Intravenous immunoglobulin for treating sepsis, severe sepsis and septic shock

  • Conclusions changed
  • Review
  • Intervention

Authors

  • Marissa M Alejandria,

    Corresponding author
    1. Department of Medicine, Philippine General Hospital, University of the Philippines, Department of Clinical Epidemiology and Section of Infectious Diseases, Manila, Philippines
    • Marissa M Alejandria, Department of Clinical Epidemiology and Section of Infectious Diseases, Department of Medicine, Philippine General Hospital, University of the Philippines, Manila, 1000, Philippines. issa.alejandria@gmail.com.

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  • Mary Ann D Lansang,

    1. Department of Medicine, Philippine General Hospital, University of the Philippines, Department of Clinical Epidemiology and Section of Infectious Diseases, Manila, Philippines
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  • Leonila F Dans,

    1. University of the Philippines College of Medicine, Department of Pediatrics, Manila, National Capital Region, Philippines
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  • Jacinto Blas Mantaring III

    1. University of the Philippines, Section of Newborn Medicine, Department of Pediatrics, Manila, Philippines
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Abstract

Background

Mortality from sepsis and septic shock remains high. Results of trials on intravenous immunoglobulins (IVIG) as adjunctive therapy for sepsis have been conflicting. This is an update of a Cochrane review that was originally published in 1999 and updated in 2002 and 2010.

Objectives

To estimate the effects of IVIG as adjunctive therapy in patients with bacterial sepsis or septic shock on mortality, bacteriological failure rates, and duration of stay in hospital.

Search methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 6), MEDLINE (1966 to December 2012), and EMBASE (1988 to December 2012). We contacted investigators in the field for unpublished data. The original search was performed in 1999 and updated in 2002 and 2008.

Selection criteria

We included randomized controlled trials comparing IVIG (monoclonal or polyclonal) with placebo or no intervention in patients of any age with bacterial sepsis or septic shock.

Data collection and analysis

Two authors independently assessed the studies for inclusion and undertook methodologic quality assessment and data abstraction. We conducted pre-specified subgroup analyses by type of immunoglobulin preparation.

Main results

We included 43 studies that met our inclusion criteria in this updated review out of 88 potentially eligible studies. The studies included a large polyclonal IVIG trial in neonates that was concluded in 2011 and classified as ongoing in the 2010 version of this review. Pooled analysis of polyclonal and monoclonal IVIG was not done due to clinical heterogeneity. Subgroup analysis of 10 polyclonal IVIG trials (n = 1430) and seven trials on IgM-enriched polyclonal IVIG (n = 528) showed significant reductions in mortality in adults with sepsis compared to placebo or no intervention (relative risk (RR) 0.81; 95% confidence interval (CI) 0.70 to 0.93 and RR 0.66; 95% CI 0.51 to 0.85, respectively). Subgroup analysis of polyclonal IVIG in neonates, which now includes the recently concluded large polyclonal IVIG trial, showed no significant reduction in mortality for standard IVIG (RR 1.00; 95% CI 0.92 to 1.08; five trials, n = 3667) and IgM-enriched polyclonal IVIG (RR 0.57; 95% CI 0.31 to 1.04; three trials, n = 164). Sensitivity analysis of trials with low risk of bias showed no reduction in mortality with polyclonal IVIG in adults (RR 0.97; 95% CI 0.81 to 1.15; five trials, n = 945) and neonates (RR 1.01; 95% CI 0.93 to 1.09; three trials, n = 3561). Mortality was not reduced among patients (eight trials, n = 4671) who received anti-endotoxin antibodies (RR 0.99; 95% CI 0.91 to1.06) while anti-cytokines (nine trials, n = 7893) demonstrated a marginal reduction in mortality (RR 0.92; 95% CI 0.86 to 0.97).

Authors' conclusions

Polyclonal IVIG reduced mortality among adults with sepsis but this benefit was not seen in trials with low risk of bias. Among neonates with sepsis, there is sufficient evidence that standard polyclonal IVIG, as adjunctive therapy, does not reduce mortality based on the inclusion of the large polyclonal IVIG trial on neonates. For Ig-M enriched IVIG, the trials on neonates and adults were small and the totality of the evidence is still insufficient to support a robust conclusion of benefit. Adjunctive therapy with monoclonal IVIGs remains experimental.

