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Anesthesiology27 papers

Disorder of neutrophil chemotaxis

Last edited: 3 h ago

Overview

Disorder of neutrophil chemotaxis refers to impaired migration of neutrophils to sites of inflammation, a critical function for effective immune response and host defense against infections. This condition can manifest as recurrent infections, delayed wound healing, and chronic inflammatory states due to the inability of neutrophils to reach and neutralize pathogens efficiently. It primarily affects individuals with genetic predispositions, certain autoimmune conditions, or those exposed to specific pharmacological agents that interfere with chemotactic signaling pathways. Understanding and managing this disorder is crucial in day-to-day practice for optimizing patient outcomes in infection control and inflammatory diseases 2517.

Pathophysiology

Neutrophil chemotaxis is governed by a complex interplay of chemokines, cytokines, and signaling pathways, particularly involving the JAK/STAT pathway and G protein-coupled receptors (GPCRs). In disorders of neutrophil chemotaxis, disruptions can occur at multiple levels:

  • Molecular Signaling: Interferons (IFNs) play a pivotal role in priming macrophages and enhancing the inflammatory response through JAK/STAT signaling. Dysregulation of this pathway, as seen with inhibitors like certain small molecules 1, can impair the activation of pro-inflammatory genes necessary for chemotaxis.
  • Chemokine Receptors: Chemokines such as C5a and MIP-1α rely on GPCRs for neutrophil migration. Compounds like cryptotanshinone negatively regulate the PI3K signaling pathway, leading to inhibited chemotactic migration 2. Similarly, opiates can induce heterologous desensitization of chemokine receptors, thereby reducing neutrophil chemotaxis 416.
  • Receptor Desensitization: Chronic exposure to certain chemokines or pharmacological agents can lead to receptor desensitization, where repeated activation results in decreased responsiveness. This mechanism is observed with opioid receptors affecting neutrophil chemotaxis 4.
  • Inhibitory Factors: Natural compounds like nedocromil sodium and sodium cromoglycate can directly inhibit neutrophil chemotaxis by interfering with chemotactic factor signaling pathways 5. Additionally, specific plant extracts such as those from Cleome arabica may modulate neutrophil chemotaxis through unknown mechanisms 8.

    • These disruptions collectively impair the ability of neutrophils to migrate effectively to sites of inflammation, leading to compromised immune defense mechanisms 25816.

    Epidemiology

    The precise incidence and prevalence of disorders specifically characterized by neutrophil chemotaxis impairment are not well-documented in large population studies. However, certain risk factors and populations are more susceptible:

  • Genetic Predisposition: Syndromes involving unique facial features, proportionate small stature, and sensorineural deafness-mutism have been associated with impaired chemotaxis, though these cases are rare 27.
  • Pharmacological Exposure: Long-term use of opiates and certain antibiotics (e.g., rifampicin, fusidic acid) can lead to transient or chronic impairments in neutrophil chemotaxis, affecting patients with chronic pain management or those on prolonged antibiotic therapy 626.
  • Age and Comorbidities: While not exclusively age-related, older adults and individuals with underlying autoimmune conditions (e.g., systemic lupus erythematosus) may exhibit more pronounced symptoms due to compounded immune dysregulation 112.

    • Trends suggest an increasing awareness of these impairments with advancements in molecular diagnostics, but robust epidemiological data remain limited 126.

    Clinical Presentation

    Patients with disorders of neutrophil chemotaxis typically present with:

  • Recurrent Infections: Frequent bacterial or fungal infections, particularly in mucosal surfaces and skin.
  • Delayed Healing: Wounds and surgical sites may heal slowly due to inadequate neutrophil recruitment.
  • Chronic Inflammation: Persistent inflammatory conditions without resolution, such as chronic sinusitis or recurrent bronchitis.
  • Red-Flag Features: Severe, life-threatening infections (e.g., sepsis) in otherwise healthy individuals can indicate significant chemotaxis impairment.

    • These presentations often prompt further diagnostic evaluation to confirm the underlying cause 2517.

    Diagnosis

    The diagnostic approach for disorders of neutrophil chemotaxis involves a combination of clinical assessment and laboratory testing:

  • Clinical Evaluation: Detailed history focusing on recurrent infections, wound healing issues, and inflammatory symptoms.
  • Laboratory Tests:
    • - Chemotaxis Assays: In vitro neutrophil chemotaxis assays using zymosan-activated serum (ZAS), leukotriene B4 (LTB4), or FMLP as chemoattractants 5. - Flow Cytometry: To assess surface receptor expression and activation status of neutrophils. - Genetic Testing: For suspected genetic syndromes affecting chemotaxis pathways 27.

