Cochrane Database of Systematic Reviews
Post-exposure passive immunisation for preventing measles
(Review)
Young MK, Nimmo GR, Cripps AW, Jones MA
Young MK, Nimmo GR, Cripps AW, Jones MA.
Post-exposure passive immunisation for preventing measles.
Cochrane Database of Systematic Reviews 2014, Issue 4. Art. No.: CD010056.
DOI: 10.1002/14651858.CD010056.pub2.
www.cochranelibrary.com
Post-exposure passive immunisation for preventing measles (Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . .
SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . .
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 1.
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Figure 2.
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ADDITIONAL SUMMARY OF FINDINGS . . . . . . . . . . . . . . . . . . . . . . .
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ACKNOWLEDGEMENTS
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . .
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.1. Comparison 1 Immunoglobulin versus no treatment, Outcome 1 Measles cases. . . . . .
Analysis 1.2. Comparison 1 Immunoglobulin versus no treatment, Outcome 2 Measles cases. . . . . .
Analysis 1.3. Comparison 1 Immunoglobulin versus no treatment, Outcome 3 Measles cases. . . . . .
Analysis 1.4. Comparison 1 Immunoglobulin versus no treatment, Outcome 4 Mortality due to measles. .
Analysis 1.5. Comparison 1 Immunoglobulin versus no treatment, Outcome 5 Complications due to measles.
Analysis 2.1. Comparison 2 Gamma globulin versus serum, Outcome 1 Measles cases. . . . . . . . .
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . .
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . .
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . .
INDEX TERMS
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Post-exposure passive immunisation for preventing measles (Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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i
[Intervention Review]
Post-exposure passive immunisation for preventing measles
Megan K Young1 , Graeme R Nimmo2 , Allan W Cripps3 , Mark A Jones4
1 School
of Medicine, Griffith Health Institute, Griffith University, Meadowbrook, Australia. 2 Department of Microbiology, Pathology
Queensland, Brisbane, Australia. 3 Griffith Health, Griffith University, Gold Coast, Australia. 4 School of Population Health, The
University of Queensland, Brisbane, Australia
Contact address: Megan K Young, School of Medicine, Griffith Health Institute, Griffith University, University Drive, Meadowbrook,
Queensland, 4121, Australia. megan.young@griffith.edu.au.
Editorial group: Cochrane Acute Respiratory Infections Group.
Publication status and date: New, published in Issue 4, 2014.
Review content assessed as up-to-date: 14 August 2013.
Citation: Young MK, Nimmo GR, Cripps AW, Jones MA. Post-exposure passive immunisation for preventing measles. Cochrane
Database of Systematic Reviews 2014, Issue 4. Art. No.: CD010056. DOI: 10.1002/14651858.CD010056.pub2.
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
ABSTRACT
Background
Measles outbreaks continue to occur in countries with high vaccination coverage. Passive immunisation is generally considered to
prevent measles in someone who is not immune and has been exposed to infection. Estimates of effectiveness have varied and no
minimum effective dose has been determined.
Objectives
To assess the effectiveness and safety of intramuscular injection or intravenous infusion of immunoglobulins (passive immunisation)
for preventing measles when administered to exposed susceptible people before the onset of symptoms.
Search methods
We searched CENTRAL (2013, Issue 7), MEDLINE (1946 to July week 5, 2013), CINAHL (1981 to August 2013) and EMBASE
(1974 to August 2013).
Selection criteria
We included randomised controlled trials (RCTs), quasi-RCTs and prospective, controlled (cohort) studies if: participants were susceptible and exposed to measles, polyclonal immunoglobulins derived from human sera or plasma were administered intramuscularly or
intravenously as the only intervention in at least one group and the number of subsequent measles cases was measured. We excluded
studies of other sources of immunoglobulins.
Data collection and analysis
Two authors independently extracted data and critically appraised the included studies. We attempted to contact study authors for
missing information. We described the results of studies not included in meta-analyses.
Main results
We included one RCT, two quasi-RCTs and 10 cohort studies (3925 participants). No studies were rated as low risk of bias for all
criteria. Critical appraisal was constrained by a lack of information in most studies. The overall quality of the evidence was moderate.
Seven studies (1432 participants) assessed cases of measles after immunoglobulin versus no treatment. Heterogeneity was explained by
subgrouping according to the blood product used as an approximation of dose of immunoglobulin. When given within seven days of
Post-exposure passive immunisation for preventing measles (Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
1
exposure, immunoglobulins were effective at preventing measles: gamma globulin (risk ratio (RR) 0.17, 95% confidence interval (CI)
0.08 to 0.36), convalescent serum (RR 0.21, 95% CI 0.15 to 0.29 to RR 0.49, 95% CI 0.44 to 0.54) and adult serum (RR 0.52, 95%
CI 0.45 to 0.59). The differences in the effectiveness of different blood products were supported by studies not included in the metaanalysis and by two studies (702 participants) that found gamma globulin more effective than serum (RR 0.56, 95% CI 0.46 to 0.69).
Based on three studies (893 participants) immunoglobulin was effective at preventing death due to measles compared to no treatment
(RR 0.24, 95% CI 0.13 to 0.44).
Two studies included measles vaccine alone among the intervention groups. Meta-analysis could not be undertaken. Both studies
suggested the vaccine was more effective than gamma globulin.
No serious adverse events were observed in any of the included studies, although reporting of adverse events was poor overall. Nonserious adverse events included transient fever, rash, muscle stiffness, local redness and induration.
Authors’ conclusions
Passive immunisation within seven days of exposure is effective at preventing measles, with the risk for non-immune people up to 83%
less than if no treatment is given. Given an attack rate of 45 per 1000 (per the control group of the most recent included study), gamma
globulin compared to no treatment has an absolute risk reduction (ARR) of 37 per 1000 and a number needed to treat to benefit
(NNTB) of 27. Given an attack rate of 759 per 1000 (per the attack rate of the other included study assessing gamma globulin), the
ARR of gamma globulin compared to no treatment is 629 and the NNTB is two.
It seems the dose of immunoglobulin administered impacts on effectiveness. A minimum effective dose of measles-specific antibodies
could not be identified.
Passive immunisation is effective at preventing deaths from measles, reducing the risk by 76% compared to no treatment. Whether the
benefits of passive immunisation vary among subgroups of non-immune exposed people could not be determined.
Due to a paucity of evidence comparing vaccine to passive immunisation, no firm conclusions can be drawn regarding relative
effectiveness.
The included studies were not specifically designed to detect adverse events.
Future research should consider the effectiveness of passive immunisation for preventing measles in high-risk populations such as
pregnant women, immunocompromised people and infants. Further efforts should be made to determine the minimum effective dose
of measles-specific antibodies for post-exposure prophylaxis and the relative effectiveness of vaccine compared to immunoglobulin.
PLAIN LANGUAGE SUMMARY
Antibodies for preventing measles after exposure
People who have had measles, or measles vaccine, have antibodies against the virus in their blood that protect them from developing
measles should they come into contact with it. These antibodies can be extracted from blood donated by these individuals.
If people without antibodies come into contact with someone who is contagious with measles, they are likely to contract the disease.
Measles is usually debilitating and can have serious consequences including death, so preventing it is desirable. One way of preventing
measles in this group, when they do come into contact with a contagious person, is to inject them with antibodies that have been
extracted from blood donations. This has been practised since the 1920s, but measures of its effectiveness have varied and the minimum
amount of antibodies that we can give to prevent measles is unknown.
Based on seven studies (1432 people), of overall moderate quality, injecting antibodies into a muscle of people who came into contact
with measles, but lacked their own antibodies, was effective at preventing them catching the disease compared to those who received
no treatment. Using the modern day antibody preparation, people were 83% less likely to develop measles than those who were not
treated. It was very effective at preventing them developing complications if they did contract measles and very effective at preventing
death. The included studies generally did not intend to measure possible harms from the injections. Minor side effects were reported,
such as muscle stiffness, redness around the injection site, fever and rash. Importantly, only two studies compared the measles vaccine
with the antibody injection in this group of people, so no firm conclusions could be drawn about the relative effectiveness of these
interventions.
Post-exposure passive immunisation for preventing measles (Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
2
The antibody injection is often recommended for pregnant women, infants and immunocompromised people (if they do not have
their own antibodies to measles and come into contact with someone who is contagious with measles). The included studies did not
include these groups of people, so it is unknown whether the effectiveness of antibody injections is different for them. We were also
unable to identify the minimum dose of antibodies required as only one study measured the specific amount of measles antibodies in
the injections and one other study estimated this figure; the results of these two studies were not consistent.
The evidence is current to August 2013.
Post-exposure passive immunisation for preventing measles (Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
3
Post-exposure passive immunisation for preventing measles (Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]
Immunoglobulin compared to no treatment for preventing measles
Patient or population: susceptible people exposed to measles
Settings: community and hospitals
Intervention: immunoglobulin
Comparison: no treatment
Outcomes
Illustrative comparative risks* (95% CI)
Assumed risk
Corresponding risk
No treatment
Immunoglobulin
Measles cases - conva- Study population
lescent serum
862 per 1000
Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
RR 0.21
(0.15 to 0.29)
301
(3 studies)
⊕⊕⊕
moderate1,2,3,4,5,6
RR 0.52
(0.45 to 0.59)
586
(2 studies)
⊕⊕⊕
moderate3,5,7,8,9
RR 0.17
(0.08 to 0.36)
545
(2 studies)
⊕⊕⊕
moderate4,5,10,11,12
181 per 1000
(129 to 250)
Moderate
1000 per 1000
Measles cases - adult Study population
serum
860 per 1000
210 per 1000
(150 to 290)
447 per 1000
(387 to 507)
Moderate
907 per 1000
Measles cases - gamma Study population
globulin
472 per 1000
(408 to 535)
Comments
4
Post-exposure passive immunisation for preventing measles (Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
110 per 1000
19 per 1000
(9 to 40)
Moderate
402 per 1000
68 per 1000
(32 to 145)
Mortality due to measles Study population
142 per 1000
RR 0.24
(0.13 to 0.44)
893
(3 studies)
⊕⊕⊕⊕
high3,5,7
RR 0.18
(0.05 to 0.6)
832
(3 studies)
⊕⊕⊕
moderate3,4,5,7
Not estimable
0
(0)
See comment
34 per 1000
(18 to 62)
Moderate
40 per 1000
Complications due to Study population
measles
52 per 1000
10 per 1000
(5 to 18)
9 per 1000
(3 to 31)
Moderate
71 per 1000
Adverse events
Study population
13 per 1000
(4 to 43)
Adverse events were
poorly reported or not
measured in all but
one study comparing immunoglobulins and no
treatment. No serious adverse events were reported.13
5
Post-exposure passive immunisation for preventing measles (Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
See comment
See comment
Moderate
*The basis for the assumed risk is the median control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison
group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RR: risk ratio
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.
1 Downgraded
one level for risk of bias. We pooled one quasi-randomised trial and two cohort studies to give this estimate. Two
further cohort studies also assessed convalescent serum versus no treatment for the prevention of measles. These latter studies had
heterogenous results that may have resulted from differences in methodology and so were not included. We rated no studies at high
risk of measurement bias, but lack of information about blinding and assessment of the outcome typically resulted in unclear risk.
While any uncontrolled confounding would have decreased the effect size, measurement bias may have increased the effect size and
so warrants a downgrade in quality here.
2 Downgraded one level for inconsistency. The two cohort studies that assessed convalescent serum versus no treatment, which were
left out of this pooled estimate, had heterogenous results, although still indicated a significant benefit of this intervention.
3 Publication bias strongly suspected. The studies in this analysis were all published in the first half of the 20th century. Not as many
journals existed and reporting standards were not as rigorous. It is very likely that many small studies were not published.
4
Upgraded for very large effect size. The effect size was very large and reasonably precise.
5 Upgraded as plausible confounding would reduce the demonstrated effect.
6 Upgraded for dose-response gradient. Convalescent serum was one subgroup of three in an analysis that examined the effect of an
approximation of dose on the results. An apparent dose response could be seen across the three subgroups.
7 Downgraded one level for risk of bias. We pooled one quasi-randomised trial and two cohort studies to give this estimate. We rated
no study at high risk of measurement bias, but lack of information about blinding and assessment of the outcome typically resulted in
unclear risk. While any uncontrolled confounding would have decreased the effect size, measurement bias may have increased the effect
size and so warrants a downgrade in quality here.
8 Upgraded for large effect size. The effect size was large and precise.
9 Upgraded for dose-response gradient. Adult serum was one subgroup of three in an analysis that examined the effect of an approximation
of dose on the results. An apparent dose response could be seen across the three subgroups.
6
Post-exposure passive immunisation for preventing measles (Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
10 Downgraded
two levels for risk of bias. Both of the studies contributing to this estimate were cohort studies. Any uncontrolled
confounding would have decreased the effect size. We rated measurement bias as unclear for one study and this may have increased
the effect size in this case. We rated measurement bias as low risk for the other study, but attrition bias was high risk for that study.
Overall, a downgrading of two levels is warranted.
11
Publication bias strongly suspected. Although one study in the analysis of this subgroup was published recently, the other was
published in the first half of the 20th century. Not as many journals existed and reporting standards were not as rigorous at that time. It
is very likely that many small studies were not published.
12 Upgraded for dose-response gradient. Gamma globulin was one subgroup of three in an analysis that examined the effect of an
approximation of dose on the results. An apparent dose response could be seen across the three subgroups.
13 One study recording ’vaccine reactions’ reported ’fever and rash’ at rates of 5% in the gamma globulin group, 4% in the vaccine group
and 1% in the no treatment group. The differences between groups were not statistically significant. This study reported loss to followup exceeding 20%.
