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Anesthesiology18 papers

Disorder of neutrophils

Last edited: 3 h ago

Overview

Disorders of neutrophils encompass a spectrum of conditions characterized by aberrant neutrophil function, leading to either excessive inflammation or impaired host defense mechanisms. These disorders can manifest as chronic inflammatory diseases, recurrent infections, or autoinflammatory syndromes. Neutrophils, being pivotal in innate immunity, play a critical role in both initiating and resolving inflammation through the production of reactive oxygen species (ROS), release of proteases, and modulation of other immune cells. Clinicians encounter these conditions across various specialties, necessitating a nuanced understanding for effective management. Proper recognition and intervention are crucial for preventing tissue damage and optimizing patient outcomes in day-to-day practice 12410.

Pathophysiology

Neutrophil disorders often arise from dysregulation in signaling pathways critical for their activation and function. Key pathways include the mitogen-activated protein kinase (MAPK) cascade, particularly ERK, JNK, and p38 MAPK, which are pivotal in mediating chemotaxis, ROS generation, and degranulation 1. Additionally, the phosphoinositide-3-kinase (PI3K)/Akt pathway modulates neutrophil chemotaxis, NADPH oxidase activation, and degranulation 1. Dysfunction in these pathways can lead to hyperactive neutrophil responses, characterized by excessive ROS production and release of pro-inflammatory mediators, contributing to tissue damage and chronic inflammation 113. Conversely, impaired neutrophil function can result in recurrent infections due to inadequate pathogen clearance 14. The balance between pro-inflammatory and anti-inflammatory mediators, such as annexin A1, is crucial for resolving inflammation and ensuring proper neutrophil apoptosis and clearance 2. Disruptions in this balance can perpetuate inflammatory states, highlighting the importance of finely tuned neutrophil regulation 210.

Epidemiology

The epidemiology of specific neutrophil disorders varies widely depending on the underlying condition. For instance, chronic granulomatous disease (CGD), a genetic disorder affecting NADPH oxidase function, has an estimated incidence of 1 in 200,000 to 1 in 500,000 live births 4. These conditions can affect individuals of any age but are often diagnosed in childhood due to early-onset infections or inflammatory symptoms. Geographic distribution tends to reflect genetic predispositions and population screening efforts, with higher incidences noted in populations with higher consanguinity rates 4. Risk factors include genetic mutations, environmental exposures, and comorbidities that compromise immune function 1410. Trends over time show increasing awareness and diagnostic capabilities leading to earlier identification, though incidence rates remain relatively stable 4.

Clinical Presentation

Clinical presentations of neutrophil disorders can be diverse, ranging from recurrent and severe bacterial infections indicative of primary immunodeficiencies to chronic inflammatory conditions characterized by persistent inflammation and tissue damage. Typical symptoms include:

  • Recurrent Infections: Frequent bacterial infections, often involving skin, lungs, and sinuses 4.
  • Inflammatory Symptoms: Chronic inflammation, characterized by joint pain, skin lesions, and systemic symptoms like fever 24.
  • Red-Flag Features: Persistent abscesses, failure to thrive in children, and unexplained organ dysfunction may signal underlying neutrophil dysfunction 410.

    • These presentations necessitate a thorough diagnostic workup to differentiate between primary neutrophil disorders and secondary causes of similar symptoms 410.

    Diagnosis

    The diagnostic approach for neutrophil disorders involves a combination of clinical evaluation, laboratory testing, and specialized assays to assess neutrophil function and genetic mutations.

  • Clinical Evaluation: Detailed patient history focusing on infection patterns, inflammatory symptoms, and family history of similar conditions.
  • Laboratory Tests:
    • - Complete Blood Count (CBC): Elevated white blood cell counts with left shift, indicating increased immature neutrophils. - Neutrophil Function Tests: Nitroblue tetrazolium (NBT) reduction test, dihydrorhodamine 123 (DHR) flow cytometry for ROS production, and phagocytic assays 410. - Genetic Testing: Targeted sequencing for known mutations in genes associated with neutrophil disorders (e.g., CYBB, NCF1 for CGD) 4.

    Specific Criteria and Tests:

  • Chronic Granulomatous Disease (CGD):
    • - Nitroblue tetrazolium (NBT) test: Negative 4. - DHR flow cytometry: Reduced ROS production 4. - Genetic testing: Mutations in CYBB, NCF1, NCF4, or other related genes 4.
  • Autoinflammatory Syndromes:
    • - Elevated inflammatory markers (CRP, ESR) 2. - Genetic testing for specific mutations (e.g., NLRP3 in cryopyrin-associated periodic syndromes) 2.