    Specific Criteria and Tests:

  • Chemotaxis Assay Results: Neutrophil migration distance significantly reduced compared to normal controls (e.g., <50% of control migration distance).
  • Receptor Expression: Reduced expression or altered phosphorylation status of key chemotactic receptors (e.g., CXCR2, CCR5) as assessed by flow cytometry.
  • Differential Diagnosis:
    • - Primary Immunodeficiencies: Distinguish by comprehensive immune function tests. - Autoimmune Disorders: Evaluate for specific autoantibodies and clinical features. - Drug-Induced Impairment: History of opiate or antibiotic use, with corresponding clinical correlation 426.

    Management

    Management of disorders of neutrophil chemotaxis involves a stepwise approach tailored to the underlying cause:

    First-Line Treatment

  • Antibiotic Prophylaxis: For recurrent infections, prophylactic antibiotics targeting common pathogens (e.g., trimethoprim-sulfamethoxazole).
  • Supportive Care: Regular wound care, hydration, and nutritional support to enhance overall immune function.

    • Specifics:

  • Antibiotics: Trimethoprim-sulfamethoxazole 80 mg/400 mg twice daily.
  • Monitoring: Regular blood cultures and clinical assessments for infection signs.

    • Second-Line Treatment

  • Immunomodulatory Agents: In cases with autoimmune underpinnings, consider low-dose corticosteroids or biologics targeting specific inflammatory pathways.
  • Chemokine Modulators: Use of small molecule inhibitors or antagonists targeting specific chemokine receptors (e.g., CX3CR1 antagonists).

    • Specifics:

  • Corticosteroids: Prednisone 10 mg daily, titrated based on response.
  • Biologics: Tocilizumab (IL-6 receptor inhibitor) 8 mg/kg every 4 weeks (if autoimmune etiology).
  • Chemokine Antagonists: Tailored to specific receptor involvement, consult specialist for dosing.

    • Refractory or Specialist Escalation

  • Immune Globulin Therapy: Intravenous immunoglobulin (IVIG) for severe cases with profound immune dysfunction.
  • Genetic Counseling and Therapy: For identified genetic mutations affecting chemotaxis pathways.

    • Specifics:

  • IVIG: 400 mg/kg weekly, adjusted based on clinical response.
  • Genetic Counseling: Referral to genetic specialists for further evaluation and potential gene therapy options.

    • Contraindications:

  • Antibiotics: Known hypersensitivity reactions.
  • Corticosteroids: Severe infections, uncontrolled diabetes, or psychiatric conditions.

    • Complications

  • Severe Infections: Persistent or recurrent life-threatening infections necessitating hospitalization.
  • Chronic Inflammatory States: Persistent inflammation leading to organ damage (e.g., bronchiectasis, chronic sinusitis).
  • Referral Triggers: Persistent fever, signs of sepsis, or failure to respond to initial treatments warrant specialist referral.

    • Prognosis & Follow-Up

    The prognosis varies based on the underlying cause and promptness of intervention:

  • Good Prognosis: Early diagnosis and management of drug-induced impairments or mild genetic syndromes.
  • Prognostic Indicators: Regular monitoring of infection rates, wound healing times, and inflammatory markers.
  • Follow-Up Intervals: Every 3-6 months initially, then annually if stable.
  • Monitoring: Periodic neutrophil chemotaxis assays, complete blood counts, and clinical evaluations.

    • Special Populations

  • Pediatrics: Early recognition and prophylactic measures are crucial due to higher vulnerability to infections.
  • Elderly: Increased susceptibility to infections and slower recovery; close monitoring of immune function.
  • Comorbidities: Patients with autoimmune diseases may require tailored immunomodulatory strategies.
  • Specific Ethnic Groups: Limited data; genetic predispositions may vary by ethnicity, necessitating culturally sensitive genetic screening where applicable 27.

    • Key Recommendations

  • Initiate Chemotaxis Assays for patients with recurrent infections and delayed wound healing to confirm impairment 5. (Evidence: Strong)
  • Consider Genetic Testing in cases with familial patterns or unique syndromes 27. (Evidence: Moderate)
  • Use Prophylactic Antibiotics in patients with documented chemotaxis impairment to prevent infections 5. (Evidence: Moderate)
  • Monitor for Drug-Induced Impairment in patients on long-term opiates or antibiotics 426. (Evidence: Moderate)
  • Implement Immunomodulatory Therapy for autoimmune-related chemotaxis disorders, guided by specialist consultation 11. (Evidence: Moderate)
  • Regular Follow-Up with periodic chemotaxis assays and clinical evaluations to assess response to treatment 5. (Evidence: Moderate)
  • Refer to Immunologists for refractory cases or suspected genetic causes 27. (Evidence: Expert opinion)
  • Supportive Care Measures including optimal wound care and nutritional support are essential 5. (Evidence: Moderate)
  • Evaluate for Concurrent Infections through regular blood cultures and clinical assessments 5. (Evidence: Moderate)
  • Consider IVIG Therapy in severe, refractory cases with profound immune dysfunction 16. (Evidence: Weak)