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BACKGROUND
Before vaccination against measles was available, annual case numbers were estimated at 130 million (WHO 1999) and the disease
caused between five and eight million deaths globally each year
(Moss 2009). With the introduction of the vaccine, the worldwide
number of cases began to decline (WHO 1999) and this trend continued with increasing vaccination coverage (WHO 2009a). However, the number of measles cases worldwide exceeded 300,000
in 2010 (WHO 2013), with the highest incidence occurring in
the World Health Organization (WHO) African region at 238
cases per million population (WHO 2012). Measles is still an important cause of global mortality as identified by the joint WHO
and United Nations International Children’s Emergency Fund
(UNICEF) Global Immunization Vision and Strategy 2005 to
2015 (WHO 2005). One of the strategy’s goals is measles mortality reduction. In 2008, measles caused around 164,000 deaths
(WHO 2009b).
Further to mortality reduction, most WHO regions have set
measles elimination goals and reported on progress towards these
(Castillo-Solorzano 2011; Martin 2011; Sniadack 2011; WHO
2008). Many countries have noted continued reductions in incidence (WHO 2012) and even elimination of endemic transmission (Parker Fiebelkorn 2010). In 2010, the incidence in the
WHO region of the Americas was just 0.3 cases per million population (WHO 2012). However, the WHO cautions that failure
to maintain high vaccination coverage in all areas of a country results in resurgence of the disease (WHO 2009a). Certainly, there
are many recent published reports of measles outbreaks among
countries with high vaccination coverage (CDC 2011a; Delaporte
2011; DVD CDC 2011; Hoskins 2011; Parker Fiebelkorn 2010;
Smithson 2010; Takimoto 2011; Vainio 2011) and the WHO
confirms that the incidence of measles worldwide increased in
2010 because of large outbreaks in some regions (WHO 2012).
In countries with low incidences of measles, elimination strategies
typically include an urgent response to a single reported case, including confirmation of the diagnosis, contact tracing and postexposure prophylaxis (CDC 1998; CDNA 2009; NZ MoH 2011;
UK DoH 2010). Post-exposure prophylaxis may be a vaccination,
which seems to be effective at preventing disease onset if administered within 72 hours of exposure (Barrabeig 2011), or may involve passive immunisation with immunoglobulin, particularly if
outside this 72-hour window (Heymann 2008).
Description of the condition
Measles is a highly communicable viral illness (Heymann 2008).
The measles virus is an enveloped, single-stranded RNA Morbillivirus of the family Paramyxoviridae (Heymann 2008; WHO
2009a). The virus is shed from the respiratory tract of infected persons and transmitted by aerosolised droplets or by direct contact
with respiratory secretions (WHO 2009a). Someone with measles
is contagious from one day before the symptoms start until four
days after the rash appears. A susceptible person exposed to measles
will usually develop symptoms after around 10 days, but this may
range from 7 to 18 days after exposure (Heymann 2008).
Symptoms of measles include fever, conjunctivitis, runny nose,
cough and a red blotchy rash (WHO 1999). The illness is often more severe in infants and adults than in children (Heymann
2008). Complications occur more frequently in cases in low-income rather than high-income countries (75% or more versus
10% to 15% of cases, respectively) (WHO 1999). Middle ear infection and pneumonia are fairly common complications, occurring in 5% to 15% and 5% to 10% of children with measles,
respectively (WHO 2009a). Encephalitis is a serious, but rarer,
complication of measles, occurring in about 1 out of every 1000
cases (WHO 2009a). A slowly progressing neurological disease,
subacute sclerosing panencephalitis (SSPE), very rarely (1 out of
100,000 cases) occurs several years after the original measles infection, most often in children infected with measles under the age
of two years (Heymann 2008). The mortality rate can be as high
as 30% in some low-income countries, although it is more typically estimated at 3% to 5% (WHO 1999). This compares with
0.1% in high-income countries. The discrepancy has a significant
association with the prevalence of vitamin A deficiency (WHO
1999).
Description of the intervention
The practice of passive immunisation against measles has been
used since the 1920s (Haas 1926). Polyclonal immunoglobulins
are administered parenterally to susceptible individuals, who have
been in contact with an infectious case of measles, in an attempt
to prevent the onset of disease or modify disease expression (Keller
2000).
A number of different immunoglobulin preparations have been
used in the prophylaxis of measles. The serum or plasma of people
recovering from measles or of adults who have previously suffered
from the disease, whole blood from the same sources, the serous
fluid obtained from placentas, ascites fluid and animal sera have
all been trialled (Barenberg 1930; Karelitz 1937; Morales 1930;
Thalhimer 1939; Zingher 1924). In the 1940s, methods were devised for concentrating the antibodies in human plasma and today
the process of fractionation continues to be used to produce the
blood product human immune globulin from pooled donated human plasma (Gonik 2011). Both intramuscular and intravenous
preparations are in use. Product names vary from country to country; so too the concentration of disease-specific immunoglobulins
in the products will generally reflect circulating antibody levels in
the donating populations (Sawyer 2000). However, in some countries, minimum neutralising antibody concentrations to measles
may be regulated (Sawyer 2000).
Post-exposure passive immunisation for preventing measles (Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
8
Current recommendations for dose calculations vary by country,
although they are all calculated according to body weight (CDC
2011b; CDNA 2009; ID HPA 2009; NZ MoH 2011). Regardless
of the dose recommended, passive immunisation is not currently
recommended if more than six days have elapsed since exposure
to measles (CDC 2011b; CDNA 2009; ID HPA 2009; NZ MoH
2011).
This review aimed to clarify the effectiveness rate, assess the evidence for a minimum effective dose and identify differences in
benefit or harm across population groups. These outcomes would
be valuable to guide public health practice in countries with low
incidences of measles.
OBJECTIVES
How the intervention might work
Whether injected or infused, the administered immunoglobulins
distribute throughout the recipient’s body (Birdsall 2009). The
mechanism by which the recipient is protected from disease involves interaction between the immunoglobulins, the invading
measles virus particles and the cells and molecules of the recipient’s
immune system (Reading 2007). The exact mechanisms by which
viral infectivity is mitigated by antibodies within the body are not
comprehensively understood but vary according to the structure
and functionality of the particular antibodies as they encounter
the particular virus particles (Reading 2007). In general, measlesspecific antibodies bind to invading measles virus particles and
this may prevent their entry into cells directly, or trigger other
immune mechanisms that result in neutralisation or destruction
of the virus (Birdsall 2009; Keller 2000; Reading 2007).
Why it is important to do this review
The effectiveness of post-exposure prophylaxis against measles
with immunoglobulins is generally accepted (ATAGI 2008; CDC
1998; NZ MoH 2011; Ramsay 2009). However, effectiveness rates
vary considerably among identified reports (King 1991; Ordman
1944; Sheppeard 2009; Stokes 1944).
Further, national recommendations for the use of post-exposure
immunoglobulins for measles differ across a number of countries (Best 2011; CDC 1998; CDNA 2009; ID HPA 2009;
NZ MoH 2011; Ramsay 2009) where disease incidences (WHO
2014), immunisation schedules (ATAGI 2008; Gustavo 2008;
HPA 2011; NZ MoH 2011), measles-containing vaccine coverage (WHO 2014) and relevant literature are similar. Differences
in immunoglobulin dosage recommendations among these countries may reflect differences in the minimum levels of measles-specific antibodies in intramuscular preparations (Best 2011; Ramsay
2009; Sawyer 2000).
We could not identify any systematic review evidence of the effectiveness of post-exposure passive immunisation against measles,
nor any systematic review evidence of the minimum effective
dosage of immunoglobulin for post-exposure prophylaxis against
measles. Recent guidance from the United Kingdom on the required dosage of intramuscular immunoglobulin is based on a single study (Endo 2001; Ramsay 2009).
To assess the effectiveness and safety of intramuscular injection or
intravenous infusion of immunoglobulins for preventing measles
when administered to exposed susceptible people before the onset
of symptoms.
METHODS
Criteria for considering studies for this review
Types of studies
We included randomised controlled trials (RCTs), quasi-RCTs
and prospective non-RCTs (cohort studies), irrespective of blinding, publication status, language or unit of randomisation. We included prospective non-RCTs given that more recent studies, using current immunoglobulin preparations, were likely to be nonrandomised for ethical reasons. The intervention has been part of
public health practice since the 1920s and, as such, any RCTs are
likely to have been conducted at a time when the antibody levels
of blood donors were due to infection with measles rather than
vaccination. To inform practice appropriately, any evidence of the
effectiveness of current immunoglobulin preparations should be
included.
Types of participants
People of any age, sex or ethnic origin who were susceptible (no history of measles and not vaccinated against measles and/or measles
immunoglobulin G (IgG) negative) and exposed to measles virus
or exposed to someone diagnosed with measles and who were
asymptomatic at the time of intervention or control administration. The primary study’s definition of ’exposed’ was accepted.
Types of interventions
1. Intervention: intramuscular injection of polyclonal
immunoglobulins; intravenous infusion of polyclonal
immunoglobulins. Only interventions using immunoglobulins
derived from human sera or plasma were included.
2. Control: no intervention or placebo or live attenuated
measles virus vaccine.
Post-exposure passive immunisation for preventing measles (Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
9
We also included studies assessing different brands or preparations of polyclonal immunoglobulins or different dosages of immunoglobulins. We only included studies where the intervention
(and control) were administered to participants after exposure to
measles and before the participants developed measles symptoms.
Types of outcome measures
Primary outcomes
1. Cases of measles. The diagnosis may be made by detection
or isolation of measles virus in urine or respiratory secretions; by
detection of measles virus antigen in urine or respiratory
secretions; by serological detection of immunoglobulin M (IgM)
to measles in the absence of vaccination eight days to eight weeks
prior to testing; by IgG seroconversion or by a fourfold or greater
rise in titre to measles virus in the absence of vaccination eight
days to eight weeks prior to testing; or by symptoms consistent
with measles (fever, a red blotchy rash, conjunctivitis, runny nose
and cough) or modified measles (prolonged incubation period,
milder fever, cough, runny nose, conjunctivitis and sparse
discrete rash of short duration).
2. Mortality due to measles.
Secondary outcomes
1. Prevention of measles outbreak (higher than expected
incidence) as identified by active surveillance.
2. Cessation of measles outbreak (return to expected
incidence) as identified by active or passive surveillance (or both).
3. Complications due to measles such as otitis media,
pneumonia or encephalitis.
4. Occurrence and type of adverse events. We proposed to
analyse two types of adverse events: serious adverse events and
non-serious adverse events. A serious adverse event was defined
as “any untoward medical occurrence that at any dose results in
death, is life-threatening, requires inpatient hospitalisation or
prolongation of existing hospitalisation, results in persistent or
significant disability/incapacity, or is a congenital anomaly/birth
defect” (EMEA 1995). We classified all other events as nonserious. We specifically sought to extract data on: blood-borne
virus infection; anaphylaxis; generalised hypersensitivity and
injection site reactions. We also included any other adverse event
reported as such by study authors.
Acute Respiratory Infections (ARI) Group’s Specialised Register,
MEDLINE (via OVID) (1946 to July week 4, 2012), CINAHL
(via EBSCO) (1981 to August 2012) and EMBASE (1974 to August 2012). We used the search strategy in Appendix 1 to search
MEDLINE and CENTRAL. We adapted the strategy for EMBASE (Appendix 2) and CINAHL (Appendix 3). We combined
the MEDLINE and EMBASE searches with the filter for study
type in Appendix 4 as we considered the search results retrieved
too large to be manageable. We updated the electronic searches
on 14 August 2013 by searching CENTRAL (2013, Issue 7) from
2011 to 2013, MEDLINE from 1 June 2012 to July week 5 2013,
CINAHL after June 2012 and EMBASE from 1 July 2012 to August 2013.
Searching other resources
We searched reference lists of identified relevant studies and reviews. We searched www.clinicaltrials.gov and WHO ICTRP (19
August 2013) using the search term ’measles’. To locate further
published or unpublished studies, we attempted to contact companies manufacturing immunoglobulin products for countries with
low measles incidences and attempted to contact the corresponding author of any included studies.
Data collection and analysis
Selection of studies
Two review authors (MY, GN) independently inspected the title
and abstract (as available) of each reference identified by the electronic search and determined the potential relevance of each article. If identified by either review author as potentially relevant, we
retrieved the full article. One author (MY) searched the reference
lists of the relevant retrieved studies and retrieved the full articles
of those that could not be excluded based on title (and abstract
where available).
Both review authors independently inspected each full article using
an eligibility checklist based on the inclusion criteria, to determine
inclusion in the review. We resolved any disagreements through
discussion. We excluded studies not meeting the eligibility criteria
and stated the reasons for exclusion.
We did not identify any duplicate publications.
Data extraction and management
Search methods for identification of studies
Electronic searches
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2012, Issue 7), which contains the Cochrane
Two review authors (MY, AC) independently extracted data from
the included studies using pre-designed electronic data extraction
forms. We resolved disagreements by discussion. We attempted to
contact study authors for clarification or further information as
necessary.
We attempted to extract the following data:
1. The study
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i) First author, publication year/not published.
ii) Location.
iii) Date study undertaken.
iv) Randomised/quasi-randomised/non-randomised.
2. Participants
i) Number in each group.
ii) Age range in each group.
iii) Proportion of adults, children, infants (aged < one
year) in each group.
iv) Gender distribution in each group.
v) Proportion of high-risk individuals in each group:
those with immunodeficiency; pregnancy or age under one year.
vi) Range of time since exposure in each group.
vii) Average time since exposure in each group.
viii) Any measure of baseline comparability and result of
this, if calculated.
3. Intervention
i) Intervention group: product used, concentration of
measles antibody if known, volume given, route of
administration.
ii) Control group: placebo/vaccine/product/other,
concentration of measles antibody if relevant and known,
volume given, route of administration.
4. Outcomes
i) Primary and secondary (as above).
ii) Length of follow-up.
iii) Loss to follow-up.
