Clinical efficacy of IgM-enriched immunoglobulin as adjunctive therapy in neonatal and pediatric sepsis: a systematic review and meta-analysis

Background Sepsis is a major cause of mortality and morbidity globally, with around one-quarter of all sepsis-related deaths occurring in children under the age of 5. We conducted a meta-analysis and systematic review of the literature to evaluate the clinical effectiveness of an IgM-enriched immunoglobulin preparation in pediatrics patients and neonates with sepsis. Methods Systematic searches of PubMed, the Cochrane Library and Embase databases were performed in November 2022, with no date limitations, to identify studies in which IgM-enriched immunoglobulin was used as adjunctive therapy in neonatal and pediatric patients with sepsis. Results In total, 15 studies fulfilled the eligibility criteria, 13 neonatal studies and 2 pediatric studies. Pooled estimates from all studies indicated that mortality rates were significantly lower in patients who received treatment with the IgM-enriched immunoglobulin compared with controls (OR 0.41; 95% CI 0.32-0.55). Further analyses in neonatal studies, alone, showed a significant benefit with longer treatment durations (>3 days) vs. the recommended treatment duration (3 days) (OR 0.32; 95% CI 0.22-0.47) vs. (OR 0.61; 95% CI 0.41-0.92). Treatment with IgM-enriched immunoglobulin was associated with a lower mortality risk compared with controls in prospective studies vs. retrospective analyses (OR 0.37; 95% CI 0.27-0.51) vs. (OR 0.73; 95% CI 0.41-1.30). Conclusions This systematic review suggests that adjunctive treatment with IgM-enriched immunoglobulin may reduce the risk of mortality in neonatal and pediatric populations. However, large randomized controlled trials are required to further substantiate and evaluate these findings.

[1]  Fabian Bohländer.  A new hope? Possibilities of therapeutic IgA antibodies in the treatment of inflammatory lung diseases , 2023, Frontiers in Immunology.

[2]  J. H. Lee,et al.  Contemporary Trends in Global Mortality of Sepsis Among Young Infants Less Than 90 Days: A Systematic Review and Meta-Analysis , 2022, Frontiers in Pediatrics.

[3]  G. Grasselli,et al.  Higher levels of IgA and IgG at sepsis onset are associated with higher mortality: results from the Albumin Italian Outcome Sepsis (ALBIOS) trial , 2021, Annals of Intensive Care.

[4]  R. Polin,et al.  Neonatal sepsis definitions from randomised clinical trials , 2021, Pediatric Research.

[5]  C. Sprung,et al.  Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021. , 2021, Critical care medicine.

[6]  Q. Aga,et al.  Pentaglobin (immunoglobulin M-enriched immunoglobulin) as adjuvant therapy for premature and very low-birth-weight neonates with sepsis , 2021, Indian Journal of Pharmacology.

[7]  E. Giamarellos‐Bourboulis,et al.  Treatment with IgM-enriched immunoglobulin in sepsis: a matched case-control analysis. , 2021, Journal of critical care.

[8]  E. Roman-Pognuz,et al.  Kinetics of Immunoglobulins in Septic Shock Patients Treated With an IgM- and IgA-Enriched Intravenous Preparation: An Observational Study , 2021, Frontiers in Medicine.

[9]  Chompoonoot Boonsopa.  Comparison of Adjunctive Treatment with IgMEnriched IVIG and Antibiotics Alone in Treatment of Neonatal Sepsis , 2021, Siriraj Medical Journal.

[10]  F. Raimondi,et al.  IgM and IgA enriched polyclonal immunoglobulins reduce short term mortality in extremely low birth weight infants with sepsis: a retrospective cohort study , 2021 .

[11]  S. Nadel,et al.  Sepsis in children: state-of-the-art treatment , 2021, Therapeutic advances in infectious disease.

[12]  E. Giannoni,et al.  Editorial: Sepsis in Neonates and Children , 2020, Frontiers in Pediatrics.

[13]  M. Girardis,et al.  Best-practice IgM- and IgA-enriched immunoglobulin use in patients with sepsis , 2020, Annals of Intensive Care.

[14]  Y. Masuda,et al.  Low immunoglobulin G level is associated with poor outcomes in patients with sepsis and septic shock. , 2020, Journal of microbiology, immunology, and infection = Wei mian yu gan ran za zhi.