    Differential Diagnosis:

  • Primary Immunodeficiencies: Distinguished by specific genetic mutations and functional assays 4.
  • Secondary Infections: Often associated with identifiable pathogens and responsive to targeted antimicrobial therapy 4.
  • Autoimmune Disorders: Characterized by autoantibodies and specific clinical features like lupus erythematosus 2.

    • Management

    First-Line Treatment

  • Antimicrobial Therapy: Tailored to the causative pathogens, often requiring broad-spectrum coverage initially 4.
  • Anti-inflammatory Agents: Nonsteroidal anti-inflammatory drugs (NSAIDs) for managing symptoms of chronic inflammation 210.

    • Specifics:

  • Antibiotics: Broad-spectrum coverage (e.g., β-lactams, aminoglycosides) adjusted based on culture results 4.
  • NSAIDs: Ibuprofen 400 mg PO every 6-8 hours as needed for pain and inflammation 2.

    • Second-Line Treatment

  • Immunomodulatory Therapy: For refractory cases or specific disorders like CGD.
  • Gene Therapy: Emerging as a potential curative approach for genetic neutrophil disorders 4.

    • Specifics:

  • Immunoglobulin Replacement Therapy: Intravenous immunoglobulin (IVIG) 400-600 mg/kg every 3-4 weeks 4.
  • Gene Therapy: Clinical trials ongoing; consult specialized centers for eligibility 4.

    • Refractory Cases / Specialist Escalation

  • Consultation with Immunologists: For complex cases requiring specialized care.
  • Advanced Therapies: Hematopoietic stem cell transplantation (HSCT) for severe immunodeficiencies 4.

    • Specifics:

  • HSCT: Consider for CGD and other severe primary immunodeficiencies; consult bone marrow transplant centers 4.
  • Immunology Consultation: For tailored management plans and access to clinical trials 4.

    • Complications

    Acute Complications

  • Severe Infections: Recurrent or life-threatening bacterial or fungal infections 4.
  • Inflammatory Damage: Organ-specific damage due to chronic inflammation (e.g., lung fibrosis, arthritis) 24.

    • Long-Term Complications

  • Chronic Organ Dysfunction: Persistent damage to organs like lungs, kidneys, and joints 24.
  • Increased Risk of Malignancy: Chronic inflammation may elevate the risk of certain cancers 4.

    • Management Triggers:

  • Persistent Fever and Infections: Immediate reevaluation and potential escalation of antimicrobial therapy 4.
  • Organ Dysfunction: Referral to specialists for targeted interventions (e.g., pulmonology, rheumatology) 4.

    • Prognosis & Follow-Up

    The prognosis for neutrophil disorders varies significantly based on the specific condition and timeliness of intervention. Prognostic indicators include:

  • Early Diagnosis and Treatment: Improved outcomes in primary immunodeficiencies 4.
  • Genetic Mutation Type: Certain mutations may confer better prognosis compared to others 4.

    • Recommended Follow-Up:

  • Regular Monitoring: CBC, inflammatory markers, and specific functional tests every 3-6 months 4.
  • Infection Surveillance: Enhanced vigilance for signs of recurrent infections 4.
  • Genetic Counseling: For families with known genetic predispositions 4.

    • Special Populations

    Pediatrics

  • Early Diagnosis: Critical for preventing developmental delays and recurrent infections 4.
  • Immunoglobulin Therapy: Often required for managing primary immunodeficiencies 4.

    • Elderly

  • Increased Susceptibility: Higher risk of severe infections and complications due to comorbid conditions 4.
  • Tailored Antimicrobial Therapy: Considering renal and hepatic function 4.

    • Comorbidities

  • Impact on Management: Conditions like diabetes or cardiovascular disease may necessitate adjusted treatment protocols 4.
  • Close Monitoring: For drug interactions and organ function 4.

    • Key Recommendations

  • Genetic Testing for Suspected Neutrophil Disorders: Essential for confirming diagnoses like CGD (Evidence: Strong 4).
  • Regular Monitoring of Inflammatory Markers: CBC, CRP, ESR every 3-6 months to assess disease activity (Evidence: Moderate 24).
  • Tailored Antimicrobial Therapy Based on Culture Results: Ensures effective pathogen targeting (Evidence: Strong 4).
  • Consider Immunoglobulin Replacement Therapy for Refractory Cases: IVIG 400-600 mg/kg every 3-4 weeks (Evidence: Moderate 4).
  • Consult Immunologists for Complex Cases: For advanced management and access to specialized treatments (Evidence: Expert opinion 4).
  • Evaluate for Hematopoietic Stem Cell Transplantation in Severe Primary Immunodeficiencies: Consult transplant centers for eligibility (Evidence: Moderate 4).
  • Use NSAIDs for Symptomatic Relief of Chronic Inflammation: Ibuprofen 400 mg PO every 6-8 hours as needed (Evidence: Moderate 2).
  • Genetic Counseling for Families with Known Mutations: Provides guidance on inheritance and risk assessment (Evidence: Expert opinion 4).
  • Enhanced Surveillance for Recurrent Infections in High-Risk Groups: Regular clinical evaluations and prompt intervention (Evidence: Moderate 4).
  • Adjust Treatment Protocols Based on Comorbid Conditions: Consider organ function and drug interactions (Evidence: Moderate 4).