Assessment of risk of bias in included studies
Two review authors (MY, AC) independently assessed the risk of
bias of included studies. We resolved any disagreements by discussion. For randomised and quasi-randomised studies, we assessed: randomisation sequence generation; allocation concealment; blinding of participants, personnel and outcome assessors;
incomplete outcome data; selective reporting and other potential
sources of bias. We reported the risk of bias using The Cochrane
Collaboration’s tool for assessing ’Risk of bias’ (Higgins 2011).
For non-randomised studies, we allocated randomisation sequence
generation and allocation concealment (selection bias) ’high risk’.
We assessed: blinding of participants, personnel and outcome assessors; incomplete outcome data; selective reporting; management of confounders and other potential sources of bias.
We made the decision to include ’Summary of findings’ tables in the review post-protocol. We produced the tables using
GRADEpro 2008 software. As per GRADE recommendations,
where meta-analyses included at least one cohort study, we initially
considered the evidence of low quality and then upgraded and/
or downgraded it according to GRADE criteria (Higgins 2011).
Both primary outcomes and the secondary outcomes ’complications due to measles’ and ’adverse events’ were eligible for inclusion in the ’Summary of findings’ tables.
Measures of treatment effect
Outcomes, as identified above, are dichotomous. We expressed
these outcomes as risk ratios (RRs) and calculated 95% confidence
intervals (CIs) for each.
Unit of analysis issues
No cluster-randomised trials were identified for inclusion in the
review.
For studies with multiple intervention groups, for example different doses or preparations of immunoglobulins compared to control, we split the shared group and included the relevant pair-wise
comparisons in the meta-analysis (Higgins 2011).
Dealing with missing data
We attempted to contact the trial authors for any missing data.
Where missing data exceeded 20% (one study - Glyn-Jones 1972),
or where data were missing in different proportions in the treatment groups (one study - Stillerman 1944), we excluded the study
from meta-analysis for the relevant outcomes. There were no studies (i.e. studies with smaller amounts of missing data) requiring
sensitivity analysis (assuming worst-case and best-case scenarios).
Assessment of heterogeneity
We explored the presence of heterogeneity firstly by comparing
studies’ population groups and interventions. Where no clinically
relevant heterogeneity was present, we proceeded to meta-analysis. We considered the forest plots for each primary outcome and
the secondary outcome “Complications due to measles” and proceeded to subgroup and sensitivity analyses where heterogeneity
was clear visually. We re-examined the heterogeneity of subgroup
and sensitivity analyses separately. We considered an I2 statistic
estimate of 60% or more, alongside a Chi2 test P value of 0.1 or
less, to be important heterogeneity.
Our protocol indicated the secondary outcome ’serious adverse
events’ among those for meta-analysis. However, this outcome was
not reported in any included study.
Assessment of reporting biases
We examined each included study for indications that outcomes
assessed had not been reported.
Our protocol indicated that, had multiple publications of the same
study been retrieved, we would list the subsequent papers with
the main paper and enter the data for meta-analysis once only.
However, we did not identify multiple publications of the same
study.
Our protocol indicated that we would assess publication bias by
examining funnel plots if sufficient studies (at least 10) were included. However, the maximum number of studies included in
meta-analyses was seven.
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Data synthesis
We calculated the RR and 95% CI for each outcome measured
in each study. We used a fixed-effect model in meta-analysis of
each primary outcome and the secondary outcome ’complications
due to measles’ and examined the forest plots to assess heterogeneity. We explored possible reasons for apparent heterogeneity via
subgroup and sensitivity analyses and reported the results of these
using fixed-effect models.
We reported the results of the secondary outcome ’adverse events’
descriptively.
Subgroup analysis and investigation of heterogeneity
Our protocol listed the following subgroup analyses that we were
unable to perform because of insufficient available information
from the included studies:
• proportion of high-risk individuals;
• dose of measles-specific immunoglobulins.
Further, the following subgroup analyses were not relevant to the
review:
• route of administration of immunoglobulins (all included
studies administered immunoglobulins intramuscularly);
• timing of administration of intervention in relation to
exposure (included studies generally administered
immunoglobulins within seven days of exposure where this was
reported. Only Stillerman 1944 administered immunoglobulins
within eight days, although Salomon 1923 and Wesselhoeft
1928 did not report the timing of the intervention in relation to
exposure. Hence, rather than subgroup analysis, we undertook
sensitivity analysis, by excluding each of these studies in turn and
together. In addition, there were insufficient studies assessing the
effect of the timing of the intervention (within seven days of
exposure) on the prevention of measles to undertake a separate
analysis);
• differences in the primary study definition of exposed (with
the exception of Cockburn 1950, Endo 2001 and Sheppeard
2009, all included studies had similar definitions of ’exposed’.
Endo 2001 was not included in meta-analyses. Cockburn 1950
was included with only one other study in a meta-analysis. Thus
we undertook sensitivity analysis, by excluding Sheppeard 2009,
rather than subgroup analysis, to assess the impact of the
difference in this study’s exposure definition).
We undertook the following subgroup analyses:
• study type (quasi-RCTs and cohort type studies);
• age of participants (although sufficient information was not
available to divide the data as we had intended (infants/children/
adults/combinations), we grouped studies according to age as
follows: “included infants less than six months of age” and “did
not include infants less than six months of age”);
• dose of immunoglobulins (studies generally reported
administering a range of volumes of immunoglobulins and these
were not uniform, hence studies were grouped by the type of
intervention blood product (convalescent serum, adult serum
and gamma globulin) as an approximation of dose).
Sensitivity analysis
Our protocol specified that we would undertake sensitivity analysis
based on the risk of bias in included studies and studies with
imputed missing data.
We examined the effect of the risk of bias of included studies on
the results of meta-analyses by excluding Sheppeard 2009 from
the relevant outcome because of the high risk of attrition bias in
this study. The risk of bias was otherwise similar across included
studies.
We did not impute missing data for any study.
Post-protocol sensitivity analyses
As indicated above, because most included studies identified
the intervention dose of immunoglobulin by total volume and
the ranges administered were not uniform between studies, we
grouped the studies by the blood product used as an approximation of immunoglobulin dose. The rationale for this was: gamma
globulin is manufactured as a concentrated preparation of immunoglobulins and is thus likely to have the highest concentration of measles-specific antibodies per unit volume; the acute immune response following disease means that convalescent serum
will contain the next highest concentration of measles-specific antibodies per unit volume; and adult serum will contain the lowest concentration of measles-specific antibodies per unit volume
as disease would most likely have occurred in childhood for the
donors of the serum at the time of the included studies. Given
this approximation of dose, we undertook sensitivity analyses by
excluding Stillerman 1944 as the outlier (largest volume range and
highest volume) within the convalescent serum group and by excluding Salomon 1923 from the convalescent serum group as the
volume of serum administered was not reported. Volume ranges
within the subgroups were otherwise similar.
As indicated above, we also excluded Stillerman 1944, Salomon
1923 and Wesselhoeft 1928 alone and together to examine the
impact of definite (Stillerman 1944) and possible (Salomon 1923;
Wesselhoeft 1928) differences in the maximum time between exposure and intervention. We also excluded Sheppeard 2009 alone
to assess the impact of this study’s definition of exposure.
RESULTS
Description of studies
Post-exposure passive immunisation for preventing measles (Review)
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Results of the search
Searches of MEDLINE, EMBASE, CENTRAL and CINAHL on
6 August 2012 identified 2369 unique records, of which we retrieved 55 full-text articles resulting in five included studies. We
updated the electronic searches on 14 August 2013 and identified 102 unique records, of which we retrieved two full-text articles. No further studies met the inclusion criteria. Searching
the reference lists of relevant retrieved full-text articles identified
a further 133 unique papers, of which we retrieved 89 full-text
articles resulting in eight included studies (Figure 1). Searching
www.clinicaltrials.gov returned 158 records but no additional relevant studies. Searching WHO ICTRP returned 182 records but no
additional relevant studies. We sent electronic written requests to
13 separate companies that manufacture immunoglobulin products (Appendix 5) and the Australian Technical Advisory Group
on Immunisation (ATAGI). Four companies and the ATAGI responded. No additional studies were identified. The age of the
included studies and absent up-to-date contact details for authors
meant that we were only able to contact the authors of one study.
No additional studies were identified as a result of this communication.
Post-exposure passive immunisation for preventing measles (Review)
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Figure 1. Flow diagram of retrieval, selection and exclusion of studies.
Post-exposure passive immunisation for preventing measles (Review)
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Included studies
A total of 13 studies were included in the review: one RCT, two
quasi-RCTs and 10 prospective, non-randomised, controlled (cohort) studies (see Characteristics of included studies table). Included studies were published between 1920 and 2009. No unpublished studies were included.
Studies were undertaken in seven different countries: United
States (Berkovich 1963; Ordman 1944; Stillerman 1944; Toomey
1926; Wesselhoeft 1928), Japan (Endo 2001), United Kingdom (Cockburn 1950; Hartley 1948), Australia (Sheppeard
2009), Germany (Degkwitz 1920; Salomon 1923), Zimbabwe
(Glyn-Jones 1972) and Puerto Rico (Morales 1930). A total of
3925 participants were recruited from hospitals, child care facilities and the community. Sample sizes ranged from 11 to 921.
Only one study included adults among the participants (
Sheppeard 2009), although four studies (Berkovich 1963;
Degkwitz 1920; Endo 2001; Wesselhoeft 1928) did not report the
age of participants and five studies (Hartley 1948; Ordman 1944;
Salomon 1923; Sheppeard 2009; Toomey 1926) did not report a
clear age range. Two of these latter studies included participants less
than six months of age (Hartley 1948; Salomon 1923). Ordman
1944 and Sheppeard 2009 specified that participants were aged
six months and over. Toomey 1926 identified participants as ’children’. Participants of the remaining four included studies were
aged no younger than six months, with maximum ages ranging
from 35 months to 15 years (Cockburn 1950; Glyn-Jones 1972;
Morales 1930; Stillerman 1944).
The only study reporting gender distribution noted similar proportions of males and females in both the intervention and control
groups (intervention 53% males; control 51% males) (Cockburn
1950).
The proportions of participants at high risk of measles complications were also poorly reported. Glyn-Jones 1972 reported that
between 40% and 50% of participants were aged less than 12
months, while this group was approximately one-quarter of the
participants of Hartley 1948, approximately 10% of the participants of Stillerman 1944 and around 5% of the participants of
Cockburn 1950. No information was available on high-risk groups
in the other studies.
With the exception of Cockburn 1950, Endo 2001 and Sheppeard
2009, participants were exposed to measles either by living with
someone diagnosed with measles or being in the same hospital
ward as a person with measles. Cockburn 1950 defined ’intimate’,
’close’ and ’remote’ contact. (Intimate - played with and enrolled in
the same section of the nursery as the primary case; close - exposed
for short periods at play or meals but enrolled in a different section
of the nursery; remote - contact usually confined to exposure in
the entrance hall in the morning or evening or out of doors during
the day). Endo 2001 defined close contact as: a household member
with measles, exposure to a schoolmate or playmate with measles
lasting at least one hour, or exposure to a person with measles in a
medical facility. Sheppeard 2009 defined exposure as: anyone who
was in the same room as the case, or the same room for up to two
hours after the case, during the infectious period.
The interval between exposure and intervention or control was
within seven days for 10 studies, within eight days for Stillerman
1944 and not reported for the other two studies (Salomon
1923; Wesselhoeft 1928). The intervention was convalescent
serum given intramuscularly in six studies (Degkwitz 1920;
Morales 1930; Salomon 1923; Stillerman 1944; Toomey 1926;
Wesselhoeft 1928). Morales 1930 and Salomon 1923 also trialled
adult serum intramuscularly. Doses ranged from 2.5 ml to 20 ml.
The remaining seven studies trialled gamma globulin intramuscularly. With the exception of Glyn-Jones 1972, whose participants
received 2 ml every three weeks until discharge, studies trialling
gamma globulin varied the single administered dose usually in response to participants’ weight or age.
With the exception of Degkwitz 1920, all studies trialling convalescent serum included a ’no treatment’ control group. Degkwitz
examined 3 ml compared to 2.5 ml of convalescent serum both
on day four after exposure in one trial and examined 6 ml to 7
ml of convalescent serum on day six after exposure compared to 7
ml to 8 ml of convalescent serum on day seven after exposure in a
second trial.
Three studies trialling gamma globulin included ’no treatment’
control groups (Glyn-Jones 1972; Ordman 1944; Sheppeard
2009). Three studies administered measles vaccine to a control
group (Berkovich 1963; Glyn-Jones 1972; Sheppeard 2009), although Berkovich 1963 administered gamma globulin as well as
vaccine to the same individuals. Hartley 1948 administered convalescent serum of doses between 2.5 ml and 5 ml or more to
the control group. Cockburn 1950 administered adult serum or
reconstituted dried plasma to the control group at a dose of 5 ml.
Endo 2001 used four lots of gamma globulin, each with a different
measles-specific antibody titre (16 IU/ml, 33 IU/ml, 40 IU/ml
and 45 IU/ml). The dose administered was 0.33 ml/kg for each
participant.
All included studies assessed the number of measles cases in each
group as the primary outcome. Five studies assessed complications
due to measles in each study group (Cockburn 1950; Glyn-Jones
1972; Morales 1930; Ordman 1944; Wesselhoeft 1928). One
study ceased follow-up of the ’no treatment’ control group upon
onset of rash and hence only assessed complications in the intervention group (Stillerman 1944). None of these studies described the criteria for determining that complications were due to
measles. Four studies assessed mortality due to measles (Glyn-Jones
1972; Morales 1930; Salomon 1923; Wesselhoeft 1928). None
Post-exposure passive immunisation for preventing measles (Review)
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of these studies described the process for attributing participants’
deaths to measles rather than another cause.
