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Neutropenia

Neutropenia is a hematologic condition characterized by an abnormally low number of neutrophils, a type of white blood cell essential for the body's innate immune response against bacterial and fungal infections, typically defined by an absolute neutrophil count (ANC) below 1,500 cells per microliter of blood.^[1] This reduction can be mild (ANC 1,000–1,500/μL), moderate (500–1,000/μL), or severe (<500/μL), with severe cases posing a significant risk of life-threatening infections due to impaired phagocytosis and pathogen clearance.^[2] Neutrophils, comprising 50–70% of circulating leukocytes, are primarily produced in the bone marrow and have a short lifespan of hours to days, making their count sensitive to disruptions in production, distribution, or destruction.^[1] The condition arises from diverse etiologies, broadly classified as congenital or acquired, with acquired forms being more common and often linked to chemotherapy, infections (particularly viral), autoimmune disorders, medications, nutritional deficiencies (e.g., vitamin B12 or folate), or malignancies such as leukemia.^[1] Congenital neutropenias, including severe congenital neutropenia (Kostmann syndrome) and cyclic neutropenia, result from genetic mutations affecting neutrophil production or maturation, leading to recurrent infections from infancy.^[1] Pathophysiologically, neutropenia may stem from decreased bone marrow output (e.g., due to myelosuppression), increased peripheral destruction (e.g., via autoantibodies), or margination/sequestration in tissues, with chemotherapy-induced cases often peaking 7–12 days post-treatment in cancer patients.^[3]^[4] Clinically, mild or moderate neutropenia is often asymptomatic and discovered incidentally on routine blood tests, but severe or prolonged cases manifest with fever, sore throat, oral ulcers, skin infections, or pneumonia, particularly severe cases accompanied by fever, a condition known as febrile neutropenia, especially in immunocompromised individuals.^[5] The primary complication is heightened susceptibility to opportunistic infections, which account for substantial morbidity in affected populations, particularly those undergoing myelosuppressive therapies.^[2] Diagnosis involves complete blood count with differential, followed by bone marrow evaluation if persistent, to differentiate causes and guide management.^[6] Treatment is etiology-specific: addressing underlying causes (e.g., discontinuing offending drugs or treating infections) forms the cornerstone, while supportive measures include prophylactic antibiotics, granulocyte colony-stimulating factors (G-CSF) like filgrastim to boost neutrophil production in chemotherapy-induced cases, and hospitalization for severe infections.^[1] Prognosis varies widely; transient neutropenia from infections often resolves spontaneously, but chronic forms like autoimmune neutropenia may require immunosuppressive therapy, and congenital types can progress to myelodysplastic syndromes or leukemia if untreated.^[1] Patient education emphasizes infection prevention through hand hygiene, avoiding crowds, and prompt reporting of fever to mitigate risks.^[7]

Definition and Classification

Definition

Neutropenia is a hematologic condition defined by a reduction in the absolute neutrophil count (ANC), typically below 1,500 neutrophils per microliter of blood in adults, with age-adjusted thresholds applied in children to account for physiological variations in neutrophil levels during infancy and early childhood.^[8]^[9] Severe forms of neutropenia are characterized by an ANC below 500 cells per microliter, which significantly heightens vulnerability to infections.^[10]^[2] Neutrophils, the most abundant type of granulocytes in circulating blood, play a central role in innate immunity by migrating to sites of infection, engulfing pathogens through phagocytosis, and generating reactive oxygen species via oxidative burst to destroy bacteria and fungi.^[11]^[12] This process enables neutrophils to provide rapid, non-specific defense against microbial invasion before adaptive immune responses fully activate.^[11] The ANC is determined through a standard calculation: the total white blood cell (WBC) count is multiplied by the combined percentage of segmented neutrophils and band forms (immature neutrophils), then divided by 100, yielding the absolute number of functional neutrophils available for immune response.^[13]^[14] Neutropenia was first recognized as a distinct clinical entity in the early 20th century, with Werner Schultz describing cases of profound neutrophil depletion—later termed agranulocytosis—in 1922, highlighting its association with severe infections and hematopoietic dysfunction.^[15]^[16]