Plain language summary

Intravenous immunoglobulins for treating patients with severe sepsis and septic shock

Sepsis is the inflammatory response of the body to severe infection, which can be caused by a variety of micro-organisms including bacteria, viruses and fungi. Signs of sepsis include fever, hypothermia, rapid heart rate and respiration; and a laboratory finding of increased or decreased white blood cell count. Deaths as a result of sepsis and septic shock remain high despite giving antibiotics, especially if the functions of a persons's vital organs such as the lungs, heart and kidneys are affected. Several studies have looked into other agents than antibiotics to help the body fight the effects of sepsis. Intravenous immunoglobulin preparations contain antibodies that help the body to neutralize bacterial toxins. There are two types of preparations. These are polyclonal immunoglobulins that contain several antibodies directed at endotoxin and inflammatory mediators, and monoclonal immunoglobulins which target a specific inflammatory mediator or antigen. Intravenous immunoglobulins are blood products, specifically pooled sera derived from human donor blood.

For this updated Cochrane review, we searched the medical literature databases to January 2012. We included 43 randomized controlled trials (RCTs); 25 were RCTs of polyclonal intravenous immunoglobulins (IVIGs) with 17 in adults (1958 participants) and eight in newborn infants (3831 participants) including a large polyclonal IVIG trial on infants with sepsis that was published in 2011. The remaining 18 trials (a total of 13,413 participants) were of monoclonal antibodies. Both standard and immunoglobulin M (IgM)-enriched polyclonal immunoglobulins decreased the number of deaths in adults but not in infants. However, no reductions in adult deaths were seen with polyclonal IVIG using high quality trials only. Among newborn infants with sepsis, there is definitive evidence that standard polyclonal IVIG does not reduce the number of deaths. In the monoclonal immunoglobulin trials, anti-endotoxin antibodies showed no benefit while the anti-cytokines showed a very small reduction in deaths among adults with sepsis.

The polyclonal immunoglobulin trials in adults were small compared to the trials of monoclonal agents. The reduction in deaths observed with polyclonal IgM-enriched preparations as add-on therapy for sepsis needs to be confirmed in large studies that use high quality methods.

Laički sažetak

Intravenski imunoglobulini za liječenje pacijenata sa sepsom i septičkim šokom

Sepsa je upalni odgovor tijela na teške infekcije koje mogu biti uzrokovane raznim mikroorganizmima, uključujući bakterije, viruse i gljive. Znakovi sepse uključuju vrućicu, pothlađenost, ubrzano disanje i puls, a laboratorijski nalazi pokazuju snižen ili povišen broj bijelih krvnih stanica. Smrtnost uslijed sepse i septičnog šoka ostaje visoka unatoč korištenju antibiotika, a pogotovo ako su pogođene funkcije vitalnih organa kao što su pluća, srce i bubrezi. Provedeno je više studija o upotrebi nekog drugog sredstva, osim antibiotika, u svrhu pomaganja tijelu u borbi s posljedicama sepse. Intravenski imunoglobulinski pripravci sadrže protutitijela koja pomažu tijelu da neutralizira bakterijske toksine. Postoje dva tipa pripravaka. To su poliklonski imunoglobulini, koji sadrže više protutitijela usmjerenih na endotoksin i upalne posrednike, i monoklonski imunoglobulini, koji su usmjereni na jedan specifični upalni posrednik ili antigen. Intravenski imunoglobulini se proizvode iz krvi, a posebno pripremljen serum dobiva se od krvi ljudi koji su dobrovoljni davatelji krvi.

Za ovaj obnovljeni Cochrane sustavni pregled pretražena je medicinska literatura objavljena do siječnja 2012. Uključena su 43 randomizirana kontrolna istraživanja; 25 studija o poliklonskim intravenskim imunoglobulinima (IVIG), pri čemu 17 na odraslima (1958 ispitanika) i 8 na novorođenčadi (3831 ispitanika), uključujući veliku studiju o poliklonskim IVIB na novorođenčadi sa sepsom koja je objavljena 2011. godine. Ostalih 18 studija (ukupno 13.413 ispitanika) istražilo je monoklonska protutijela. I standardni i poliklonski imunoglobulini obogaćeni imunoglobulinom M (IgM) smanjli su broj smrti u odraslih, ali ne u djece. Ipak, ako se uzmu u obzir samo visokokvalitetno provedena istraživanja, nije pokazano smanjenje smrtnosti u odraslih korištenjem poliklonskih imunoglobulina. Kod novorođenčadi sa sepsom postoje jasni dokazi da standardni poliklonski IVIG ne smanjuju smrtnost. U istraživanju monoklonskih imunoglobulina, anti-endotoksin protutijela nisu pokazala nikakvu korist, dok su anti-citokini pokazali malo smanjenje smrtnosti u odraslih sa sepsom.