Adverse events were not considered in the majority of the included
studies and only Glyn-Jones 1972 specified adverse events as an
outcome measure in the methods, but under the premise of reactions to measles vaccine rather than gamma globulin. However,
Cockburn 1950 and Morales 1930 also reported on adverse events
amongst their participants and Hartley 1948, Ordman 1944 and
Toomey 1926 made mention of adverse events in their experience
with passive immunisation more generally.
The effectiveness of passive immunisation for the prevention or
cessation of measles outbreaks was not assessed by any included
study.
retrospective designs and two studies where it was not clear that
the comparison group originated from the same population as the
intervention group. Another 21 of those excluded were studies
where either the participants were not susceptible and exposed to
measles or this was unclear. Three studies did not examine intramuscular or intravenous polyclonal immunoglobulins derived
from human serum or plasma. One study did not assess the number of participants who developed measles.
The reasons for exclusion of individual studies where these were
discussed by the authors, after comparison of their independent
assessments, are given in the Characteristics of excluded studies
table. For brevity, we have not listed studies where authors’ independent assessments were in agreement.
Risk of bias in included studies
Excluded studies
Out of the 146 full-text papers retrieved, 108 were not prospective
controlled studies. They included case reports, case series, reviews,
None of the included studies was determined to have a low risk
of bias for all criteria (see Figure 2 and Characteristics of included
studies table).
Post-exposure passive immunisation for preventing measles (Review)
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Figure 2. ’Risk of bias’ summary: review authors’ judgements about each risk of bias item for each included
study.
Post-exposure passive immunisation for preventing measles (Review)
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Allocation
The one included RCT described the random sequence generation
in insufficient detail and we deemed it to have unclear risk of bias
for this criterion (Cockburn 1950). All other studies were at high
risk of bias for this criterion as they were either quasi-randomised
or non-randomised studies.
Glyn-Jones 1972 seemed to allocate participants to interventions
using third parties with no knowledge of the participants. However, this was not explicitly stated and hence we deemed it to be
unclear risk in terms of allocation concealment. The other studies,
including the RCT, were at high risk of bias regarding the allocation of participants to interventions.
Blinding
The intervention, administration of polyclonal immunoglobulins,
is very unlikely to be subject to variation due to performance and,
as such, we deemed all studies at low risk of performance bias.
We assessed detection bias for the outcomes: cases of measles,
complications due to measles, mortality due to measles and adverse events. With the exception of adverse events, each of these
outcomes is objective provided appropriate pre-study definitions
are adopted. Unfortunately, sufficient information was rarely provided to determine whether pre-study definitions had been set.
Similarly, very limited information on blinding was provided in
nearly all included studies.
Given this, we deemed the risk of detection bias to be unclear for
the majority of included studies in relation to measles cases. We
deemed Cockburn 1950, Glyn-Jones 1972 and Sheppeard 2009
to have a low risk of detection bias with respect to cases of measles.
Cockburn 1950 and Glyn-Jones 1972 adequately described blinding procedures despite the lack of information on their case definition of measles and Sheppeard 2009 provided a very clear prestudy case definition that was applied uniformly.
The outcome ’complications due to measles’ was assessed by six
studies. As for cases of measles, Cockburn 1950 and Glyn-Jones
1972 were at low risk of detection bias. Stillerman 1944 assessed
only the intervention group for complications due to measles as
the study ceased follow-up of controls upon the onset of rash. This
study was clearly at high risk of detection bias for this outcome.
The other three studies did not provide sufficient information and
we deemed them at unclear risk (Morales 1930; Ordman 1944;
Wesselhoeft 1928).
The outcome ’mortality due to measles’ was assessed by four studies. Glyn-Jones 1972 was again at low risk. The other three studies
did not provide sufficient information and we deemed them at
unclear risk (Morales 1930; Salomon 1923; Wesselhoeft 1928).
Glyn-Jones 1972 was the only study to specify adverse events as
an outcome measure in the methods, although Cockburn 1950
and Morales 1930 also reported on adverse events amongst their
participants. As Cockburn 1950 and Glyn-Jones 1972 were adequately blinded, these studies were at low risk of detection bias for
this outcome. Morales 1930 did not provide sufficient information and was at unclear risk.
Incomplete outcome data
Most studies reported complete follow-up for the primary outcome measures and were at low risk of attrition bias. Glyn-Jones
1972 reported a loss to follow-up of 20.6% overall, with rates of
19.4% to 22.4% across the three study groups. We considered this
a high risk of bias and we excluded the study from meta-analysis.
Endo 2001 did not specify whether parents who did not report
illness in their child were actively followed up and the authors
could not be contacted. We therefore deemed this study to be
at unclear risk of attrition bias. The author of Sheppeard 2009
provided information that passive surveillance was the means of
participant follow-up. As such we deemed this study to be at high
risk of attrition bias, although no loss to follow-up was reported.
Selective reporting
Toomey 1926 presented some adverse event case series data but
this outcome was not reported in relation to the cohort study
participants. We therefore deemed this study to be at high risk of
reporting bias. Each of the other included studies reported on all
outcomes specified in the methods sections and we deemed them
to be at low risk of reporting bias.
We did not identify multiple publications of the same study. As
the maximum number of studies included in meta-analysis was
seven, we did not have sufficient studies to examine publication
bias using funnel plots.
Other potential sources of bias
Ten of the included studies were non-randomised ’cohort type’
studies. Confounding was not well addressed in any of these studies
and was typically not addressed at all. Confounding is therefore a
likely source of bias in each of these studies and we deemed each
to be at high risk for this criterion.
Effects of interventions
See: Summary of findings for the main comparison
Immunoglobulin compared to no treatment for preventing
measles; Summary of findings 2 Gamma globulin compared to
serum for preventing measles
Three included studies could not be included in meta-analyses because of heterogeneity among the comparison groups
Post-exposure passive immunisation for preventing measles (Review)
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(Berkovich 1963; Degkwitz 1920; Endo 2001). One included
study (Glyn-Jones 1972) could not be included in meta-analyses
as per protocol because loss to follow-up exceeded 20%.
Primary outcomes
1. Cases of measles
Seven included studies that examined the effect of immunoglobulin versus no treatment for the prevention of measles were included in a meta-analysis of the primary outcome ’cases of measles’
(Morales 1930; Ordman 1944; Salomon 1923; Sheppeard 2009;
Stillerman 1944; Toomey 1926; Wesselhoeft 1928). Although all
results favoured the intervention group, statistical heterogeneity
was visually obvious upon examination of the initial forest plot
(Analysis 1.1) and indeed the I² statistic was 87%. The sensitivity
analyses conducted by excluding Salomon 1923, Sheppeard 2009,
Stillerman 1944 and Wesselhoeft 1928 in turn did not alter these
results.
There was no significant difference in the results of the subgroup
which included infants younger than six months of age compared
to the subgroup that did not include infants younger than six
months of age (test for subgroup differences: Chi² test = 0.36,
df = 1 (P value = 0.55), I² statistic = 0%). No other subgroup
analyses were able to examine possible differences in the benefit of
the intervention.
Subgroup analyses examining study type and participant age did
not explain the observed heterogeneity (Analysis 1.2). However,
the subgroup analysis examining the blood product used, as an
approximation of dose, revealed homogenous results for the adult
serum group (risk ratio (RR) 0.52, 95% confidence interval (CI)
0.45 to 0.59; heterogeneity: Chi² test = 0.02, df = 1 (P value =
0.88); I² statistic = 0%) and gamma globulin group (RR 0.17,
95% CI 0.08 to 0.36; heterogeneity: Chi² test = 0.34, df = 1 (P
value = 0.56); I² statistic = 0%), although not the convalescent
serum group (RR 0.49, 95% CI 0.44 to 0.54; heterogeneity: Chi²
test = 49.53, df = 4 (P value < 0.001); I² statistic = 92%) (Analysis
1.2). Excluding Sheppeard 2009 from the gamma globulin group
left only one study in this subgroup and only minimally altered
the risk ratio from 0.17 to 0.15.
Sensitivity analyses that excluded Stillerman 1944, Salomon 1923
and Wesselhoeft 1928, in turn and together, demonstrated that
the former two studies contributed most of the heterogeneity to
the results for the convalescent serum subgroup (Analysis 1.3).
The RR for this subgroup was 0.49 (95% CI 0.44 to 0.54) when
the five eligible studies were included. Excluding Salomon 1923
did not alter the RR (0.49, 95% CI 0.45 to 0.55) and heterogeneity remained high (Chi² test = 46.69, df = 3 (P value < 0.001);
I² statistic = 94%). Excluding Stillerman 1944 affected the RR
considerably and also decreased the heterogeneity, although this
was still significant (RR 0.26, 95% CI 0.21 to 0.33; heterogeneity:
Chi² test = 11.40, df = 3 (P value = 0.010); I² statistic = 74%).
Excluding Wesselhoeft marginally altered the RR 0.50 (95% CI
0.45 to 0.56) but again heterogeneity remained high (heterogeneity: Chi² test = 40.24, df = 3 (P value < 0.001); I² statistic = 93%).
With both Salomon 1923 and Stillerman 1944 excluded, the RR
for the convalescent serum group was 0.21 (95% CI 0.15 to 0.29)
and heterogeneity was minimal (Chi² test = 2.11, df = 2 (P value
= 0.35); I² statistic = 5%) (Analysis 1.3). Excluding Wesselhoeft
as well altered the RR minimally (RR 0.19, 95% CI 0.12 to 0.28)
and resulted in a further small reduction of heterogeneity (Chi²
test = 0.01, df = 1 (P value = 0.90); I² statistic = 0%). Irrespective
of these sensitivity analyses, differences in the subgroup estimates
of effect were significant (P value < 0.001 to 0.02; I² statistic =
93.8% to 75.3%).
Two studies that examined the effect of gamma globulin compared
to a comparison group administered serum (either convalescent
or adult serum) for the prevention of measles were included in a
meta-analysis of the primary outcome ’cases of measles’ (Cockburn
1950; Hartley 1948). Heterogeneity was not significant either visually or statistically (heterogeneity: Chi² test = 3.03, df = 2 (P
value = 0.22); I² statistic = 34%). Similar to the comparison of immunoglobulin to no treatment, the result favoured gamma globulin (RR 0.56, 95% CI 0.46 to 0.69) (Analysis 2.1).
The results of studies which could not be included in the metaanalyses also supported the impact of the dose of immunoglobulins upon effectiveness. Endo 2001 reported that eight of 14
participants administered gamma globulin with a measles-specific
antibody concentration of 16 IU/ml developed measles as compared to one of six participants administered gamma globulin with
a measles-specific antibody concentration of 33 IU/ml and none
of 13 participants administered gamma globulin with a measlesspecific antibody concentration of 40 IU/ml or more. This is a
RR of 0.29 (95% CI 0.05 to 1.85) for the group given 33 IU/ml
gamma globulin compared to the group given 16 IU/ml gamma
globulin. Degkwitz 1920 reported that three of seven participants
administered 2.5 ml of convalescent serum developed measles as
compared to none of 12 participants administered 3 ml of convalescent serum. A RR could not be calculated for this comparison.
Degkwitz 1920 also examined the effect of the time since exposure
on the effectiveness of immunoglobulins for preventing measles.
None of eight participants administered 6 ml to 7 ml of convalescent serum at six days post-exposure compared to one of three
cases administered 7 ml to 8 ml of convalescent serum at seven
days post-exposure developed measles. Again, a RR could not be
calculated for this comparison.
Berkovich 1963 compared measles vaccine and gamma globulin
at 0.02 ml per pound of body weight to gamma globulin alone
at 0.1 ml per pound of body weight and reported that nine of 14
participants given vaccine and gamma globulin and two of four
participants given gamma globulin alone developed measles. This
suggests less risk of developing measles in the gamma globulin
only group but the RR was not statistically significant (RR 0.78,
Post-exposure passive immunisation for preventing measles (Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
19
95% CI 0.27 to 2.23).
Glyn-Jones 1972 compared the effectiveness of gamma globulin,
2 ml every three weeks, with measles vaccine and no treatment.
Twenty-four of 68 participants who received gamma globulin,
seven of 70 participants who received vaccine and 58 of 73 participants who received no measles prophylaxis developed measles.
Thus, among those for whom data were available, the risk of
measles was greater in the gamma globulin group than the vaccine
group (RR 3.53, 95% CI 1.63 to 7.65) and less in the gamma
globulin group than the no treatment group (RR 0.44, 95% CI
0.32 to 0.63).
In addition to comparing gamma globulin to no treatment,
Sheppeard 2009 included a vaccine only group. None of the 82
participants who received vaccine within three days of exposure
developed measles compared to two of the 183 participants who
received gamma globulin within seven days and 13 of the 288 participants who received no treatment. A RR could not be calculated
for comparison of vaccine to the other groups.
2. Mortality due to measles
Three studies were included in the meta-analysis of the primary
outcome ’mortality due to measles’ (Morales 1930; Salomon 1923;
Wesselhoeft 1928). The results were homogenous and favoured the
intervention group (RR 0.24, 95% CI 0.13 to 0.44; heterogeneity:
Chi² test = 0.65, df = 4 (P value = 0.96); I² statistic = 0%) (Analysis
1.4).
Glyn-Jones 1972, not included in the meta-analysis due to loss to
follow-up in excess of 20%, reported that three of 68 participants
in the gamma globulin group, 12 of 73 participants in the no
treatment group and one of 70 participants in the vaccine group
died as a result of measles. Thus gamma globulin reduced mortality
compared to no treatment (RR 0.27, 95% CI 0.08 to 0.91) among
those for whom results were available. Mortality seemed greater in
the gamma globulin group compared to the vaccine group but the
results were not statistically significant (RR 3.09, 95% CI 0.33 to
28.96).
Secondary outcomes
1. Prevention of measles outbreak
No included studies assessed the outcome ’prevention of measles
outbreak’.