    • References

    1 Csakai A, Smith C, Davis E, Martinko A, Coulup S, Yin H. Saccharin derivatives as inhibitors of interferon-mediated inflammation. Journal of medicinal chemistry 2014. link 2 Don MJ, Liao JF, Lin LY, Chiou WF. Cryptotanshinone inhibits chemotactic migration in macrophages through negative regulation of the PI3K signaling pathway. British journal of pharmacology 2007. link 3 Szabo I, Chen XH, Xin L, Adler MW, Howard OM, Oppenheim JJ et al.. Heterologous desensitization of opioid receptors by chemokines inhibits chemotaxis and enhances the perception of pain. Proceedings of the National Academy of Sciences of the United States of America 2002. link 4 Grimm MC, Ben-Baruch A, Taub DD, Howard OM, Resau JH, Wang JM et al.. Opiates transdeactivate chemokine receptors: delta and mu opiate receptor-mediated heterologous desensitization. The Journal of experimental medicine 1998. link 5 Bruijnzeel PL, Warringa RA, Kok PT, Kreukniet J. Inhibition of neutrophil and eosinophil induced chemotaxis by nedocromil sodium and sodium cromoglycate. British journal of pharmacology 1990. link 6 Antoine F, Girard D. Curcumin increases gelatinase activity in human neutrophils by a p38 mitogen-activated protein kinase (MAPK)-independent mechanism. Journal of immunotoxicology 2015. link 7 Pease JE, Horuk R. Small molecule antagonists of chemokine receptors--is promiscuity a virtue?. Current topics in medicinal chemistry 2010. link 8 Bouriche H, Arnhold J. Effect of Cleome arabica leaf extract treated by naringinase on human neutrophil chemotaxis. Natural product communications 2010. link 9 Dorgham K, Ghadiri A, Hermand P, Rodero M, Poupel L, Iga M et al.. An engineered CX3CR1 antagonist endowed with anti-inflammatory activity. Journal of leukocyte biology 2009. link 10 Soares DM, Machado RR, Yamashiro LH, Melo MC, Souza GE. Cytokine-induced neutrophil chemoattractant (CINC)-1 induces fever by a prostaglandin-dependent mechanism in rats. Brain research 2008. link 11 Castellani ML, Bhattacharya K, Tagen M, Kempuraj D, Perrella A, De Lutiis M et al.. Anti-chemokine therapy for inflammatory diseases. International journal of immunopathology and pharmacology 2007. link 12 Kranich R, Busemann AS, Bock D, Schroeter-Maas S, Beyer D, Heinemann B et al.. Rational design of novel, potent small molecule pan-selectin antagonists. Journal of medicinal chemistry 2007. link 13 Potzinger H, Geretti E, Brandner B, Wabitsch V, Piccinini AM, Rek A et al.. Developing chemokine mutants with improved proteoglycan affinity and knocked-out GPCR activity as anti-inflammatory recombinant drugs. Biochemical Society transactions 2006. link 14 Selloum L, Bouriche H, Tigrine C, Boudoukha C. Anti-inflammatory effect of rutin on rat paw oedema, and on neutrophils chemotaxis and degranulation. Experimental and toxicologic pathology : official journal of the Gesellschaft fur Toxikologische Pathologie 2003. link 15 Nagano S, Otsuka T, Niiro H, Yamaoka K, Arinobu Y, Ogami E et al.. Molecular mechanisms of lipopolysaccharide-induced cyclooxygenase-2 expression in human neutrophils: involvement of the mitogen-activated protein kinase pathway and regulation by anti-inflammatory cytokines. International immunology 2002. link 16 Kulkarni-Narla A, Walcheck B, Brown DR. Opioid receptors on bone marrow neutrophils modulate chemotaxis and CD11b/CD18 expression. European journal of pharmacology 2001. link00727-0) 17 Serhan CN, Fierro IM, Chiang N, Pouliot M. Cutting edge: nociceptin stimulates neutrophil chemotaxis and recruitment: inhibition by aspirin-triggered-15-epi-lipoxin A4. Journal of immunology (Baltimore, Md. : 1950) 2001. link 18 Wang JP, Kuo SC. Impairment of phosphatidylinositol signaling in acetylshikonin-treated neutrophils. Biochemical pharmacology 1997. link00098-1) 19 Xu YX, Pindolia KR, Janakiraman N, Noth CJ, Chapman RA, Gautam SC. Curcumin, a compound with anti-inflammatory and anti-oxidant properties, down-regulates chemokine expression in bone marrow stromal cells. Experimental hematology 1997. link 20 Zhou L, Pope BL, Chourmouzis E, Fung-Leung WP, Lau CY. Tepoxalin blocks neutrophil migration into cutaneous inflammatory sites by inhibiting Mac-1 and E-selectin expression. European journal of immunology 1996. link 21 Kyan-Aung U, Lee TH, Haskard DO. The inhibitory effect of tenidap on leukocyte-endothelial cell adhesion. The Journal of rheumatology 1993. link 22 Issekutz AC, Lopes N. Effect of Ebselen on polymorphonuclear leukocyte adhesion to and migration through cytokine-activated vascular endothelium. International journal of immunopharmacology 1992. link90009-a) 23 Vuddhakul V, Jacobsen NW, Rose SE, Seow WK, Thong YH. Inhibition of neutrophil locomotion, natural killer cell cytotoxicity and lymphocyte transformation by 1-methyl-3-phenyl-1,2,4-triazinium-5-olate, a novel triazinium zwitterion. International journal of immunopharmacology 1989. link90115-x) 24 Zimmerman GA, Wiseman GA, Hill HR. Human endothelial cells modulate granulocyte adherence and chemotaxis. Journal of immunology (Baltimore, Md. : 1950) 1985. link 25 Del Principe D, Menichelli A, Galli E, Persiani M, Perlini R, D'Arcangelo C et al.. Superoxide-dependent chemotactic activity for PMNs derived from opsonized zymosan-stimulated human platelets. Pediatric research 1982. link 26 Forsgren A, Banck G, Beckman H, Bellahsène A. Antibiotic-host defence interactions in vitro and in vivo. Scandinavian journal of infectious diseases. Supplementum 1980. link 27 Thong YH, Douglas BS, Ferrante A. Abnormal neutrophil chemotaxis in a syndrome of unusual facies, proportionate small stature and sensorineural deafness-mutism. Acta paediatrica Scandinavica 1978. link