Classification and Severity

Neutropenia is primarily classified by the severity of the absolute neutrophil count (ANC) reduction, which guides clinical risk assessment and management. Mild neutropenia is defined as an ANC of 1,000 to 1,500 neutrophils per microliter (μL), moderate as 500 to 1,000/μL, and severe as less than 500/μL.^[1]^[2] These thresholds reflect increasing infection risk, with severe cases (ANC <500/μL) associated with life-threatening complications and agranulocytosis defined at ANC <100/μL.^[17] Beyond severity, neutropenia is categorized temporally as acute (lasting less than 3 months) or chronic (persisting beyond 3 months).^[18] It can also be isolated, affecting only neutrophils, or occur as part of pancytopenia, involving reductions in multiple blood cell lines such as red cells and platelets.^[18] Special subtypes include cyclic neutropenia, characterized by predictable oscillations in ANC every 21 days, leading to recurrent episodes of severe neutropenia.^[19] Idiopathic neutropenia refers to chronic cases lasting over 3 months without identifiable etiology, often immune-mediated.^[20] Benign ethnic neutropenia is a variant observed in individuals of African, Middle Eastern, or West Indian descent, where ANC ranges from 800 to 1,200/μL without increased infection risk or clinical significance.^[21] In oncology, standardized grading systems such as the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 6.0 (2025) and the World Health Organization (WHO) criteria are used to quantify neutropenia severity for chemotherapy-related events. These systems grade as follows:

Grade	NCI CTCAE v6.0 Neutrophils (/mm³)	Description
1	<1,500 - 1,000	Mild; asymptomatic or mild symptoms
2	<1,000 - 500	Moderate; minimal intervention needed
3	<500 - 100	Severe; medically significant but not immediately life-threatening
4	<100	Life-threatening consequences; urgent intervention indicated

The WHO grading aligns closely, emphasizing grade 4 as life-threatening.^[23] Febrile neutropenia represents an acute emergency subcategory, defined as ANC <500/μL (or expected to decline below this) accompanied by fever of 38.3°C or higher on a single reading, or 38°C or higher sustained over 1 hour.^[24]^[25] This condition warrants immediate evaluation due to high mortality risk from infections.^[24]

Etiology

Acquired Causes

Acquired causes of neutropenia involve environmental, therapeutic, or disease-related factors that disrupt neutrophil production, distribution, or survival after birth, distinct from congenital genetic defects. These etiologies are common in clinical practice and often reversible upon addressing the underlying trigger. Iatrogenic interventions, infections, autoimmune processes, idiosyncratic drug reactions, nutritional deficiencies, and hypersplenism represent the primary categories, each contributing to bone marrow suppression, increased peripheral destruction, or sequestration of neutrophils. Iatrogenic causes, particularly cytotoxic chemotherapy, are among the most frequent acquired etiologies, affecting up to 40% of patients treated for malignancies. Alkylating agents and antimetabolites suppress bone marrow function, leading to neutropenia typically within 7-14 days of initiation. Radiation therapy targeting multiple active bone marrow sites similarly impairs hematopoiesis by damaging progenitor cells. These effects heighten infection risk during treatment cycles. Infections represent another major acquired pathway, with viral agents like HIV, hepatitis viruses, Epstein-Barr virus (EBV), and parvovirus B19 commonly implicated through direct bone marrow suppression or immune-mediated neutrophil destruction. Bacterial infections, including overwhelming sepsis and typhoid fever caused by Salmonella typhi, can deplete neutrophils by excessive consumption during acute response or by inducing marrow hypoplasia. Such infectious triggers often result in transient neutropenia that resolves with pathogen clearance. Autoimmune and drug-induced mechanisms frequently overlap, as certain medications provoke immune responses mimicking autoimmune neutropenia. In systemic lupus erythematosus (SLE), antineutrophil antibodies target neutrophil surface antigens, promoting peripheral destruction and contributing to cytopenias in up to 40% of cases. Idiosyncratic reactions to drugs like clozapine cause neutropenia in approximately 1% of users, usually within the first three months, via immune-mediated clearance. Beta-lactam antibiotics, such as penicillins and cephalosporins, are associated with this complication in about 10% of prolonged courses exceeding two weeks, often through hapten-induced antibody formation. Nutritional deficiencies, particularly of vitamin B12 or folate, lead to megaloblastic changes that impair DNA synthesis in granulocyte precursors, halting effective granulopoiesis and causing neutropenia alongside anemia. These are prevalent in malabsorption syndromes, strict vegan diets, or alcoholism, and correction via supplementation typically restores counts within weeks. Copper deficiency, though rarer, similarly disrupts neutrophil maturation. Hypersplenism, often arising from portal hypertension in liver cirrhosis, results in excessive neutrophil sequestration and premature destruction within an enlarged spleen, reducing circulating levels without primary marrow failure. This peripheral pooling exacerbates cytopenias in chronic liver disease, where up to 80% of patients exhibit splenomegaly-related hematologic abnormalities.