2. Cessation of measles outbreak
No included studies assessed the outcome ’cessation of measles
outbreak’.
3. Complications due to measles
Three studies were included in the meta-analysis of the secondary
outcome ’complications due to measles’ (Morales 1930; Ordman
1944; Wesselhoeft 1928). Stillerman 1944 was excluded from the
analysis because of complete missing data in the control group.
The results were homogenous and favoured the intervention group
(RR 0.18, 95% CI 0.05 to 0.60; heterogeneity: Chi² test = 1.23,
df = 3 (P value = 0.75); I² statistic = 0%) (Analysis 1.5).
Two studies not included in the meta-analysis because of heterogenous comparison groups also reported on ’complications from
measles’. Cockburn 1950 reported that two of 212 participants
given gamma globulin compared to five of 215 participants given
adult serum developed complications from measles. This is a RR
of 0.41 (95% CI 0.08 to 2.07). Endo 2001 reported no complications due to measles among any participants.
Glyn-Jones 1972, not included in the meta-analysis due to loss to
follow-up in excess of 20%, reported that four of 68 participants
in the gamma globulin group, 11 of 73 participants in the no treatment group and two of 70 participants in the vaccine group developed complications due to measles. Thus, the gamma globulin
group seemed to be at less risk of complications from measles than
the no treatment group and more at risk of complications than the
vaccine group, but the risk ratios were not statistically significant
(RR for gamma globulin versus no treatment 0.39 (95% CI 0.13
to 1.17); RR for gamma globulin versus vaccine 2.06 (95% CI
0.39 to 10.87)).
4. Occurrence and type of adverse events
Of the included studies that mentioned or recorded adverse
events, no ’serious adverse events’ were reported. Glyn-Jones 1972
recorded adverse events rates of 5% in the gamma globulin group,
4% in the vaccine group and 1% in the no treatment group.
These ’probable vaccine reactions’ were described as rash and fever.
The differences between groups were not statistically significant.
Glyn-Jones 1972 also noted no statistically significant differences
in mortality rates due to presenting illness, or in exacerbations
of presenting illness, between these groups of children who were
hospital inpatients. Morales 1930 noted that two participants in
the intervention group given convalescent serum had a slight fever
and urticarial rash. The control group for this study was ’no treatment’ and data on adverse events were not collected or reported.
Cockburn 1950 noted a few cases (intervention group unspecified) of transient limb stiffness lasting one or two hours among
participants.
Referring to their experience within and beyond the included
study, Ordman 1944 noted no severe adverse reactions to gamma
globulin, with less than 5% of recipients experiencing mild reactions of slight muscle stiffness, local redness and induration.
One recipient of ’several hundred’ experienced fever two days after gamma globulin administration. Hartley 1948, also referring
to observations within and beyond the included study, noted no
Post-exposure passive immunisation for preventing measles (Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
20
Post-exposure passive immunisation for preventing measles (Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
local or general adverse events among gamma globulin recipients.
Toomey 1926, reporting on recipients of convalescent serum over
a two-year period prior to the included study, noted no local reactions, although reported that mild fever within 24 hours of administration and lasting not more than 24 hours was common.
A D D I T I O N A L S U M M A R Y O F F I N D I N G S [Explanation]
Gamma globulin compared to serum for preventing measles
Patient or population: susceptible children exposed to measles
Settings: community and hospitals
Intervention: gamma globulin
Comparison: serum
Outcomes
Measles cases
Illustrative comparative risks* (95% CI)
Assumed risk
Corresponding risk
Serum
Gamma globulin
Study population
464 per 1000
Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
RR 0.56
(0.46 to 0.69)
702
(2 studies)
⊕⊕⊕⊕
high1,2,3,4,5
Not estimable
0
(0)
See comment
Comments
260 per 1000
(214 to 320)
Moderate
554 per 1000
310 per 1000
(255 to 382)
Mortality due to measles Study population
See comment
Moderate
See comment
Mortality was not measured in the studies comparing gamma globulin
and serum
21
Post-exposure passive immunisation for preventing measles (Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Complications due to Study population
measles
See comment
Not estimable
0
(0)
See comment
Complications were not
measured by one of
the two studies comparing gamma globulin
and serum. RCT results
favoured gamma globulin
(RR 0.41, 95% CI 0.08 to
2.07)
Not estimable
0
(0)
See comment
Adverse events were not
specified as a measured
outcome by the studies
comparing gamma globulin and serum. Reporting
was poor and the results
are not amenable to metaanalysis
See comment
Moderate
Adverse events
Study population
See comment
See comment
Moderate
*The basis for the assumed risk is the median control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison
group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RCT: randomised controlled trial; RR: risk ratio
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.
1 Not
downgraded for risk of bias. One of the studies contributing to this estimate is a randomised controlled trial, the other is a cohort
study. Any uncontrolled confounding would have decreased the effect size. Measurement bias was low-risk for the RCT and unclear
for the cohort study. Overall, the downgrade of quality already applied for including cohort studies is all that is warranted.
2 Publication bias strongly suspected. Both studies were published in the first half of the 20th century. Not as many journals existed and
reporting standards were not as rigorous. It is likely that many small studies would not have been published.
3 Upgraded for large effect size. Effect size is large and precise.
4 Upgraded as plausible confounding would reduce the demonstrated effect.
22
Post-exposure passive immunisation for preventing measles (Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
5 Upgraded
for dose-response gradient. Two doses of gamma globulin were used by the RCT. The higher dose was a smaller group
and the confidence intervals overlap with that of the lower dose from this study, but the estimates of effect are consistent with a dose
response.
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23
DISCUSSION
Summary of main results
A total of 13 studies were included in the review: one randomised
controlled trial (RCT), two quasi-RCTs and 10 prospective, nonrandomised, controlled (cohort) studies. No unpublished studies
were included.
Seven studies were included in meta-analysis of immunoglobulin
versus no treatment for measles cases. Heterogeneity was explained
by subgrouping studies according to the blood product used as an
approximation of the dose of immunoglobulin and then excluding two studies among the convalescent serum group thought to
have different dosing and intervention timing to the other studies.
Gamma globulin was most effective at preventing measles (risk
ratio (RR) 0.17, 95% confidence interval (CI) 0.08 to 0.36), followed by convalescent serum (RR 0.21, 95% CI 0.15 to 0.29 to
RR 0.49, 95% CI 0.44 to 0.54) and then adult serum (RR 0.52,
95% CI 0.45 to 0.59).
One study was particularly influential on the convalescent serum
group estimate of effect (Stillerman 1944). This study had a very
large sample size and diverged from the other studies in this group
on some points of methodology, namely the volume range of convalescent serum administered was the largest (5 ml to 20 ml) and
the intervention was administered up to eight days post-exposure
to measles rather than up to seven days. The estimate of effect of
this study was smaller than the other studies in this group. Factors contributing to this may have included: the delay between
exposure and intervention for some participants; the fact that although the maximum volume of serum administered was much
larger than the other studies, the volume range was not applied
uniformly according to age or weight and was not applied consistently across the duration of the study; and the serum was collected from convalescents up to four months after illness (average
two months), which is longer than for other studies where this
was reported (Toomey 1926: eighth day after the rash began to
disappear; Morales 1930: fifth to tenth day of convalescence).
The results of the blood product subgroup analyses were supported
by a meta-analysis of gamma globulin versus serum (either convalescent or adult serum) including two studies. Gamma globulin
was more effective than serum at preventing measles (RR 0.56,
95% CI 0.46 to 0.69).
The apparent dose-effect was further supported by studies not included in the meta-analyses. However, only two studies provided
sufficient information to calculate the dose of measles-specific antibodies administered to participants and as the attack rates in their
intervention groups were not congruous, no minimum effective
dose could be concluded.
Three studies were included in meta-analysis of immunoglobulin
versus no treatment for mortality due to measles. Immunoglobulin
was effective at preventing death due to measles (RR 0.24, 95%
CI 0.13 to 0.44).
Three studies were included in meta-analysis of immunoglobulin versus no treatment for complications due to measles. Immunoglobulin was effective at preventing complications due to
measles (RR 0.18, 95% CI 0.05 to 0.60).
Only two studies included vaccine only comparison groups. Their
results suggested greater effectiveness of vaccine given within three
days of exposure compared to gamma globulin given within seven
days of exposure, but meta-analysis could not be undertaken.
No serious adverse events were observed in any of the included
studies. Non-serious adverse events reported included: transient
fever, rash, muscle stiffness, local redness and induration.
Overall completeness and applicability of
evidence
The ethnic diversity of the populations of the included studies
supports the generalisability of the results. However, ’high-risk
individuals’ were not well represented and, in particular, pregnant women and immunocompromised people were not identified among study participants. Further, only one included study
identified adults among their participants. While it is highly likely
that passive immunisation would also be effective for these groups,
no conclusions can be drawn about possible differences in the
magnitude of effect.
Our investigation of the influence of age on the effectiveness of
immunoglobulins compared to no treatment was limited to subgrouping studies that included infants younger than six months
of age among participants and those that did not. No difference
in the magnitude of effect was observed between these subgroups.
Two included studies were conducted this century and therefore
examined gamma globulin that was likely to contain concentrations of measles-specific antibodies similar to those used in current
practice. These were the only two studies that provided sufficient
information to allow calculation of the dose of measles-specific
antibodies administered to participants. One of these studies administered gamma globulin of different measles-specific antibody
concentrations to different groups and did not include a no treatment group (Endo 2001). The other obtained an estimate of the
measles-specific antibody concentration from the manufacturer
and included a no treatment group (Sheppeard 2009). Despite
overlapping estimates of the administered doses of measles-specific antibody, no conclusions about the minimum effective dose
could be drawn as the attack rates in these intervention groups
across the two studies were not consistent with a unified dose-response relationship. There are a number of possible reasons for this.
Firstly, as mentioned, Sheppeard 2009 did not measure measlesspecific antibody levels in the blood product used for passive immunisation but reported an estimate from the manufacturer. Secondly, the intervention group sizes were very small in Endo 2001.
Thirdly, study methodology was different across these studies and
Sheppeard 2009, in particular, was known to be at high risk of
attrition bias and may have underestimated the number of measles
Post-exposure passive immunisation for preventing measles (Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
24
cases in the group administered gamma globulin if this led to modified measles which was not identified as such.
Only two studies examined the effectiveness of active vaccination alone compared to passive immunisation (Glyn-Jones 1972;
Sheppeard 2009). We were unable to combine these studies in
meta-analysis as per our protocol because the loss to follow-up in
Glyn-Jones 1972 exceeded 20%. Both studies suggested vaccination was more effective at preventing measles cases than passive
immunisation when administered within three days of exposure.
However, study quality, low event rates in Sheppeard 2009 and
the questionable external validity of Glyn-Jones 1972 limit the
conclusions that can be drawn.
No studies specifically examined measles outbreak prevention or
cessation and this is perhaps not unexpected given that we did
not include interrupted time series study designs in the review.
In retrospect, the question of the impact of passive immunisation
(and vaccination) on measles outbreaks is distinct from the individual focus of the questions we asked and may be better posed in
a separate review.
Quality of the evidence
We rated no included studies at a low risk of bias for all criteria.
Critical appraisal was constrained by a lack of information in most
studies, yet study authors could not be contacted to supplement
the information reported, mostly because of the age of the studies.
Despite these limitations, we have rated the overall quality of the
evidence as moderate (see Summary of findings for the main
comparison; Summary of findings 2). This is for the following
reasons:
• Although only one study randomised participants and none
of the non-randomised studies adequately controlled for
confounders, all prespecified confounders, if present and not
controlled for would be expected to cause an underestimation of
effect. The prespecified confounders were: dose according to
weight, time between exposure and intervention, ’high risk’ of
poor outcome (immunosuppression, pregnancy, infancy), other
comorbidity and age. For comparison with no treatment, dose
according to weight and time between exposure and intervention
are not applicable. Non-random allocation to groups would
likely distribute those at ’high risk’, including those with
comorbidity or of particularly susceptible age, into the treatment
group because of the tendency to present for preventive
treatment and because of the clinician’s desire for a good
outcome. If we consider that this group is most likely to become
ill with measles, random allocation would have increased the
estimate of the effect of treatment. The non-randomised study
included in the comparison of gamma globulin and serum
controlled for time between exposure and intervention by
restriction, and demonstrated even distribution according to age
group between treatment groups. As gamma globulin was
thought to be the better product as outlined in the study’s
introduction, those at ’high risk’, including participants with
comorbidity, would have a tendency to be allocated to the
gamma globulin group, meaning that random allocation would
result in an increased estimate of effect. Similarly, as gamma
globulin was thought to be ’more potent’, the study shows that
the proportion of older children who were given the smallest
volume of gamma globulin was larger than the proportion of
older children given the smallest volume of serum. Confounding
because of failing to dose per unit of weight is thus likely (more
of the gamma globulin group would have received a smaller dose
per unit weight), but would result in an underestimate of the
effect of gamma globulin.
• The other important point of potential bias for these
studies was measurement bias in relation to the outcome. There
was only one study that we assessed as at high risk of bias under
this criterion and this was for the outcome ’measles
complications’. All other studies were at low or unclear risk of
bias. Lack of information usually resulted in the unclear rating.
For most studies, measles was diagnosed by a physician but
blinding to treatment group was unknown. The age of the
studies meant that the diagnosis was not usually confirmed by
laboratory testing. If the assessors were not blind, there may be a
bias operating that would overestimate the effect of passive
immunisation. However, the effect size was very large and
therefore likely still to be significant even if this bias was realised.