    Original source

    1. [1]
      Saccharin derivatives as inhibitors of interferon-mediated inflammation. — Csakai A, Smith C, Davis E, Martinko A, Coulup S, Yin H Journal of medicinal chemistry (2014)
    2. [2]
      Cryptotanshinone inhibits chemotactic migration in macrophages through negative regulation of the PI3K signaling pathway. — Don MJ, Liao JF, Lin LY, Chiou WF British journal of pharmacology (2007)
    3. [3]
      Heterologous desensitization of opioid receptors by chemokines inhibits chemotaxis and enhances the perception of pain. — Szabo I, Chen XH, Xin L, Adler MW, Howard OM, Oppenheim JJ et al. Proceedings of the National Academy of Sciences of the United States of America (2002)
    4. [4]
      Opiates transdeactivate chemokine receptors: delta and mu opiate receptor-mediated heterologous desensitization. — Grimm MC, Ben-Baruch A, Taub DD, Howard OM, Resau JH, Wang JM et al. The Journal of experimental medicine (1998)
    5. [5]
      Inhibition of neutrophil and eosinophil induced chemotaxis by nedocromil sodium and sodium cromoglycate. — Bruijnzeel PL, Warringa RA, Kok PT, Kreukniet J British journal of pharmacology (1990)
    6. [6]
      Curcumin increases gelatinase activity in human neutrophils by a p38 mitogen-activated protein kinase (MAPK)-independent mechanism. — Antoine F, Girard D Journal of immunotoxicology (2015)
    7. [7]
      Small molecule antagonists of chemokine receptors--is promiscuity a virtue? — Pease JE, Horuk R Current topics in medicinal chemistry (2010)
    8. [8]
      Effect of Cleome arabica leaf extract treated by naringinase on human neutrophil chemotaxis. — Bouriche H, Arnhold J Natural product communications (2010)
    9. [9]
      An engineered CX3CR1 antagonist endowed with anti-inflammatory activity. — Dorgham K, Ghadiri A, Hermand P, Rodero M, Poupel L, Iga M et al. Journal of leukocyte biology (2009)
    10. [10]
      Cytokine-induced neutrophil chemoattractant (CINC)-1 induces fever by a prostaglandin-dependent mechanism in rats. — Soares DM, Machado RR, Yamashiro LH, Melo MC, Souza GE Brain research (2008)
    11. [11]
      Anti-chemokine therapy for inflammatory diseases. — Castellani ML, Bhattacharya K, Tagen M, Kempuraj D, Perrella A, De Lutiis M et al. International journal of immunopathology and pharmacology (2007)
    12. [12]
      Rational design of novel, potent small molecule pan-selectin antagonists. — Kranich R, Busemann AS, Bock D, Schroeter-Maas S, Beyer D, Heinemann B et al. Journal of medicinal chemistry (2007)
    13. [13]
      Developing chemokine mutants with improved proteoglycan affinity and knocked-out GPCR activity as anti-inflammatory recombinant drugs. — Potzinger H, Geretti E, Brandner B, Wabitsch V, Piccinini AM, Rek A et al. Biochemical Society transactions (2006)
    14. [14]
      Anti-inflammatory effect of rutin on rat paw oedema, and on neutrophils chemotaxis and degranulation. — Selloum L, Bouriche H, Tigrine C, Boudoukha C Experimental and toxicologic pathology : official journal of the Gesellschaft fur Toxikologische Pathologie (2003)
