and myalgia when the neutrophil counts nadir and pharyngitis and oral ulcerations are common physical findings. [neutropenia.ca]

  Focal symptoms (eg, oral ulcers) may develop but are often subtle. Patients with drug-induced neutropenia due to hypersensitivity may have a fever, rash, and lymphadenopathy as a result of the hypersensitivity. [merckmanuals.com]

• Osteopenia

  Sixteen randomly selected women, 7 with CIN-associated osteoporosis and 9 with CIN-associated osteopenia, and 14 age- and menopausal status-matched healthy volunteers, were enrolled in the study. [ncbi.nlm.nih.gov]

  Osteopenia occurs in 44.4% and osteoporosis in 15.6% of CIN patients. [medscape.com]

  […] inhibitors of hematopoiesis, including transforming growth factor‐β1 and tumor necrosis factor‐α; (b) lymphopenia due to selective loss of primed/memory T‐cells and NK cells; (c) increased splenic volume on ultrasonography in 48.1% of patients; (d) osteopenia [onlinelibrary.wiley.com]

  Skeletal roentgenograms and bone scans of this patient showed osteolytic lesions and osteopenia of the thoracic and lumbar spine and osteolytic destruction of the right half of the sacrum. [clinchem.aaccjnls.org]

• Suggestibility

  The variability in responses to endotoxin suggests that CBIN is not entirely homogeneous with respect to mechanism. [ncbi.nlm.nih.gov]

  Our results suggest that high levels of FasL contribute to IN pathology. Additionally, the plasma from acute IN patients was found to have higher levels of soluble FasL than chronic IN patients. [eurekaselect.com]

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]:

• Neutropenia persists for more than three months.
• Anamnestic data don't imply drug-induced neutropenia; no prior radiotherapy.
• Exclusion of cyclic neutropenia and familial neutropenia.
• Exclusion of other hematological disorders, immune-mediated and infectious diseases.
• Exclusion of PAN as described in the following paragraph.

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].

• Rectal Ulcer

  In severe neutropenia, the patient is likely to develop periodontal disease, oral and rectal ulcers, fever, and bacterial pneumonia. Fever recurring every 19-30 days suggests cyclical neutropenia. [medical-dictionary.thefreedictionary.com]

• Capnocytophaga Ochracea

  Among the predominant species were Porphyromonas gingivalis (17.6%-7.3%), Prevotella intermedia (12.4%-4.7%), Capnocytophaga sputigena (14.4%-10.4%), Capnocytophaga ochracea (13.2%-6.9%) and Actinobacillus actinomycetemcomitans (9.3%-5.5%). [ncbi.nlm.nih.gov]

• Complement Fixing Antibody

  […] mixed IgG-IgM and complement-fixing antibodies. [ncbi.nlm.nih.gov]

• Capnocytophaga

  Among the predominant species were Porphyromonas gingivalis (17.6%-7.3%), Prevotella intermedia (12.4%-4.7%), Capnocytophaga sputigena (14.4%-10.4%), Capnocytophaga ochracea (13.2%-6.9%) and Actinobacillus actinomycetemcomitans (9.3%-5.5%). [ncbi.nlm.nih.gov]

• HLA-DR4

  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. [cancertherapyadvisor.com]

• Hypercellular Bone Marrow

  Abstract The presence of immune-complexes (IC) and antipolymorphonuclear neutrophil (PMN) autoantibodies was investigated in 28 patients with chronic idiopathic neutropenia and normal or hypercellular bone marrow, 19 with a metamyelocyte arrest and 9 [ncbi.nlm.nih.gov]

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]:

• Congenital neutropenia (Kostmann syndrome), including severe congenital neutropenia and cyclic neutropenia
• Shwachman syndrome
• Barth syndrome
• Glycogen storage disease type 1b
• X-linked agammaglobulinemia
• Chronic idiopathic neutropenia
• Tuberculosis
• Rubella, measles, varicella
• Infection with human immunodeficiency virus
• Primary autoimmune neutropenia
• Secondary autoimmune neutropenia in patients suffering from rheumatoid arthritis or systemic lupus erythematosus
• Splenomegaly
• Aplastic anemia
• Leukemia, lymphoma
• Bone marrow infiltration by metastases

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.

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