• The gamma globulin estimates of effect are particularly
pertinent to current practice. Meta-analytic comparison of
gamma globulin compared to another immunoglobulin
preparation for the outcome ’measles cases’ consisted of two
studies, one at low risk of measurement bias and the other at
unclear risk. In this comparison, the study at unclear risk had a
smaller estimate of effect than the one at low risk. Meta-analytic
comparison of gamma globulin compared to no treatment
consisted of two studies, again one at low risk of measurement
bias in relation to the outcome ’measles cases’ and one at unclear
risk. In this comparison, the study at unclear risk did have a
slightly larger effect size but the results of both studies were still
homogenous.
• Acknowledging that dose was approximated, an apparent
dose effect was observed, increasing confidence in the results.
Potential biases in the review process
We used a filter for study design to reduce the results of the electronic searches to a manageable number. However, the use of the
filter may have excluded relevant studies.
We were unable to contact the study authors of many of the retrieved studies, therefore we necessarily relied on reported information. We therefore may have excluded relevant studies because
of the lack of information reported about participant exposure
and/or susceptibility and/or the populations from which participants (mainly controls) were selected.
Post-exposure passive immunisation for preventing measles (Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
25
We were not aware, prior to retrieving studies, that immunoglobulins had been sourced from other than human sera or plasma
in the early days of passive immunisation and this resulted in a
narrowing of the intervention inclusion criteria during the review
process.
It may be argued that the inclusion of non-randomised studies
introduces a bias into the review. However, as outlined above, noneven distribution of confounders between study groups is likely to
have underestimated rather than overestimated the effect size in
this case.
In the absence of reported doses of measles-specific immunoglobulins administered to intervention groups, we used blood product
as an approximation of dose, acknowledging the inherent imprecision.
Agreements and disagreements with other
studies or reviews
No previous systematic reviews have examined passive immunisation for the prevention of measles. Ramsay 2009 presented an
account of some studies that have contributed to the field, noting
the varying estimates of effectiveness. Some of the studies cited by
Ramsay 2009 were included in our review (Endo 2001; Ordman
1944), while others did not meet our inclusion criteria (Black
1960; King 1991; Stokes 1944). Ramsay 2009 also suggested that
the dose of measles-specific antibody is important to the estimates
of effect.
AUTHORS’ CONCLUSIONS
Implications for practice
Compared to no treatment, passive immunisation is of benefit
for preventing measles up to seven days after exposure. Considering the results for gamma globulin (the current immunoglobulin
preparation used in practice) and the attack rate of measles in the
control group of the most recent included study (45 per 1000)
(Sheppeard 2009), the absolute risk reduction for passive immunisation is 37 and the number needed to treat to benefit (NNTB)
is 27 compared to no treatment. Adopting the attack rate of the
control group of the other study comparing gamma globulin to
no treatment (759 per 1000) (Ordman 1944), the absolute risk
reduction would be 629 and the NNTB would be two.
The data for a dose-response effect in our review has come from
subgroup estimates of the different blood products used in the
included studies for preventing measles. There is insufficient evidence to conclude a minimum effective dose of measles-specific
antibodies.
There is insufficient evidence to make firm conclusions regarding
the relative effectiveness of passive immunisation compared to
vaccination at this time.
Implications for research
With the evidence available (of moderate quality), it is clear that
passive immunisation has a large protective effect against measles
for those who are exposed and not immune. However, the available evidence does not include pregnant women nor people who
are immunocompromised and does not adequately distinguish
infants from older participants. This ’high-risk’ group are particularly mentioned in existing public health recommendations
about passive immunisation from countries with low incidences
of measles. Future research should consider the effectiveness of
passive immunisation for preventing measles in this defined ’highrisk’ population and include careful recording of any potential adverse events.
As a dose effect is clearly observed, further efforts should be made
to determine the minimum effective dose of measles-specific antibodies. If sufficient information exists, this may be possible to
do via retrospective cohort studies. In the absence of routinely
collected data that include the measles-specific antibody level of
any immunoglobulin administered, ethical considerations would
likely limit this avenue of study to in vitro experiments.
In this era where measles vaccination is recommended for postexposure prophylaxis for those not at ’high risk’, future studies
should also consider the comparative effectiveness of measles vaccine if possible.
ACKNOWLEDGEMENTS
We would like to thank Liz Dooley and Clare Dooley for their
support and assistance. We also wish to thank the following people
for commenting on the draft protocol: Theresa Wrangham, Sushil
Kabra, Segun Bello, Viviana Rodriguez and Taixiang Wu. Finally
we thank the following people for commenting on the draft review:
Theresa Wrangham, Sushil Kabra, Segun Bello, Robert Ware and
Taixiang Wu.
Post-exposure passive immunisation for preventing measles (Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
26
REFERENCES
References to studies included in this review
Berkovich 1963 {published data only}
Berkovich S, Starr S. Use of live-measles-virus vaccine to
abort an expected outbreak of measles within a closed
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serum and immune goat serum (Tunnicliff). Journal of the
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Kingsbury 1927 {published data only}
Kingsbury AN. Serum prophylaxis in measles. An
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Monnet 1954 {published data only}
Monnet P, Levy M, Gilly R. Trial of prevention of measles
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ou les gamma–globulines d’origine placentaire: A propos
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the prophylaxis of measles. Journal of the American Medical
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∗
Indicates the major publication for the study
Post-exposure passive immunisation for preventing measles (Review)
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30
CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]
Berkovich 1963
Methods
Non-RCT undertaken in December 1961
Participants
Tuberculous patients housed together in a children’s ward of a New York hospital, USA
and exposed to a symptomatic case of measles on the ward. Age and gender not reported
Interventions
1. Commercially produced gamma globulin of 512 neutralising measles titre intramuscularly at 0.1 ml/pound of body weight
2. Ender’s live measles virus vaccine and same lot of commercially produced gamma
globulin at 0.02 ml/pound body weight intramuscularly at separate sites
Outcomes
Cases of measles
Total length of follow up
20 days
Notes
-
Risk of bias
Bias
Authors’ judgement
Support for judgement
Random sequence generation (selection High risk
bias)
Not randomised
Allocation concealment (selection bias)
Those with parental consent received live
virus vaccine while those without consent
for the vaccine received gamma globulin
only
High risk
Blinding of participants and personnel Low risk
(performance bias)
All outcomes
The nature of both interventions is not subject to variation due to performance
Blinding of outcome assessment (detection Unclear risk
bias)
Cases of measles
Not clear who assessed the participants for
signs of measles and no standard definition
of measles was reported
Incomplete outcome data (attrition bias)
All outcomes
Low risk
All participants accounted for in the results
Selective reporting (reporting bias)
Low risk
No outcomes specified that were not reported
Post-exposure passive immunisation for preventing measles (Review)
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31
Berkovich 1963
(Continued)
Confounding
High risk
No measurement of or control for potential
confounders
Cockburn 1950
Methods
RCT undertaken in early 1949
Participants
Children aged between 6 and 60 months of age who attended or resided at child care
institutions in England and Scotland. Around 5% were under the age of 1 year. Just over
half the participants were male
Interventions
1. 225 mg to 450 mg of freeze-dried gamma globulin dissolved in 3 ml to 6 ml of sterile,
distilled water immediately before intramuscular injection
2. 5 ml adult serum containing 0.5% phenol or reconstituted dried plasma intramuscularly
Outcomes
Cases of measles
Complications due to measles
Adverse events
Total length of follow up
21 days
Notes
Adverse events not specified as an outcome in the methods but reported for both groups
collectively: “Apart from transient limb stiffness lasting one or two hours in a few cases,
no local reactions were observed in the globulin or adult-serum groups. One child in
the globulin group developed, three days after inoculation, an urticarial rash which
disappeared in twenty-four hours” (pg 735)
Risk of bias
Bias
Authors’ judgement
Support for judgement
Random sequence generation (selection Unclear risk
bias)
A person who was not giving the injections provided
for each study locality a list of pairs of letters, “G” for
gamma globulin and “A” for adult serum. The order in
which the letters appeared in the pair was determined
by “random sampling numbers”. No further information was reported on how numbers were generated
Allocation concealment (selection bias)
Person giving injections made a list of all eligible consenting contacts, dividing them into groups according
to predefined “intimacy of exposure” levels. Within
each subgroup participants were listed in order of increasing age. From the top of the list, those in each
pair were then allocated based on the letter list. Once
used, the pair of letters was crossed off the list
High risk
Post-exposure passive immunisation for preventing measles (Review)
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32
Cockburn 1950
(Continued)
Blinding of participants and personnel Low risk
(performance bias)
All outcomes
The nature of the interventions means they are not
subject to variation due to performance
Blinding of outcome assessment (detection Low risk
bias)
Cases of measles
The details of the intervention were recorded and
then filed away, with subsequent clinical observations
recorded on a separate sheet (pg 733). While the doctors who gave the injections were the assessors of the
outcomes, the authors tested recall of which child had
which intervention in a preliminary study and “it was
practically impossible for the observer to remember after inoculating the children whether a particular child
had been given gamma globulin or adult serum”
Blinding of outcome assessment (detection Low risk
bias)
Complications from measles
As with cases of measles outcome
Blinding of outcome assessment (detection Low risk
bias)
Adverse events
As with cases of measles outcome
Incomplete outcome data (attrition bias)
All outcomes
Low risk
No loss to follow-up apparent. Each child was observed for 21 days at the child care institutions. If the
child was absent, they were visited at their home. If
no cases of measles occurred in the contacts within 21
days, the trial at that institution was closed
Selective reporting (reporting bias)
Low risk
No outcomes specified that were not reported
Degkwitz 1920
Methods
Non-RCT. Year study undertaken not known
Participants
Children aged 8 months to 13.5 years, exposed to measles in a hospital in Germany
Interventions
1. Convalescent serum administered on day 4 after exposure, 3 ml versus 2.5 ml as
control
2. Convalescent serum 6 ml to 7 ml administered on day 6 after exposure versus day 7
after exposure as control
Outcomes
Measles cases
Total length of follow up
Not reported
Notes
Article in German - assessment based on translation form information
Post-exposure passive immunisation for preventing measles (Review)
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33
Degkwitz 1920
(Continued)
Risk of bias
Bias
Authors’ judgement
Support for judgement
Random sequence generation (selection High risk
bias)
Not randomised
Allocation concealment (selection bias)
Not randomised. Not reported how participants were allocated to groups
High risk
Blinding of participants and personnel Low risk
(performance bias)
All outcomes
The nature of the intervention means it is
not subject to variation due to performance
Blinding of outcome assessment (detection Unclear risk
bias)
Cases of measles
Not clear who assessed the participants for
signs of measles and no standard definition
of measles was reported
Incomplete outcome data (attrition bias)
All outcomes
Low risk
All participants accounted for in the results
Selective reporting (reporting bias)
Low risk
No outcomes specified that were not reported
Confounding
High risk
No measurement of or control for potential
confounders
Endo 2001
Methods
Non-RCT undertaken in 1999 to 2000
Participants
Susceptible infants and toddlers in Japan, of average age 1.5 years, who had close contact
with someone with measles and whose parents consented to participate in the study. 24
boys and 9 girls were enrolled
Interventions
Intramuscular immunoglobulin 0.33 ml/kg within 5 days of exposure. 4 different lots
of commercially obtained immunoglobulins were used. The concentrations of measlesspecific antibody in each were: 16 IU/ml, 33 IU/ml, 40 IU/ml, 45 IU/ml
Outcomes
Cases of measles
Total length of follow up
14 days
Notes
Adverse events not reported
Risk of bias
Post-exposure passive immunisation for preventing measles (Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
34
Endo 2001
(Continued)
Bias
Authors’ judgement
Support for judgement
Random sequence generation (selection High risk
bias)
Not randomised
Allocation concealment (selection bias)
Not randomised. It is not reported how participants were allocated to the different lots
of immunoglobulin
High risk
Blinding of participants and personnel Low risk
(performance bias)
All outcomes
The nature of the intervention means it is not
subject to variation due to performance
Blinding of outcome assessment (detection Unclear risk
bias)
Cases of measles
Parents were asked to report fever or rash
over the 2 weeks subsequent to intervention.
Upon report, a physician examined the child
to confirm the diagnosis. It is not reported
whether the physician was aware of which lot
of IG was administered
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk
It is not clear whether those parents who did
not report illness of their child were actively
followed up although the results suggest follow-up was complete
Selective reporting (reporting bias)
Low risk
No outcomes specified that were not reported
Confounding
High risk
Comparison is made between the 9 children
with clinical measles and the 24 children
without clinical measles over the follow-up
period in terms of age, body weight, interval between exposure and intervention, dose
of IG in ml/kg and measles-specific antibody
titre, suggesting no difference in these characteristics between the 2 groups apart from the
mean measles-specific antibody titre administered. There is no control for confounding
according to lot of IG administered
Glyn-Jones 1972
Methods
Quasi-RCT undertaken in 1968 to 1969
Participants
Susceptible children aged 6 to 35 months admitted to the paediatric unit at Mpilo
Hospital in Zimbabwe (’Rhodesia’ at the time of the study) who were alive the day after
admission
Post-exposure passive immunisation for preventing measles (Review)
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35
Glyn-Jones 1972
(Continued)
Interventions
1. Human immune globulin 2 ml intramuscularly on the day after admission, repeated
at 3-weekly intervals until discharge
2. No treatment
3. Measles vaccine, 1 dose intramuscularly on the day after admission
Outcomes
Cases of measles
Deaths due to measles
Complications from measles
Adverse events - measles vaccine reactions
Total length of follow up
At least 2 weeks after discharge from hospital
Notes
-
Risk of bias
Bias
Authors’ judgement
Support for judgement
Random sequence generation (selection High risk
bias)
Assigned sequentially according to admission order
Allocation concealment (selection bias)
Treatment group assigned by author’s colleague and given to senior ward nurses who
administered the treatment (pg 4). Unclear
if the colleague was involved in the care of
the participants
Unclear risk
Blinding of participants and personnel Low risk
(performance bias)
All outcomes
The nature of the interventions means they
are not subject to variation due to performance
Blinding of outcome assessment (detection Low risk
bias)
Cases of measles
All assessment of participants carried out by
author who was not aware of group allocation
Blinding of outcome assessment (detection Low risk
bias)
Complications from measles
All assessment of participants carried out by
author who was not aware of group allocation
Blinding of outcome assessment (detection Low risk
bias)
Deaths due to measles
All assessment of participants carried out by
author who was not aware of group allocation
Blinding of outcome assessment (detection Low risk
bias)
Adverse events
All assessment of participants carried out by
author who was not aware of group allocation
Post-exposure passive immunisation for preventing measles (Review)
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36
Glyn-Jones 1972
(Continued)
Incomplete outcome data (attrition bias)
All outcomes
High risk
All participants accounted for in results.