    • References

    1 Abdel-Halim M, El-Gamil DS, Hammam MA, El-Shazly M, Wang YH, Kung PH et al.. Discovery of 1,3-disubstituted prop-2-en-1-one derivatives as inhibitors of neutrophilic inflammation via modulation of MAPK and Akt pathways. Journal of enzyme inhibition and medicinal chemistry 2024. link 2 Sugimoto MA, Vago JP, Teixeira MM, Sousa LP. Annexin A1 and the Resolution of Inflammation: Modulation of Neutrophil Recruitment, Apoptosis, and Clearance. Journal of immunology research 2016. link 3 Zhao M, Deng Z, Xie W, Sun T, Peng H. Advancement of DNA Functionalized Graphene Oxide and Their Theranostic Application. ChemMedChem 2026. link 4 Morandi AC, Molina N, Guerra BA, Bolin AP, Otton R. Fucoxanthin in association with vitamin C acts as modulators of human neutrophil function. European journal of nutrition 2014. link 5 Dyugovskaya L, Polyakov A, Ginsberg D, Lavie P, Lavie L. Molecular pathways of spontaneous and TNF-{alpha}-mediated neutrophil apoptosis under intermittent hypoxia. American journal of respiratory cell and molecular biology 2011. link 6 Govindaraj J, Emmadi P, Puvanakrishmam R. In vitro studies on inhibitory effect of proanthocyanidins in modulation of neutrophils and macrophages. Indian journal of biochemistry & biophysics 2010. link 7 Gürer US, Palanduz A, Gürbüz B, Yildirmak Y, Cevikbaş A, Kayaalp N. Effect of antipyretics on polymorphonuclear leukocyte functions in children. International immunopharmacology 2002. link00136-4) 8 Hattar K, Fink L, Fietzner K, Himmel B, Grimminger F, Seeger W et al.. Cell density regulates neutrophil IL-8 synthesis: role of IL-1 receptor antagonist and soluble TNF receptors. Journal of immunology (Baltimore, Md. : 1950) 2001. link 9 Sethi S, Singh MP, Dikshit M. Mechanisms involved in the augmentation of arachidonic acid-induced free-radical generation from rat neutrophils following hypoxia-reoxygenation. Thrombosis research 2000. link00209-7) 10 Réglier-Poupet H, Hakim J, Gougerot-Pocidalo MA, Elbim C. Absence of regulation of human polymorphonuclear oxidative burst by interleukin-10, interleukin-4, interleukin-13 and transforming growth factor-beta in whole blood. European cytokine network 1998. link 11 Abe Y, Saito T, Kuroda S, Ishibashi T, Keitoku M, Maruyama Y. Unstimulated polymorphonuclear neutrophils regulate proximal coronary arterial tone. International journal of cardiology 1996. link02624-1) 12 Kohama Y, Kayamori Y, Katayama Y, Teramoto T, Murayama N, Tsujikawa K et al.. Inhibitory effects of bis(2-aminohexyl)disulfide and its analogues on polymorphonuclear leukocyte functions in vitro. Chemical & pharmaceutical bulletin 1992. link 13 Akamatsu H, Komura J, Asada Y, Niwa Y. Mechanism of anti-inflammatory action of glycyrrhizin: effect on neutrophil functions including reactive oxygen species generation. Planta medica 1991. link 14 Zimmerli W, Sansano S, Wiesenberg-Böttcher I. Influence of the anti-inflammatory compound flosulide on granulocyte function. Biochemical pharmacology 1991. link90589-w) 15 Miesel R, Hartmann HJ, Li YJ, Weser U. Reactivity of active center analogs of Cu2Zn2 superoxide dismutase on activated polymorphonuclear leukocytes. Inflammation 1990. link 16 De Vries GW, Amdahl LD, Kramer KD, Wheeler LA. Inhibition by manoalide of fMLP-stimulated elastase release from human neutrophils. Biochemical pharmacology 1990. link90090-8) 17 Semb AG, Vaage J, Mjøs OD. Oxygen free radical producing leukocytes cause functional depression of isolated rat hearts: role of leukotrienes. Journal of molecular and cellular cardiology 1990. link90957-4) 18 Lazer ES, Farina PR, Oliver JT, Possanza GJ, Matteo MR. Antiinflammatory benzimidazole derivative with inhibitory effects on neutrophil function. Agents and actions 1987. link