[15]  E. Dinleyici,et al.  Clinical, laboratory features and prognosis of children receiving IgM-enriched immunoglobulin (3 days vs. 5 days) as adjuvant treatment for serious infectious disease in pediatric intensive care unit: a retrospective single-center experience (PIGMENT study) , 2020, Human vaccines & immunotherapeutics.

[16]  Niranjan Kissoon,et al.  Global, regional, and national sepsis incidence and mortality, 1990–2017: analysis for the Global Burden of Disease Study , 2020, The Lancet.

[17]  Deanne K. Thompson,et al.  Short- and Long-Term Neurodevelopmental Outcomes of Very Preterm Infants with Neonatal Sepsis: A Systematic Review and Meta-Analysis , 2019, Children.

[18]  N. Baumgarth,et al.  Secreted IgM: New tricks for an old molecule , 2019, Journal of leukocyte biology.

[19]  Zhen Chen,et al.  The clinical efficacy of intravenous IgM-enriched immunoglobulin (pentaglobin) in sepsis or septic shock: a meta-analysis with trial sequential analysis , 2019, Annals of Intensive Care.

[20]  G. Barbati,et al.  Effects of the timing of administration of IgM- and IgA-enriched intravenous polyclonal immunoglobulins on the outcome of septic shock patients , 2018, Annals of Intensive Care.

[21]  R. Grützmann,et al.  Reduced circulating B cells and plasma IgM levels are associated with decreased survival in sepsis ‐ A meta‐analysis , 2018, Journal of critical care.

[22]  Xiaoming Zhang,et al.  Unique aspects of the perinatal immune system , 2017, Nature Reviews Immunology.

[23]  M. Singer,et al.  Activation-Associated Accelerated Apoptosis of Memory B Cells in Critically Ill Patients With Sepsis , 2017, Critical care medicine.

[24]  A. Armaganidis,et al.  Improving outcomes of severe infections by multidrug-resistant pathogens with polyclonal IgM-enriched immunoglobulins. , 2016, Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases.

[25]  S. Larson,et al.  Pediatric sepsis , 2016, Current opinion in pediatrics.

[26]  R. Bellomo,et al.  The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). , 2016, JAMA.

[27]  E. Celaj,et al.  Efficacy of an IgM preparation in the treatment of patients with sepsis: a double-blind randomized clinical trial in a pediatric intensive care unit , 2015, South Eastern European Journal of Public Health.

[28]  Derek Wheeler,et al.  Global epidemiology of pediatric severe sepsis: the sepsis prevalence, outcomes, and therapies study. , 2015, American journal of respiratory and critical care medicine.

[29]  R. Pisanti,et al.  Role of immunoglobulins in neonatal sepsis , 2014, Translational medicine @ UniSa.

[30]  J. Huebner,et al.  In vitro and in vivo activity of hyperimmune globulin preparations against multiresistant nosocomial pathogens , 2014, Infection.

[31]  R. Herrán-Monge,et al.  Immunoglobulins IgG1, IgM and IgA: a synergistic team influencing survival in sepsis , 2014, Journal of internal medicine.

[32]  F. Raimondi,et al.  The influence of IgM-enriched immunoglobulin therapy on neonatal mortality and hematological variables in newborn infants with blood culture-proven sepsis. , 2014, Turkish Journal of Pediatrics.

[33]  U. Dilmen,et al.  Role of Pentoxifylline and/or IgM-Enriched Intravenous Immunoglobulin in the Management of Neonatal Sepsis , 2014, American Journal of Perinatology.

[34]  H. Davies,et al.  Early-Onset Neonatal Sepsis , 2014, Clinical Microbiology Reviews.

[35]  H. Goossens,et al.  Antibiotic resistance—the need for global solutions , 2013, BDJ.

[36]  A. Armaganidis,et al.  Kinetics of circulating immunoglobulin M in sepsis: relationship with final outcome , 2013, Critical Care.

[37]  F. Raimondi,et al.  Are IgM-enriched immunoglobulins an effective adjuvant in septic VLBW infants? , 2013, Italian Journal of Pediatrics.

[38]  L. Dans,et al.  Intravenous immunoglobulin for treating sepsis, severe sepsis and septic shock. , 2013, The Cochrane database of systematic reviews.