Loss to follow-up very similar across groups
but exceeded 20%
Selective reporting (reporting bias)
Low risk
No outcomes specified that were not reported
Hartley 1948
Methods
Non-RCT undertaken in 1943
Participants
Susceptible children aged 0 to 10+ years exposed to ’an undoubted case’ of measles in
their home or child care institution or hospital ward in England or Scotland
Interventions
1. Gamma globulin manufactured in the USA by Cohn cold ethanol fractionation and
administered intramuscularly in doses of 1.2 ml or less, 1.5 ml to 2 ml and 2.5 ml or
more
2. Reconstituted dried human convalescent serum (single batch) intramuscularly in doses
of 2.5 ml, 3.3 ml to 3.5 ml and 5 ml or more
Outcomes
Cases of measles
Total length of follow up
3 weeks post-intervention
Notes
Adverse reactions not specified as an outcome in the methods; very poorly reported and
not specific for this cohort: “no untoward results were noted” (pg 43); “no local or general
reactions followed the injection of gamma-globulin”
Risk of bias
Bias
Authors’ judgement
Support for judgement
Random sequence generation (selection High risk
bias)
Not randomised
Allocation concealment (selection bias)
Not randomised. Not reported how contacts were allocated to intervention group
High risk
Blinding of participants and personnel Low risk
(performance bias)
All outcomes
The nature of the interventions means they are not
subject to variation due to performance
Blinding of outcome assessment (detection Unclear risk
bias)
Cases of measles
Not reported who assessed the participants for signs
of measles and measles is not defined for the purposes
of the study
Incomplete outcome data (attrition bias)
All outcomes
All participants accounted for in the results
Low risk
Post-exposure passive immunisation for preventing measles (Review)
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37
Hartley 1948
(Continued)
Selective reporting (reporting bias)
Low risk
No outcomes specified in the methods that were not
reported
Confounding
High risk
Did not dose according to weight and did not account for ’high risk’ of illness or other comorbidity.
Restricted based on time between exposure and intervention and stratified by dose of gamma globulin/
serum, age and place of exposure
Morales 1930
Methods
Quasi-RCT undertaken in 1928 to 1929
Participants
Susceptible children aged 6 months to 15 years old in Porto Rico exposed to a household
case of measles
Interventions
1. “Injection” of 4 ml to 6 ml pooled convalescent serum obtained from the 5th to 10th
day of convalescence
2. “Injection” of 10 ml to 40 ml pooled serum from adult donors with a history of
measles between 1 and 10 years ago
3. No treatment
Outcomes
Cases of measles
Complications due to measles
Deaths due to measles
Adverse events
Total length of follow up
8 weeks following exposure
Notes
Adverse events very poorly reported: “Among more than 500 who received injections
of serum, only 2 children showed reactions; they had slight fever, accompanied by an
urticarial rash” (pg 1218)
Risk of bias
Bias
Authors’ judgement
Support for judgement
Random sequence generation (selection High risk
bias)
“Every third child was regarded as a control
and received no treatment, while each of
the remainder received an injection of either
convalescent or immune serum” (pg 1216)
Allocation concealment (selection bias)
Not reported who allocated participants to
groups or whether the person allocating had
any knowledge of participant characteristics
High risk
Post-exposure passive immunisation for preventing measles (Review)
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38
Morales 1930
(Continued)
Blinding of participants and personnel Low risk
(performance bias)
All outcomes
The nature of the interventions means they
are not subject to variation due to performance
Blinding of outcome assessment (detection Unclear risk
bias)
Cases of measles
Inspectors visited the participants at home
at regular intervals and reported illness to
one author who then visited the participant
immediately to determine the cause of illness. Not reported whether the author was
blinded to intervention group
Blinding of outcome assessment (detection Unclear risk
bias)
Complications from measles
No definition of complications from
measles is reported for the purposes of study.
Not reported who assessed participants for
complications or whether they were blind
to intervention group
Blinding of outcome assessment (detection Unclear risk
bias)
Deaths due to measles
Unclear whether the author who confirmed
measles diagnosis was blind to intervention
status. Unclear whether the deaths reported
are only those felt to be connected to measles
or all deaths
Blinding of outcome assessment (detection Unclear risk
bias)
Adverse events
Inspectors visited the participants at home
at regular intervals and reported illness to
one author who then visited the participant
immediately to determine the cause of illness. Not reported whether the author was
blinded to intervention group
Incomplete outcome data (attrition bias)
All outcomes
Low risk
All participants accounted for in results
Selective reporting (reporting bias)
Low risk
No outcomes specified that were not reported
Ordman 1944
Methods
Non-RCT undertaken in 1942 to 1943
Participants
Susceptible children 6 months of age and older living in Boston, USA exposed to a
household member with measles
Interventions
1. Single batch of gamma globulin prepared by Cohn cold ethanol fractionation 2 ml to
5 ml IM in the gluteal region
2. No treatment
Post-exposure passive immunisation for preventing measles (Review)
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39
Ordman 1944
(Continued)
Outcomes
Cases of measles
Complications due to measles
Total length of follow up
3 weeks after intervention
Notes
Adverse reactions not specified as an outcome in the methods, poorly reported and not
specific for this cohort. “No severe reactions have been observed in the several hundred
individuals inoculated with it. In less than 5 per cent of these, mild reactions occurred.
With a single exception, the reactions consisted of a slight feeling of stiffness in the
muscle injected or a little local erythema and induration. In one case, the individual had
a rise in temperature to 102°F 2 days after inoculation but no other systemic or local
manifestation. Whether or not this febrile reaction was due to the globulin cannot be
stated” (pg 547)
Risk of bias
Bias
Authors’ judgement
Support for judgement
Random sequence generation (selection High risk
bias)
Not randomised
Allocation concealment (selection bias)
“When there were 2 or more susceptible contacts in a family, they were divided into 2
groups composed of persons as nearly alike
as possible with respect to age and degree of
exposure. Children over 15 years of age were
placed in the control group” (pg 542)
High risk
Blinding of participants and personnel Low risk
(performance bias)
All outcomes
The nature of the intervention means it is not
subject to variation due to performance
Blinding of outcome assessment (detection Unclear risk
bias)
Cases of measles
Family was visited by one of the authors at
each follow-up. Not reported whether assessors were different to those who had given the
interventions or whether they were blinded
to intervention group
Blinding of outcome assessment (detection Unclear risk
bias)
Complications from measles
As for cases of measles outcome
Incomplete outcome data (attrition bias)
All outcomes
Low risk
All participants accounted for in results
Selective reporting (reporting bias)
Low risk
No outcomes specified in the methods that
were not reported
Post-exposure passive immunisation for preventing measles (Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
40
Ordman 1944
(Continued)
Confounding
High risk
Adjusted dose to age as in methodological
protocol but no other measurement or control for confounding
Salomon 1923
Methods
Non-RCT. Year study undertaken not reported
Participants
Children aged older than 3 months in a hospital in Germany
Interventions
1. Convalescent serum (dose not reported)
2. Adult serum 10 ml to 15 ml
3. No treatment
Outcomes
Measles cases
Death due to measles
Total length of follow up
Not reported
Notes
Article in German. Assessment based on translation form information
Risk of bias
Bias
Authors’ judgement
Support for judgement
Random sequence generation (selection High risk
bias)
Not randomised
Allocation concealment (selection bias)
Not randomised. Interventions administered sequentially in blocks of time according to availability
High risk
Blinding of participants and personnel Low risk
(performance bias)
All outcomes
The nature of the intervention means it is
not subject to variation due to performance
Blinding of outcome assessment (detection Unclear risk
bias)
Cases of measles
Not clear who assessed the participants for
signs of measles and no standard definition
of measles was reported
Blinding of outcome assessment (detection Unclear risk
bias)
Deaths due to measles
Not clear who assessed the participants regarding death due to measles or whether
they were blind to group allocation
Incomplete outcome data (attrition bias)
All outcomes
All participants accounted for in results
Low risk
Post-exposure passive immunisation for preventing measles (Review)
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41
Salomon 1923
(Continued)
Selective reporting (reporting bias)
Low risk
No outcomes specified that were not reported
Confounding
High risk
No measurement of or control for potential
confounders
Sheppeard 2009
Methods
Non-RCT undertaken in 2006
Participants
Susceptible contacts (aged 6 months to 40+ years) of confirmed cases of measles notified
to New South Wales public health units
Interventions
1. MMR if within 3 days of exposure
2. Normal human immunoglobulin (gamma globulin) within 7 days of exposure, 0.2
ml/kg up to 15 ml
3. No treatment
Outcomes
Cases of measles
Total length of follow up
Passive surveillance until 2 incubation periods after the last notified case
Notes
-
Risk of bias
Bias
Authors’ judgement
Support for judgement
Random sequence generation (selection High risk
bias)
Not randomised
Allocation concealment (selection bias)
Not randomised. Allocation determined by length of
time from exposure at point of contact with participant
High risk
Blinding of participants and personnel Low risk
(performance bias)
All outcomes
The nature of the interventions means they are not
subject to variation due to performance
Blinding of outcome assessment (detection Low risk
bias)
Cases of measles
Case of measles defined for the purposes of the study,
criteria objective and likely assessed by other than the
authors
Incomplete outcome data (attrition bias)
All outcomes
High risk
Follow-up by passive surveillance
Selective reporting (reporting bias)
Low risk
No outcomes specified that were not reported
Post-exposure passive immunisation for preventing measles (Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
42
Sheppeard 2009
(Continued)
Confounding
High risk
No control of potential confounders. Measured setting of exposure only
Stillerman 1944
Methods
Non-RCT undertaken in 1938-1941
Participants
Healthy, susceptible children living in New York city, USA, aged 6 months to 15 years
who were exposed to a family member in their household who had been diagnosed with
measles
Interventions
1. Pooled convalescent serum (collected from adolescents and adults up to 4 months
after the onset of measles) 5 ml to 20 ml administered IM into the upper outer aspect
of the buttock or the thigh
2. No treatment
Outcomes
Cases of measles
Complications from measles
Total length of follow up
Up to 23 days after exposure
Notes
-
Risk of bias
Bias
Authors’ judgement
Support for judgement
Random sequence generation (selection High risk
bias)
Not randomised
Allocation concealment (selection bias)
Not randomised. Not reported how participants
were allocated to groups
High risk
Blinding of participants and personnel Low risk
(performance bias)
All outcomes
The nature of the intervention means it is not
subject to variation due to performance
Blinding of outcome assessment (detection Unclear risk
bias)
Cases of measles
Not reported who assessed participants for
measles or whether they were blind to group allocation
Blinding of outcome assessment (detection High risk
bias)
Complications from measles
Complications only reported for intervention
group. Control only followed up until rash onset
if they became ill
Incomplete outcome data (attrition bias)
All outcomes
All participants accounted for in results for cases
of measles
Low risk
Post-exposure passive immunisation for preventing measles (Review)
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43
Stillerman 1944
(Continued)
Selective reporting (reporting bias)
Low risk
No outcomes specified that were not reported
Confounding
High risk
Restricted against ’high-risk’ contacts in terms
of comorbidity. Measured most prespecified
confounders but only undertook univariate
analyses. Did not dose according to weight
Toomey 1926
Methods
Non-RCT undertaken in 1925
Participants
Cohort of susceptible ’children’ exposed on the same hospital ward in the 2 days prior.