Congenital Causes

Congenital neutropenia arises from genetic defects that impair neutrophil production or maturation in the bone marrow, often manifesting in infancy with persistent or intermittent low absolute neutrophil counts (ANC). These disorders are distinct from acquired forms due to their lifelong presence and hereditary patterns, including autosomal dominant, recessive, and X-linked inheritance. Key examples include severe congenital neutropenia (SCN), cyclic neutropenia, and syndromic forms associated with multisystem involvement. Severe congenital neutropenia (SCN), first described as Kostmann syndrome, is characterized by profound neutropenia with ANC typically below 200/μL from birth, leading to recurrent severe bacterial infections such as omphalitis, pneumonia, and skin abscesses.^[26] The most common genetic cause involves heterozygous pathogenic variants in the ELANE gene, encoding neutrophil elastase, which account for 40-60% of SCN cases and follow autosomal dominant inheritance, often de novo.^[26]^[27] In the classic autosomal recessive form of Kostmann syndrome, biallelic mutations in HAX1 disrupt mitochondrial integrity and neutrophil survival.^[26] Individuals with SCN face a significantly elevated risk of progression to myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), with cumulative incidences reaching 15-36% over 15 years.^[26] Cyclic neutropenia represents another primary genetic form, marked by predictable oscillations in neutrophil counts every 21-28 days, with ANC dropping below 0.2 × 10⁹/L for 3-5 days during nadirs, accompanied by fever, oral ulcers, and mild infections.^[26] Nearly all cases result from heterozygous ELANE mutations with autosomal dominant inheritance, causing periodic disruptions in granulopoiesis.^[26] Diagnosis requires serial complete blood counts (CBCs) over at least three months to confirm the cyclic pattern, distinguishing it from non-cyclic SCN.^[26] Several syndromic congenital neutropenias involve additional organ systems. Shwachman-Diamond syndrome, caused by biallelic mutations in the SBDS gene in approximately 90% of cases, features persistent or intermittent neutropenia alongside exocrine pancreatic insufficiency, leading to malabsorption and failure to thrive in infancy, as well as skeletal dysplasia and short stature; it follows autosomal recessive inheritance with a prevalence of about 1 in 80,000.^[28] Barth syndrome, an X-linked disorder due to mutations in TAFAZZIN affecting cardiolipin remodeling, presents with chronic, intermittent, or cyclic neutropenia in most affected males, often alongside dilated cardiomyopathy, skeletal myopathy, and growth delay, increasing susceptibility to bacterial infections.^[29] Cartilage-hair hypoplasia, resulting from homozygous or compound heterozygous variants in the noncoding RNA gene RMRP, is an autosomal recessive metaphyseal chondrodysplasia with variable neutropenia, fine sparse hair, short-limbed dwarfism, and T-cell immunodeficiency, contributing to recurrent infections.^[30] Benign ethnic neutropenia, particularly the Duffy-null phenotype prevalent in individuals of African descent (affecting up to 66-80%), stems from homozygosity for the FY*0 allele (rs2814778) in the ACKR1 gene, which encodes the Duffy antigen receptor for chemokines, resulting in mildly reduced ANC without heightened infection risk or other hematologic abnormalities.^[31]^[32] Advances in genetic diagnostics, particularly next-generation sequencing (NGS) panels and whole-exome sequencing, have enhanced identification of rare variants in congenital neutropenia since 2020, such as dominant-negative mutations in GFI1, a transcriptional repressor of neutrophil differentiation genes, found in approximately 2% of SCN cases and associated with variable severity.^[33] These tools facilitate precise subtyping amid phenotypic overlap with other marrow failure syndromes.