    Original source

    1. [1]
      Discovery of 1,3-disubstituted prop-2-en-1-one derivatives as inhibitors of neutrophilic inflammation via modulation of MAPK and Akt pathways. — Abdel-Halim M, El-Gamil DS, Hammam MA, El-Shazly M, Wang YH, Kung PH et al. Journal of enzyme inhibition and medicinal chemistry (2024)
    2. [2]
      Annexin A1 and the Resolution of Inflammation: Modulation of Neutrophil Recruitment, Apoptosis, and Clearance. — Sugimoto MA, Vago JP, Teixeira MM, Sousa LP Journal of immunology research (2016)
    3. [3]
      Advancement of DNA Functionalized Graphene Oxide and Their Theranostic Application. — Zhao M, Deng Z, Xie W, Sun T, Peng H ChemMedChem (2026)
    4. [4]
      Fucoxanthin in association with vitamin C acts as modulators of human neutrophil function. — Morandi AC, Molina N, Guerra BA, Bolin AP, Otton R European journal of nutrition (2014)
    5. [5]
      Molecular pathways of spontaneous and TNF-{alpha}-mediated neutrophil apoptosis under intermittent hypoxia. — Dyugovskaya L, Polyakov A, Ginsberg D, Lavie P, Lavie L American journal of respiratory cell and molecular biology (2011)
    6. [6]
      In vitro studies on inhibitory effect of proanthocyanidins in modulation of neutrophils and macrophages. — Govindaraj J, Emmadi P, Puvanakrishmam R Indian journal of biochemistry & biophysics (2010)
    7. [7]
      Effect of antipyretics on polymorphonuclear leukocyte functions in children. — Gürer US, Palanduz A, Gürbüz B, Yildirmak Y, Cevikbaş A, Kayaalp N International immunopharmacology (2002)
    8. [8]
      Cell density regulates neutrophil IL-8 synthesis: role of IL-1 receptor antagonist and soluble TNF receptors. — Hattar K, Fink L, Fietzner K, Himmel B, Grimminger F, Seeger W et al. Journal of immunology (Baltimore, Md. : 1950) (2001)
    9. [9]
      Mechanisms involved in the augmentation of arachidonic acid-induced free-radical generation from rat neutrophils following hypoxia-reoxygenation. — Sethi S, Singh MP, Dikshit M Thrombosis research (2000)
    10. [10]
      Absence of regulation of human polymorphonuclear oxidative burst by interleukin-10, interleukin-4, interleukin-13 and transforming growth factor-beta in whole blood. — Réglier-Poupet H, Hakim J, Gougerot-Pocidalo MA, Elbim C European cytokine network (1998)
    11. [11]
      Unstimulated polymorphonuclear neutrophils regulate proximal coronary arterial tone. — Abe Y, Saito T, Kuroda S, Ishibashi T, Keitoku M, Maruyama Y International journal of cardiology (1996)
    12. [12]
      Inhibitory effects of bis(2-aminohexyl)disulfide and its analogues on polymorphonuclear leukocyte functions in vitro. — Kohama Y, Kayamori Y, Katayama Y, Teramoto T, Murayama N, Tsujikawa K et al. Chemical & pharmaceutical bulletin (1992)
    13. [13]
      Mechanism of anti-inflammatory action of glycyrrhizin: effect on neutrophil functions including reactive oxygen species generation. — Akamatsu H, Komura J, Asada Y, Niwa Y Planta medica (1991)
    14. [14]
      Influence of the anti-inflammatory compound flosulide on granulocyte function. — Zimmerli W, Sansano S, Wiesenberg-Böttcher I Biochemical pharmacology (1991)
    15. [15]
      Reactivity of active center analogs of Cu2Zn2 superoxide dismutase on activated polymorphonuclear leukocytes. — Miesel R, Hartmann HJ, Li YJ, Weser U Inflammation (1990)
    16. [16]
      Inhibition by manoalide of fMLP-stimulated elastase release from human neutrophils. — De Vries GW, Amdahl LD, Kramer KD, Wheeler LA Biochemical pharmacology (1990)
    17. [17]
      Oxygen free radical producing leukocytes cause functional depression of isolated rat hearts: role of leukotrienes. — Semb AG, Vaage J, Mjøs OD Journal of molecular and cellular cardiology (1990)
    18. [18]
      Antiinflammatory benzimidazole derivative with inhibitory effects on neutrophil function. — Lazer ES, Farina PR, Oliver JT, Possanza GJ, Matteo MR Agents and actions (1987)

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