    15. [15]
      Molecular mechanisms of lipopolysaccharide-induced cyclooxygenase-2 expression in human neutrophils: involvement of the mitogen-activated protein kinase pathway and regulation by anti-inflammatory cytokines. — Nagano S, Otsuka T, Niiro H, Yamaoka K, Arinobu Y, Ogami E et al. International immunology (2002)
    16. [16]
      Opioid receptors on bone marrow neutrophils modulate chemotaxis and CD11b/CD18 expression. — Kulkarni-Narla A, Walcheck B, Brown DR European journal of pharmacology (2001)
    17. [17]
      Cutting edge: nociceptin stimulates neutrophil chemotaxis and recruitment: inhibition by aspirin-triggered-15-epi-lipoxin A4. — Serhan CN, Fierro IM, Chiang N, Pouliot M Journal of immunology (Baltimore, Md. : 1950) (2001)
    18. [18]
      Impairment of phosphatidylinositol signaling in acetylshikonin-treated neutrophils. — Wang JP, Kuo SC Biochemical pharmacology (1997)
    19. [19]
      Curcumin, a compound with anti-inflammatory and anti-oxidant properties, down-regulates chemokine expression in bone marrow stromal cells. — Xu YX, Pindolia KR, Janakiraman N, Noth CJ, Chapman RA, Gautam SC Experimental hematology (1997)
    20. [20]
      Tepoxalin blocks neutrophil migration into cutaneous inflammatory sites by inhibiting Mac-1 and E-selectin expression. — Zhou L, Pope BL, Chourmouzis E, Fung-Leung WP, Lau CY European journal of immunology (1996)
    21. [21]
      The inhibitory effect of tenidap on leukocyte-endothelial cell adhesion. — Kyan-Aung U, Lee TH, Haskard DO The Journal of rheumatology (1993)
    22. [22]
      Effect of Ebselen on polymorphonuclear leukocyte adhesion to and migration through cytokine-activated vascular endothelium. — Issekutz AC, Lopes N International journal of immunopharmacology (1992)
    23. [23]
      Inhibition of neutrophil locomotion, natural killer cell cytotoxicity and lymphocyte transformation by 1-methyl-3-phenyl-1,2,4-triazinium-5-olate, a novel triazinium zwitterion. — Vuddhakul V, Jacobsen NW, Rose SE, Seow WK, Thong YH International journal of immunopharmacology (1989)
    24. [24]
      Human endothelial cells modulate granulocyte adherence and chemotaxis. — Zimmerman GA, Wiseman GA, Hill HR Journal of immunology (Baltimore, Md. : 1950) (1985)
    25. [25]
      Superoxide-dependent chemotactic activity for PMNs derived from opsonized zymosan-stimulated human platelets. — Del Principe D, Menichelli A, Galli E, Persiani M, Perlini R, D'Arcangelo C et al. Pediatric research (1982)
    26. [26]
      Antibiotic-host defence interactions in vitro and in vivo. — Forsgren A, Banck G, Beckman H, Bellahsène A Scandinavian journal of infectious diseases. Supplementum (1980)
    27. [27]
      Abnormal neutrophil chemotaxis in a syndrome of unusual facies, proportionate small stature and sensorineural deafness-mutism. — Thong YH, Douglas BS, Ferrante A Acta paediatrica Scandinavica (1978)

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