Pathophysiology

Mechanisms of Neutropenia

Neutropenia arises from disruptions in the balance of neutrophil production, distribution, and clearance, primarily occurring within the bone marrow and peripheral blood compartments. Granulopoiesis, the process of neutrophil development from hematopoietic stem cells, is tightly regulated by cytokines and transcription factors; defects here lead to insufficient output. Conversely, accelerated loss through enhanced apoptosis or immune-mediated destruction can deplete circulating neutrophils. Distributional abnormalities, such as excessive margination or sequestration, may mimic true neutropenia by reducing the absolute neutrophil count (ANC) without altering total body neutrophil mass. These mechanisms collectively perturb neutrophil homeostasis, where daily production normally matches clearance to sustain ANC levels. Granulopoiesis failure represents a core mechanism of neutropenia, characterized by impaired differentiation of myeloid progenitors into mature neutrophils in the bone marrow. This often stems from cytokine deficiencies, particularly reduced signaling through granulocyte colony-stimulating factor (G-CSF), which is essential for progenitor proliferation, survival, and maturation. In the absence of adequate G-CSF receptor (G-CSFR) activation, myeloid cells exhibit halted differentiation at early stages, resulting in bone marrow hypocellularity for the granulocytic lineage and diminished neutrophil release into circulation. For instance, G-CSFR-deficient models demonstrate profound neutropenia due to both impaired production and increased progenitor apoptosis.^[34] Such failures can be exacerbated by broader disruptions in the cytokine milieu, including interleukin-6 (IL-6), which synergizes with G-CSF to support granulopoiesis.^[35] Increased destruction and apoptosis of neutrophils contribute significantly to neutropenia, particularly in acquired forms. Mature neutrophils have a short lifespan in circulation, estimates of which range from 6-8 hours (traditional view) to 5-6 days (recent in vivo studies), programmed to undergo apoptosis via intrinsic pathways involving Fas/Fas ligand (Fas/FasL) signaling, which activates caspase cascades leading to cell death without inflammation.^[36]^[37] In autoimmune neutropenia, antineutrophil antibodies bind to surface antigens, promoting opsonization, phagocytosis by macrophages, or direct complement-mediated lysis, thereby accelerating peripheral destruction. This immune-mediated clearance can reduce ANC rapidly, independent of production rates. Excessive margination, where neutrophils adhere excessively to vascular endothelium via integrins and selectins, also sequesters cells from the circulating pool, mimicking destruction.^[38]^[39]^[2] Pseudoneutropenia, a subset of distributional shifts, occurs without true deficits in neutrophil production or survival but due to altered compartmentalization. Splenic sequestration traps mature neutrophils in the spleen, often in hypersplenism associated with portal hypertension or hemolytic anemias, leading to low circulating ANC despite normal bone marrow output. Similarly, enhanced endothelial adhesion—driven by upregulated adhesion molecules like P-selectin—causes neutrophils to marginate in vessels, reducing the non-marginal circulating pool that ANC measures reflect. These shifts highlight that ANC represents only 4-5% of total body neutrophils, with the majority in marrow reserves or marginated states.^[40]^[2] Key molecular pathways underpin these mechanisms, with transcription factors orchestrating granulocyte maturation. CCAAT/enhancer-binding protein epsilon (C/EBPε) is pivotal for terminal neutrophil differentiation, regulating genes for granule proteins and functional maturation; its deficiency impairs late-stage granulopoiesis, resulting in neutropenia with arrested precursors. In parallel, the Fas/FasL pathway governs apoptosis in mature neutrophils, ensuring rapid turnover while preventing excessive inflammation. These pathways integrate with cytokine signals to fine-tune neutrophil numbers.^[41]^[39] Under normal conditions, daily neutrophil production approximates $10^{11} cells to match turnover, with circulating half-life varying by estimate. Disruptions, such as reduced production from G-CSF deficiency or elevated destruction from autoimmunity, shift the equilibrium, lowering ANC. More advanced models incorporate feedback loops, like G-CSF upregulation in response to low ANC, to predict dynamics in neutropenia.^[42]^[43]

Immune and Infectious Consequences

Neutropenia significantly impairs innate immune defenses by reducing the availability of neutrophils, which are essential for phagocytosis—the process by which these cells engulf and destroy pathogens such as bacteria and fungi—and for NETosis, the formation of neutrophil extracellular traps (NETs) that capture and kill extracellular microbes.^[1] This deficiency creates a critical gap in the first line of host defense, particularly against rapidly proliferating bacterial and fungal invaders, as neutrophils constitute the majority of circulating leukocytes responsible for these antimicrobial activities.^[44] In severe neutropenia (absolute neutrophil count [ANC] <500 cells/μL), the diminished phagocytic capacity allows opportunistic pathogens to establish infections more readily, while impaired NETosis further exacerbates vulnerability to invasive fungal elements that evade other immune mechanisms.^[45] The most frequent infectious consequences involve bacterial pathogens, with Gram-negative organisms such as Pseudomonas aeruginosa, Escherichia coli, and Klebsiella species predominating in early neutropenia due to their ability to translocate from the gastrointestinal tract, especially in patients with chemotherapy-induced mucositis serving as an entry portal.^[24] Gram-positive bacteria, including Staphylococcus aureus and coagulase-negative staphylococci, also contribute significantly, often originating from skin or catheter sites.^[46] Fungal infections, though less common initially, become prominent in prolonged neutropenia exceeding 7-10 days, with Candida species causing mucosal and bloodstream infections and Aspergillus leading to invasive pulmonary disease; viral infections are relatively spared owing to intact contributions from other leukocytes like lymphocytes.^[47] Febrile neutropenia represents a hallmark syndrome where fever emerges as the predominant manifestation of underlying infection in the absence of neutrophil-mediated inflammatory response, with approximately 30% of cases having a documented microbial etiology and carrying a 20-30% risk of bacteremia, particularly in profound neutropenia (ANC <100 cells/μL).^[24] This condition heightens the urgency for empirical intervention, as the lack of neutrophils masks typical localizing signs, allowing infections to disseminate rapidly from common sites like the oral mucosa or perianal region in chemotherapy recipients.^[48] Untreated or delayed recognition of these infections can progress to sepsis, with mortality rates reaching 10-20% in severe neutropenic episodes complicated by bacteremia or fungal invasion, driven by the unchecked microbial proliferation and systemic inflammatory dysregulation.^[49] Recent 2024 reviews underscore emerging roles for microbiome dysbiosis in amplifying these risks, where alterations in gut flora—often induced by antibiotics or chemotherapy—facilitate bacterial translocation and biofilm-associated persistence of pathogens like Pseudomonas, contributing to recurrent infections in chronic neutropenia.^[50]