Istraživanja korisnosti poliklonskih imunoglobulina kod odraslih bila su malena u usporedbi s istraživanjima monoklonskih pripravaka. Smanjenje smrtnosti povezano s korištenjem poliklonskih bogaćenih preparata kao dodatne terapije za sepsu treba biti potvrđeno novim istraživanjima koja će uključiti velik broj ispitanika i u koijma će se koristiti visokokvalitetne metode.

Bilješke prijevoda

Hrvatski Cochrane
Prevela: Ivana Miošić
Ovaj sažetak preveden je u okviru volonterskog projekta prevođenja Cochrane sažetaka. Uključite se u projekt i pomozite nam u prevođenju brojnih preostalih Cochrane sažetaka koji su još uvijek dostupni samo na engleskom jeziku. Kontakt: cochrane_croatia@mefst.hr

Laienverständliche Zusammenfassung

Intravenöse Immunglobuline zur Behandlung von Patienten mit schwerer Sepsis und septischem Schock

Eine Sepsis ist die Entzündungsreaktion des Körpers auf schwere Infektionen, die durch eine Vielzahl von Mikroorganismen, einschließlich Bakterien, Viren und Pilzen verursacht werden können. Zeichen einer Sepsis sind Fieber, Hypothermie, schnelle Herzfrequenz und schnelle Atmung und einen Laborbefund mit erhöhter oder verringerter Leukozytenzahl. Die Zahl der Todesfälle infolge von Sepsis und septischem Schock bleiben trotz Antibiotikagabe hoch, vor allem, wenn die Funktionen der lebenswichtigen Organe, wie Lunge, Herz und Nieren betroffen sind. Mehrere Studien haben andere Wirkstoffe als Antibiotika untersucht, um den Körper im Kampf gegen die Auswirkungen der Sepsis zu unterstützen. Intravenöse Immunglobulin-Präparate enthalten Antikörper, die dem Körper helfen, bakterielle Giftstoffe zu neutralisieren. Es gibt zwei Arten von Zubereitungen. Dies sind polyklonale Immunglobuline, eine Mischung aus mehreren Antikörpern, die auf Endotoxin und Entzündungsmediatoren gerichtet sind, und monoklonale Immunglobuline, die auf einen spezifischen Entzündungsmediator oder Antigen abzielen. Intravenöse Immunglobuline sind Blutprodukte, speziell gepoolte Seren, die von menschlichen Spenderblut entstammen.

Für diesen aktualisierten Cochrane Review durchsuchten wir die medizinischen Literaturdatenbanken bis Januar 2012. Eingeschlossen wurden 43 randomisierte kontrollierte Studien (RCTs); 25 waren RCTs über polyklonale intravenöse Immunglobuline (IVIG), davon 17 mit Erwachsenen (1958 Teilnehmer) und acht mit Neugeborenen (3831 Teilnehmer), darunter eine große polyklonale IVIG-Studie an Säuglingen mit Sepsis, die im Jahr 2011 veröffentlicht wurde. Die verbleibenden 18 Studien (insgesamt 13.413 Teilnehmer) befassten sich mit monoklonalen Antikörpern. Standard- und Immunglobulin M (IgM)-angereicherte polyklonale Immunglobuline verringerten die Zahl der Todesfälle bei Erwachsenen, aber nicht bei Säuglingen. Bei der Analyse von lediglich hochwertigen Studien, wurde jedoch keine Verringerung der Todesfälle bei Erwachsenen mit polyklonalem IVIG beobachtet. Unter Neugeborenen mit Sepsis, gibt es definitive Evidenz dafür, dass Standard-polyklonale IVIG die Zahl der Todesfälle nicht verringert. In monoklonalen Immunglobulin-Studien zeigten Anti-Endotoxin-Antikörper keinen Nutzen, während die Anti-Zytokine eine sehr geringe Abnahme der Todesfälle bei Erwachsenen mit Sepsis zeigten.

Die polyklonalen Immunglobulin-Studien bei Erwachsenen waren im Vergleich zu den Studien mit monoklonalen Wirkstoffen klein. Die Verringerung der Todesfälle, die durch den Einsatz von polyklonalen IgM-angereicherten Präparaten als Add-on-Therapie für Sepsis beobachtet wurde, muss in großen Studien, die eine hohe methodische Qualität haben, bestätigt werden.

Anmerkungen zur Übersetzung

K. Kunzweiler, Koordination durch Cochrane Schweiz.

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