[39]  B. C. Hellerud,et al.  Polyvalent immunoglobulin significantly attenuated the formation of IL-1β in Escherichia coli-induced sepsis in pigs. , 2013, Immunobiology.

[40]  M. Carneiro-Sampaio,et al.  IgG Placental Transfer in Healthy and Pathological Pregnancies , 2011, Clinical & developmental immunology.

[41]  B. Farrell,et al.  Treatment of neonatal sepsis with intravenous immune globulin. , 2011, The New England journal of medicine.

[42]  J. Vincent,et al.  &ggr;-GLOBULIN LEVELS IN PATIENTS WITH COMMUNITY-ACQUIRED SEPTIC SHOCK , 2009, Shock.

[43]  J. Hoffmann.  Neutrophil CD64: a diagnostic marker for infection and sepsis , 2009, Clinical chemistry and laboratory medicine.

[44]  A. Nierhaus,et al.  Use of polyclonal immunoglobulins as adjunctive therapy for sepsis or septic shock * , 2007, Critical care medicine.

[45]  A. Lupp,et al.  EFFECTS OF IGM-ENRICHED SOLUTION ON POLYMORPHONUCLEAR NEUTROPHIL FUNCTION, BACTERIAL CLEARANCE, AND LUNG HISTOLOGY IN ENDOTOXEMIA , 2007, Shock.

[46]  A. El-Nawawy,et al.  Intravenous polyclonal immunoglobulin administration to sepsis syndrome patients: a prospective study in a pediatric intensive care unit. , 2005, Journal of tropical pediatrics.

[47]  J. Carcillo,et al.  Scope and epidemiology of pediatric sepsis , 2005, Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.

[48]  J. Rello,et al.  EFFECTS OF HIGH-DOSE OF INTRAVENOUS IMMUNOGLOBULIN AND ANTIBIOTICS ON SURVIVAL FOR SEVERE SEPSIS UNDERGOING SURGERY , 2005, Shock.

[49]  B. Vohr,et al.  Neurodevelopmental and growth impairment among extremely low-birth-weight infants with neonatal infection. , 2004, JAMA.

[50]  Gilles Clermont,et al.  The epidemiology of severe sepsis in children in the United States. , 2003, American journal of respiratory and critical care medicine.

[51]  L. Hammarström,et al.  Relative neutralizing activity in polyspecific IgM, IgA, and IgG preparations against group A streptococcal superantigens. , 2000, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[52]  Wulf,et al.  Bacterial lipopolysaccharide (LPS)‐specific antibodies in commercial human immunoglobulin preparations: superior antibody content of an IgM‐enriched product , 1998, Clinical and experimental immunology.

[53]  H. Bahakim,et al.  Comparison of two types of intravenous immunoglobulins in the treatment of neonatal sepsis , 1995, Clinical and experimental immunology.

[54]  M. Yurdakök,et al.  The use of IgM-enriched intravenous immunoglobulin for the treatment of neonatal sepsis in preterm infants. , 1993, The Turkish journal of pediatrics.

[55]  I. Schedel,et al.  Treatment of gram-negative septic shock with an immunoglobulin preparation: a prospective, randomized clinical trial. , 1993 .

[56]  M. H. Zaidi,et al.  IgM-enriched intravenous immunoglobulin therapy in neonatal sepsis. , 1988, American journal of diseases of children.

[57]  M. Ballow,et al.  Development of The Immune System in Very Low Birth Weight (Less than 1500 g) Premature Infants: Concentrations of Plasma Immunoglobulins and Patterns of Infections , 1986, Pediatric Research.

[58]  S. Bandyopadhyay,et al.  A Study to See The Efficacy of IGM Enriched IVIG in Reducing Mortality in Neonatal Sepsis , 2019 .

[59]  K. Werdan,et al.  Serum IgG levels and mortality in patients with severe sepsis and septic shock , 2016, Medizinische Klinik - Intensivmedizin und Notfallmedizin.

[60]  B. Stoll,et al.  Neonatal sepsis: progress towards improved outcomes. , 2014, The Journal of infection.

[61]  A. Ohlsson,et al.  Intravenous immunoglobulin for suspected or subsequently proven infection in neonates. , 2010, The Cochrane database of systematic reviews.

[62]  P. Myrianthefs,et al.  Gamma-globulin levels in patients with community-acquired septic shock. , 2010, Shock.