Clinical Presentation

Signs and Symptoms

Neutropenia itself is typically asymptomatic, particularly in mild or chronic cases, where absolute neutrophil counts (ANC) above 1,000 cells/μL often result in no noticeable effects and are frequently discovered incidentally during routine blood tests.^[8] Symptoms arise primarily from increased susceptibility to infections due to impaired immune defense, with fever being the most common initial manifestation, often exceeding 38.5°C and accompanied by chills and fatigue.^[8] These infection-driven symptoms are more pronounced in severe neutropenia (ANC <500 cells/μL) or acute forms, such as those induced by chemotherapy.^[51] Local signs of infection in neutropenic patients commonly include oral ulcers, pharyngitis, skin abscesses, and perirectal pain, reflecting the vulnerability of mucosal and skin barriers to bacterial invasion.^[52] Systemic infections may present with pneumonia or urinary tract infections, leading to additional symptoms such as cough, dysuria, or shortness of breath.^[8] In pediatric cases, particularly those with cyclic neutropenia, symptoms often involve recurrent otitis media, alongside failure to thrive due to persistent low-grade infections disrupting growth and nutrition.^[53] Afebrile presentations are rare but can occur in benign ethnic neutropenia, where individuals of African, Middle Eastern, or West Indian descent maintain low ANC without increased infection risk or symptoms.^[54]

Complications

Neutropenia significantly increases the risk of life-threatening infections due to impaired immune defense, with sepsis being a primary complication that can rapidly progress to septic shock. In patients with febrile neutropenia, the overall mortality from sepsis ranges from 3% to 20%, while progression to septic shock in intensive care settings elevates mortality rates to 30-60%. Invasive fungal infections, such as mucormycosis, are particularly severe in prolonged neutropenia, often affecting immunocompromised individuals with hematologic malignancies and carrying high mortality due to delayed diagnosis and tissue invasion.^[55]^[56] Hematologically, severe neutropenia can evolve into agranulocytosis, defined by an absolute neutrophil count below 100/μL, heightening susceptibility to opportunistic infections. Neutropenia may be a presenting feature of underlying bone marrow failure syndromes, such as aplastic anemia, which involves broader hematopoietic failure. For congenital forms like severe congenital neutropenia (SCN), there is an elevated risk of leukemic transformation, with approximately 20% of patients developing myelodysplastic syndrome or acute myeloid leukemia over time.^[57]^[58]^[59] Beyond infections, neutropenia predisposes patients to deep-seated complications such as osteomyelitis and endocarditis, which arise from bacteremia in vulnerable sites like bone or heart valves. In cancer patients undergoing chemotherapy, neutropenia frequently necessitates dose reductions or treatment delays to mitigate infection risk, potentially compromising oncologic outcomes by reducing the relative dose intensity of therapy.^[60]^[61] Non-infectious complications in pediatric cases include growth delays, particularly in congenital syndromes like Shwachman-Diamond, where chronic illness and malnutrition impair physical development. Recurrent hospitalizations for infections also exert a psychological toll, contributing to anxiety, depression, and reduced quality of life among affected children and caregivers.^[62]

Diagnosis

Laboratory Evaluation

The laboratory evaluation of neutropenia primarily relies on hematologic assessments to confirm the diagnosis, quantify severity, and guide further investigation. The cornerstone test is the complete blood count (CBC) with automated or manual differential, which allows calculation of the absolute neutrophil count (ANC) by multiplying the total white blood cell count by the proportion of segmented neutrophils and bands.^[1] This test is essential for initial screening and monitoring, with repetition recommended every 2-3 days in acute settings like febrile neutropenia to track recovery or progression.^[63] In clinical practice, an ANC below 1.5 × 10^9/L confirms neutropenia, with severe cases defined as below 0.5 × 10^9/L, prompting urgent evaluation.^[6] A peripheral blood smear review complements the CBC by providing morphologic assessment of neutrophils and other cells. It helps rule out pseudoneutropenia caused by neutrophil clumping or aggregation artifacts, which can falsely lower automated counts, and identifies abnormal features such as blasts indicative of underlying leukemia or dysplastic changes suggesting myelodysplastic syndrome.^[64] Careful examination may also reveal toxic granulation or Döhle bodies in reactive neutropenia secondary to infection.^[63] For cases of persistent or unexplained neutropenia, bone marrow aspiration and biopsy are indicated, particularly if the condition lasts more than 4 weeks or if there are signs of pancytopenia or dysplasia on peripheral smear. These procedures evaluate marrow cellularity, myeloid maturation, and potential infiltrative processes; for instance, maturation arrest at the promyelocyte stage is a hallmark finding in congenital severe neutropenia.^[63] Biopsy is especially useful in distinguishing hypoplastic from hypercellular marrow failure and assessing for infections or malignancies not evident on aspiration alone.^[65] Additional laboratory tests target specific etiologies based on clinical suspicion. Reticulocyte count assesses overall bone marrow response and erythropoiesis, often reduced in marrow failure syndromes.^[1] Serum levels of vitamin B12 and folate are measured to exclude nutritional deficiencies causing megaloblastic changes that may contribute to ineffective hematopoiesis.^[66] In suspected autoimmune neutropenia, testing for anti-neutrophil antibodies via direct or indirect assays can confirm immune-mediated destruction, particularly in children with benign chronic forms.^[1] Advanced evaluations include flow cytometry on bone marrow samples to quantify cellularity, progenitor populations, and aberrant phenotypes, aiding in the diagnosis of subtle marrow disorders.^[6] Emerging tools such as next-generation sequencing (NGS) for pathogen identification or biomarkers like procalcitonin may assist in evaluating associated infections in complex cases.^[67] For pediatric patients with suspected congenital neutropenia, genetic testing via targeted panels is recommended, including sequencing of the ELANE gene for severe congenital or cyclic neutropenia, as per 2024 guidelines from pediatric hematology protocols; broader inherited bone marrow failure syndrome panels (e.g., including G6PC3) are indicated for isolated severe cases persisting beyond infancy.^[68]

Differential Diagnosis

The differential diagnosis of neutropenia encompasses a range of conditions that can mimic low neutrophil counts on complete blood count (CBC), necessitating careful evaluation to distinguish true neutropenia from artifacts or unrelated cytopenias.^[1] Key considerations include pseudoneutropenia, other cytopenias, reactive leukopenias, and rare mimics, with differentiation guided by clinical history, peripheral blood smear review, and further testing.^[64] The 2025 European guidelines on chronic neutropenias introduce a provisional category of "likely acquired neutropenia" for cases presenting in childhood to young adulthood that may involve immune dysregulation, building on prior classifications.^[69] Pseudoneutropenia refers to falsely low neutrophil counts due to laboratory artifacts, such as neutrophil clumping in EDTA-anticoagulated samples, which can be confirmed by repeating the CBC with alternative anticoagulants or immediate smear preparation.^[1] Ethnic variants, notably benign ethnic neutropenia (BEN) in individuals of African or Middle Eastern descent with Duffy antigen negativity, present with stable mild neutropenia without increased infection risk, often linked to the Duffy-null genotype (FY*O allele).^[70] Other causes include diurnal variations causing morning pseudoneutropenia or shifts post-splenectomy, where splenic sequestration is absent but marginalization alters counts; these are benign and resolve with repeat testing.^[1] Other cytopenias must be differentiated, particularly pancytopenia in aplastic anemia, characterized by hypocellular bone marrow and multilineage involvement, versus leukemia where peripheral blasts or dysplastic features on smear suggest malignancy rather than isolated neutropenia.^[1] In acute myeloid or lymphoblastic leukemia, neutropenia accompanies blasts, prompting urgent marrow evaluation to rule out infiltration.^[64] Reactive leukopenias, often transient, arise from viral suppression such as parvovirus B19 inhibiting erythropoiesis and granulopoiesis, or overwhelming infections like bacterial sepsis, where neutropenia reflects consumption without marrow failure—distinguished by normal or hypercellular marrow with left-shifted maturation.^[1] These differ from primary neutropenia by their self-limiting nature and association with acute illness.^[9] Rare mimics include hypersensitivity reactions to drugs, presenting as immune-mediated neutropenia mimicking autoimmune forms, and nutritional deficiencies like copper deficiency, which causes reversible neutropenia with anemia and vacuolated precursors on marrow exam, often post-bariatric surgery or zinc excess.^[71] The 2025 European guidelines recommend a diagnostic algorithm starting with serial CBCs every 3–4 months for chronic cases to assess persistence and stability, alongside peripheral smear to exclude artifacts, followed by bone marrow examination if counts remain low (<1.5 × 10⁹/L) or symptoms suggest malignancy, to differentiate production defects from peripheral destruction or infiltration.^[69] This approach avoids misdiagnosis of benign variants as pathologic neutropenia.^[64]

Management

Treatment Strategies

Treatment of neutropenia begins with addressing the underlying cause to promote neutrophil recovery. For drug-induced neutropenia, discontinuation of the offending agent is the primary intervention, often leading to resolution within days to weeks.^[72] In cases associated with active infections, prompt initiation of broad-spectrum antibiotics, such as piperacillin-tazobactam at 4.5 g IV every 6 hours, is essential to manage septic complications while supporting neutrophil reconstitution.^[73] For autoimmune neutropenia, immunosuppressive therapies including corticosteroids like prednisone (1-2 mg/kg/day) or other agents such as rituximab can suppress antibody-mediated destruction and elevate neutrophil counts in responsive patients.^[74] Granulocyte colony-stimulating factor (G-CSF), available as filgrastim or its pegylated form pegfilgrastim, is a cornerstone pharmacologic therapy to stimulate granulopoiesis across various neutropenia etiologies. Administered subcutaneously at a dose of 5 mcg/kg/day for filgrastim, it accelerates neutrophil recovery, reducing the duration of severe neutropenia by approximately 2-3 days in chemotherapy-induced cases.^[75]^[76] In congenital forms, such as severe congenital neutropenia (SCN), long-term G-CSF therapy maintains neutrophil counts above critical thresholds in over 90% of patients, significantly mitigating infection risks.^[77] For G-CSF-refractory SCN, hematopoietic stem cell transplantation (HSCT) offers a curative option, with overall survival rates of 80-90% in matched donor settings, though engraftment failure remains a challenge.^[78]^[79] Emerging strategies include the thrombopoietin receptor agonist eltrombopag for bone marrow failure syndromes such as aplastic anemia, which may involve hypoplastic neutropenia; it has shown potential in enhancing multilineage recovery when used in combination with immunosuppression for refractory cases.^[80] Gene therapy trials targeting ELANE mutations, responsible for many SCN cases, are advancing with CRISPR-based approaches to inhibit mutant elastase expression, showing promising preclinical restoration of neutrophil production.^[81] Splenectomy is reserved for rare instances of hypersplenism-driven neutropenia, where sequestration contributes to cytopenias, but its use is limited due to heightened postoperative infection risks.^[82]

Prophylaxis and Supportive Measures

Prophylaxis against infections is a cornerstone of managing neutropenia, particularly in patients undergoing chemotherapy or hematopoietic stem cell transplantation (HSCT), where the risk of bacterial, fungal, and viral infections is elevated due to profound and prolonged neutropenia.^[83] Antibacterial prophylaxis, such as with fluoroquinolones (e.g., levofloxacin), is recommended for high-risk adults expected to have neutropenia lasting more than 7 days with absolute neutrophil count (ANC) less than 100 cells/μL, as per guidelines from the American Society of Clinical Oncology (ASCO) and Infectious Diseases Society of America (IDSA). Antifungal prophylaxis with agents like fluconazole is advised for similar high-risk patients to prevent invasive candidiasis, while posaconazole or voriconazole may be used in settings with higher mold infection risks, such as acute myeloid leukemia induction therapy. For antiviral prophylaxis, acyclovir or valacyclovir is routinely administered to HSCT recipients to mitigate herpes simplex virus reactivation, with consideration for cytomegalovirus monitoring in seropositive patients. Risk assessment tools guide the implementation of these prophylactic measures to identify patients who benefit most. The Multinational Association for Supportive Care in Cancer (MASCC) index, validated in multiple studies, stratifies patients with febrile neutropenia; a score greater than 21 indicates low risk, allowing for outpatient management with oral prophylaxis, whereas scores of 21 or less signal high risk, warranting inpatient intravenous antibiotics and broader prophylaxis.^[84] This approach, endorsed in the 2018 ASCO/IDSA guidelines and reaffirmed in subsequent updates including UpToDate reviews through 2024, balances infection prevention with minimizing antimicrobial resistance.^[85] Supportive measures complement pharmacologic prophylaxis by reducing environmental exposure to pathogens. Strict hand hygiene, including washing with soap and water for at least 20 seconds before and after patient contact, is emphasized in all care settings to prevent healthcare-associated infections.^[86] A neutropenic diet, which avoids raw or undercooked meats, unpasteurized dairy, and uncooked fruits and vegetables, is recommended during periods of severe neutropenia (ANC <500 cells/μL) to limit ingestion of potential bacterial sources, though its impact on infection rates remains debated in recent analyses.^[87] Hospitalization is indicated for patients with ANC less than 100 cells/μL expected to persist beyond 7 days, or those with comorbidities, to enable close monitoring and prompt intervention.^[72] Granulocyte transfusions, involving donor-derived neutrophils, are reserved for refractory infections in severe neutropenia but demonstrate limited efficacy in randomized trials, with benefits primarily observed in fungal or Gram-negative cases unresponsive to other therapies.^[88] Nursing protocols play a vital role in supportive care, focusing on vigilant surveillance and infection control. Recent 2025 reviews highlight the importance of multidisciplinary teams for daily assessment, including central line care with chlorhexidine gluconate disinfection and dressing changes every 7 days to prevent catheter-related bloodstream infections.^[89] Fever monitoring every 4 hours, along with immediate reporting of temperatures ≥38°C, enables rapid escalation to empiric antibiotics, reducing mortality in febrile neutropenia.^[90] Vaccination strategies must account for immunosuppression during neutropenic periods. Live vaccines, such as oral polio or varicella, are contraindicated due to the risk of disseminated infection in immunocompromised individuals.^[91] In contrast, inactivated vaccines like the pneumococcal conjugate vaccine (PCV15 followed by PPSV23) are recommended prior to chemotherapy initiation, ideally when ANC is stable, to provide protection against Streptococcus pneumoniae, as supported by the 2024 ASCO guideline on vaccination of adults with cancer and CDC recommendations.^[91]^[92]

Prognosis and Epidemiology

Prognostic Factors

Prognostic factors in neutropenia significantly influence short- and long-term patient outcomes, with milder and transient forms generally associated with favorable recovery. Mild or transient neutropenia, often triggered by viral infections such as those following common respiratory pathogens, typically resolves spontaneously within weeks to months without long-term sequelae.^[93] Similarly, an early and robust response to granulocyte colony-stimulating factor (G-CSF) therapy can shorten the duration of neutropenia and reduce infection risk, effectively eliminating it as an independent poor prognostic indicator in treated patients.^[94] In contrast, several factors portend poorer outcomes, particularly prolonged neutropenia lasting more than 7 days, which heightens susceptibility to severe infections and increases mortality risk. Comorbidities such as advanced age, diabetes, and other chronic conditions exacerbate this vulnerability by impairing immune recovery and complicating infection management. Fungal infections during neutropenic episodes are especially ominous, associated with high mortality rates due to delayed diagnosis and treatment challenges. Underlying malignancies, notably acute myeloid leukemia (AML), further worsen prognosis, with neutropenia-related complications contributing to mortality rates of approximately 30-40% during induction therapy in affected patients.^[47]^[95]^[96] For congenital forms like severe congenital neutropenia (SCN), long-term G-CSF use has transformed management but introduces a risk of leukemic transformation, with cumulative incidence rates reaching about 20% after 15-20 years of therapy based on registry data.^[97] Risk stratification tools, such as the Multinational Association for Supportive Care in Cancer (MASCC) index for febrile neutropenia, aid in prognosis by assigning scores based on factors like symptom burden, age, and comorbidities; scores above 21 indicate low risk with mortality under 5%, while scores below 15 signal high risk exceeding 30%.^[98] Recent advancements, including a 2024 network meta-analysis of rapid diagnostic tests (RDT) combined with antimicrobial stewardship programs (ASP), have demonstrated improved outcomes by enabling earlier targeted therapy, showing a significant reduction in mortality (OR 0.72; 95% CI, 0.59–0.87) for bloodstream infections.^[99]^[100]

Incidence and Prevalence

Neutropenia affects approximately 1.24% of the US population, corresponding to about 35.5 million individuals, based on a 2023 population-based study using National Health and Nutrition Examination Survey (NHANES) data from 2011–2018.^[101] This prevalence varies by ethnicity, with higher rates observed in certain groups, but remains relatively low in the general population outside specific risk contexts; recent NHANES data report 5.36% among Black individuals. Congenital forms of neutropenia are rare. Severe congenital neutropenia (SCN) has an estimated incidence of 1 in 200,000 individuals worldwide.^[102] Cyclic neutropenia is even less common, with a frequency of about 1 case per million people. Acquired neutropenia is far more prevalent, particularly in clinical settings. Among patients receiving chemotherapy for cancer, the incidence of neutropenia ranges from 2% to 50%, depending on the regimen, cancer type, and patient factors, with severe (grade 3/4) cases occurring in 20-40% of those treated for solid tumors such as breast cancer.^[103]^[104] In untreated HIV-infected individuals, neutropenia occurs in 10-50% of cases, often linked to disease progression or opportunistic infections.^[105] Demographically, congenital neutropenia is more common in children, presenting early in life, while acquired forms predominate in adults due to iatrogenic causes like chemotherapy. Ethnic variations are notable, with benign ethnic neutropenia (BEN) affecting approximately 4-5% of individuals of African ancestry (5.36% in recent NHANES data), characterized by chronically low absolute neutrophil counts without increased infection risk; in contrast, prevalence is 0.79% among White individuals and 0.38% among Mexican-Americans using a threshold of <1.5 × 10^9/L.^[101]^[106] Globally, the incidence of neutropenia is rising in parallel with increasing cancer diagnoses and aggressive therapies, though improved supportive measures like granulocyte colony-stimulating factors have enhanced control and reduced complications, as noted in 2024 epidemiological analyses.^[6]

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