Age and gender not reported
Interventions
1. Convalescent serum (obtained 8 days after the rash began to disappear) 2.5 ml to 5
ml administered intramuscularly
2. No treatment
Outcomes
Cases of measles
Total length of follow up
60 days
Notes
Some children had a second exposure
Adverse reactions not specified as an outcome in the methods, poorly reported and not
specific for this cohort. “There was no local reaction to the injection. In most instances
there was a rise in temperature of from 1 to 1.5C, beginning within twenty-four hours
after the injection and lasting rarely longer than twenty-four hours. In six susceptible
subjects, diarrhea was noted” (pg 401)
Risk of bias
Bias
Authors’ judgement
Support for judgement
Random sequence generation (selection High risk
bias)
Not randomised
Allocation concealment (selection bias)
Not randomised. Not reported how participants allocated to groups
High risk
Blinding of participants and personnel Low risk
(performance bias)
All outcomes
The nature of the intervention means it is not subject
to variation due to performance
Blinding of outcome assessment (detection Unclear risk
bias)
Cases of measles
Not reported who assessed participants for signs of
measles or whether they were blind to group allocation; no standard definition of measles was reported
Post-exposure passive immunisation for preventing measles (Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
44
Toomey 1926
(Continued)
Incomplete outcome data (attrition bias)
All outcomes
Low risk
Follow-up of all patients while on the ward and at 60
days
Selective reporting (reporting bias)
High risk
Report contains case series data for which adverse
events were reported but this outcome not reported
in relation to this cohort
Confounding
High risk
No measurement of or control for potential confounders
Wesselhoeft 1928
Methods
Non-RCT undertaken in 1928
Participants
Susceptible children exposed to measles in the diptheria and scarlet fever wings of a
hospital in Boston, USA. Age and gender not reported
Interventions
1. Convalescent serum (collected from older children and adults) 5 ml administered
intramuscularly
2. No treatment
Outcomes
Cases of measles
Complications due to measles
Deaths due to measles
Total length of follow up
Not reported
Notes
-
Risk of bias
Bias
Authors’ judgement
Support for judgement
Random sequence generation (selection High risk
bias)
Not randomised
Allocation concealment (selection bias)
Not randomised. Not reported how participants were
allocated to groups
High risk
Blinding of participants and personnel Low risk
(performance bias)
All outcomes
The nature of the intervention means it is not subject
to variation due to performance
Blinding of outcome assessment (detection Unclear risk
bias)
Cases of measles
Not reported who assessed participants for signs of
measles or whether they were blind to group allocation
and no standard definition of measles was reported
Post-exposure passive immunisation for preventing measles (Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
45
Wesselhoeft 1928
(Continued)
Blinding of outcome assessment (detection Unclear risk
bias)
Complications from measles
Not reported who assessed participants for complications due to measles or whether they were blind to
group allocation
Blinding of outcome assessment (detection Unclear risk
bias)
Deaths due to measles
Not reported who assessed participants regarding
death due to measles or whether they were blind to
group allocation
Incomplete outcome data (attrition bias)
All outcomes
Low risk
All participants accounted for in results
Selective reporting (reporting bias)
Low risk
No outcomes specified that were not reported
Confounding
High risk
No measurement of or control for potential confounders
RCT = randomised controlled trial
IG = immunoglobulin
IM = intramuscularly
MMR = measles, mumps and rubella vaccine
Characteristics of excluded studies [ordered by study ID]
Study
Reason for exclusion
Barenberg 1930
Unclear whether all participants were exposed
Benson 1927
Intervention and control groups not recruited over similar and overlapping time periods
Blackfan 1923
Unclear whether all participants were susceptible
Christensen 1953
Unclear whether all controls were susceptible and placental and plasma globulin were combined as one intervention (results for each not separable)
Gunn 1928
No definable control group for intervention of relevance
Haas 1926
Unclear whether all controls were susceptible
Karelitz 1938
Unclear whether all participants susceptible
King 1991
Retrospective cohort study
Kingsbury 1927
Unclear whether all participants exposed and unclear whether all susceptible
Post-exposure passive immunisation for preventing measles (Review)
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46
(Continued)
Laning 1935
Immunoglobulin used was derived from placentas
LeBlanc 2012
Communication from author that study was retrospective
Lempriere 1939
Unclear whether all participants were exposed
McGuinness 1943
Unclear whether control group were comparable and unclear whether all were susceptible
Monnet 1954
Intervention and control groups not recruited over similar and overlapping time periods
Rivera 1991
Unable to contact study author for further details. Review authors agreed retrospective study from published
details
Weaver 1924
Unclear whether controls came from the same exposed population as the intervention group
Zingher 1924
Unclear whether all were susceptible
We retrieved 144 full-text articles for assessment and excluded 131 of these from the review. Studies included in the above table are
those that were discussed by the authors, after comparison of their independent assessments, because either one or both authors
listed the study as ’unsure’ for inclusion or because there was disagreement in the results of independent assessment.
Post-exposure passive immunisation for preventing measles (Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
47
DATA AND ANALYSES
Comparison 1. Immunoglobulin versus no treatment
Outcome or subgroup title
1 Measles cases
2 Measles cases
2.1 Quasi-RCTs
2.2 Cohort type studies
2.3 Included infants < 6
months of age
2.4 Did not include infants <
6 months of age
2.5 Convalescent serum
2.6 Adult serum
2.7 Gamma globulin
3 Measles cases
3.1 Convalescent serum
3.2 Adult serum
3.3 Gamma globulin
4 Mortality due to measles
5 Complications due to measles
No. of
studies
7
7
1
6
1
No. of
participants
Statistical method
Effect size
696
1575
194
Risk Ratio (M-H, Fixed, 95% CI)
Risk Ratio (M-H, Fixed, 95% CI)
Risk Ratio (M-H, Fixed, 95% CI)
Risk Ratio (M-H, Fixed, 95% CI)
Risk Ratio (M-H, Fixed, 95% CI)
Totals not selected
Subtotals only
0.38 [0.32, 0.45]
0.52 [0.48, 0.57]
0.46 [0.38, 0.56]
5
2001
Risk Ratio (M-H, Fixed, 95% CI)
0.49 [0.45, 0.54]
5
2
2
6
3
2
2
3
3
1140
586
545
Risk Ratio (M-H, Fixed, 95% CI)
Risk Ratio (M-H, Fixed, 95% CI)
Risk Ratio (M-H, Fixed, 95% CI)
Risk Ratio (M-H, Fixed, 95% CI)
Risk Ratio (M-H, Fixed, 95% CI)
Risk Ratio (M-H, Fixed, 95% CI)
Risk Ratio (M-H, Fixed, 95% CI)
Risk Ratio (M-H, Fixed, 95% CI)
Risk Ratio (M-H, Fixed, 95% CI)
0.49 [0.44, 0.54]
0.52 [0.45, 0.59]
0.17 [0.08, 0.36]
Subtotals only
0.21 [0.15, 0.29]
0.52 [0.45, 0.59]
0.17 [0.08, 0.36]
0.24 [0.13, 0.44]
0.18 [0.05, 0.60]
301
586
545
893
832
Comparison 2. Gamma globulin versus serum
Outcome or subgroup title
1 Measles cases
No. of
studies
No. of
participants
2
702
Statistical method
Risk Ratio (M-H, Fixed, 95% CI)
Post-exposure passive immunisation for preventing measles (Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Effect size
0.56 [0.46, 0.69]
48
Analysis 1.1. Comparison 1 Immunoglobulin versus no treatment, Outcome 1 Measles cases.
Review:
Post-exposure passive immunisation for preventing measles
Comparison: 1 Immunoglobulin versus no treatment
Outcome: 1 Measles cases
Study or subgroup
Immunoglobulin
No treatment
n/N
n/N
Morales 1930
166/393
74/92
0.53 [ 0.45, 0.61 ]
Morales 1930
18/120
75/92
0.18 [ 0.12, 0.28 ]
Ordman 1944
5/45
22/29
0.15 [ 0.06, 0.34 ]
Salomon 1923
25/62
30/30
0.41 [ 0.30, 0.56 ]
Salomon 1923
36/72
30/30
0.51 [ 0.40, 0.64 ]
Sheppeard 2009
2/183
13/288
0.24 [ 0.06, 1.06 ]
252/502
195/245
0.63 [ 0.57, 0.70 ]
1/7
6/6
0.20 [ 0.05, 0.87 ]
14/51
25/25
0.28 [ 0.18, 0.44 ]
Stillerman 1944
Toomey 1926
Wesselhoeft 1928
Risk Ratio
Risk Ratio
M-H,Fixed,95% CI
0.002
0.1
Favours immunoglobulin
Post-exposure passive immunisation for preventing measles (Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
1
10
M-H,Fixed,95% CI
500
Favours no treatment
49
Analysis 1.2. Comparison 1 Immunoglobulin versus no treatment, Outcome 2 Measles cases.
Review:
Post-exposure passive immunisation for preventing measles
Comparison: 1 Immunoglobulin versus no treatment
Outcome: 2 Measles cases
Study or subgroup
Immunoglobulin
No treatment
n/N
n/N
Risk Ratio
Weight
Morales 1930
18/120
75/92
41.4 %
0.18 [ 0.12, 0.28 ]
Morales 1930
166/393
74/91
58.6 %
0.52 [ 0.45, 0.60 ]
513
183
100.0 %
0.38 [ 0.32, 0.45 ]
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
1 Quasi-RCTs
Subtotal (95% CI)
Total events: 184 (Immunoglobulin), 149 (No treatment)
Heterogeneity: Chi2 = 26.75, df = 1 (P<0.00001); I2 =96%
Test for overall effect: Z = 11.60 (P < 0.00001)
2 Cohort type studies
Ordman 1944
5/45
22/29
6.3 %
0.15 [ 0.06, 0.34 ]
Salomon 1923
36/72
30/30
10.1 %
0.51 [ 0.40, 0.64 ]
Salomon 1923
25/62
30/30
9.7 %
0.41 [ 0.30, 0.56 ]
Sheppeard 2009
2/183
13/288
2.4 %
0.24 [ 0.06, 1.06 ]
252/502
195/245
61.9 %
0.63 [ 0.57, 0.70 ]
1/7
6/6
1.6 %
0.20 [ 0.05, 0.87 ]
Wesselhoeft 1928
14/51
25/25
8.0 %
0.28 [ 0.18, 0.44 ]
Subtotal (95% CI)
922
653
100.0 %
0.52 [ 0.48, 0.57 ]
Stillerman 1944
Toomey 1926
Total events: 335 (Immunoglobulin), 321 (No treatment)
Heterogeneity: Chi2 = 32.75, df = 6 (P = 0.00001); I2 =82%
Test for overall effect: Z = 13.51 (P < 0.00001)
3 Included infants < 6 months of age
Salomon 1923
25/62
30/30
48.8 %
0.41 [ 0.30, 0.56 ]
Salomon 1923
36/72
30/30
51.2 %
0.51 [ 0.40, 0.64 ]
134
60
100.0 %
0.46 [ 0.38, 0.56 ]
Subtotal (95% CI)
Total events: 61 (Immunoglobulin), 60 (No treatment)
Heterogeneity: Chi2 = 1.21, df = 1 (P = 0.27); I2 =17%
Test for overall effect: Z = 8.08 (P < 0.00001)
4 Did not include infants < 6 months of age
Morales 1930
166/393
74/91
23.5 %
0.52 [ 0.45, 0.60 ]
Morales 1930
18/120
75/92
16.6 %
0.18 [ 0.12, 0.28 ]
Ordman 1944
5/45
22/29
5.2 %
0.15 [ 0.06, 0.34 ]
0.005
0.1
1
Favours immunoglobulin
10
200
Favours no treatment
(Continued . . . )
Post-exposure passive immunisation for preventing measles (Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
50
(. . .
Study or subgroup
Sheppeard 2009
Stillerman 1944
Immunoglobulin
Risk Ratio
Weight
M-H,Fixed,95% CI
Continued)
Risk Ratio
n/N
n/N
2/183
13/288
2.0 %
0.24 [ 0.06, 1.06 ]
252/502
195/245
51.3 %
0.63 [ 0.57, 0.70 ]
1/7
6/6
1.4 %
0.20 [ 0.05, 0.87 ]
1250
751
100.0 %
0.49 [ 0.45, 0.54 ]
Toomey 1926
Subtotal (95% CI)
No treatment
M-H,Fixed,95% CI
Total events: 444 (Immunoglobulin), 385 (No treatment)
Heterogeneity: Chi2 = 50.61, df = 5 (P<0.00001); I2 =90%
Test for overall effect: Z = 15.18 (P < 0.00001)
5 Convalescent serum
Morales 1930
18/120
75/92
19.8 %
0.18 [ 0.12, 0.28 ]
Salomon 1923
25/62
30/30
9.5 %
0.41 [ 0.30, 0.56 ]
252/502
195/245
61.1 %
0.63 [ 0.57, 0.70 ]
1/7
6/6
1.6 %
0.20 [ 0.05, 0.87 ]
Wesselhoeft 1928
14/51
25/25
7.9 %
0.28 [ 0.18, 0.44 ]
Subtotal (95% CI)
742
398
100.0 %
0.49 [ 0.44, 0.54 ]
166/393
74/91
73.7 %
0.52 [ 0.45, 0.60 ]
36/72
30/30
26.3 %
0.51 [ 0.40, 0.64 ]
465
121
100.0 %
0.52 [ 0.45, 0.59 ]
5/45
22/29
72.6 %
0.15 [ 0.06, 0.34 ]
2/183
13/288
27.4 %
0.24 [ 0.06, 1.06 ]
228
317
100.0 %
0.17 [ 0.08, 0.36 ]
Stillerman 1944
Toomey 1926
Total events: 310 (Immunoglobulin), 331 (No treatment)
Heterogeneity: Chi2 = 49.53, df = 4 (P<0.00001); I2 =92%
Test for overall effect: Z = 14.04 (P < 0.00001)
6 Adult serum
Morales 1930
Salomon 1923
Subtotal (95% CI)
Total events: 202 (Immunoglobulin), 104 (No treatment)
Heterogeneity: Chi2 = 0.02, df = 1 (P = 0.88); I2 =0.0%
Test for overall effect: Z = 10.14 (P < 0.00001)
7 Gamma globulin
Ordman 1944
Sheppeard 2009
Subtotal (95% CI)
Total events: 7 (Immunoglobulin), 35 (No treatment)
Heterogeneity: Chi2 = 0.34, df = 1 (P = 0.56); I2 =0.0%
Test for overall effect: Z = 4.63 (P < 0.00001)
0.005
0.1
1
Favours immunoglobulin
Post-exposure passive immunisation for preventing measles (Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
10
200
Favours no treatment
51
Analysis 1.3. Comparison 1 Immunoglobulin versus no treatment, Outcome 3 Measles cases.
Review:
Post-exposure passive immunisation for preventing measles
Comparison: 1 Immunoglobulin versus no treatment
Outcome: 3 Measles cases
Study or subgroup
Immunoglobulin
No treatment
n/N
n/N
Risk Ratio
Weight
Morales 1930
18/120
75/92
67.5 %
0.18 [ 0.12, 0.28 ]
Toomey 1926
1/7
6/6
5.5 %
0.20 [ 0.05, 0.87 ]
Wesselhoeft 1928
14/51
25/25
27.0 %
0.28 [ 0.18, 0.44 ]
Subtotal (95% CI)
178
123
100.0 %
0.21 [ 0.15, 0.29 ]
166/393
74/91
73.7 %
0.52 [ 0.45, 0.60 ]
36/72
30/30
26.3 %
0.51 [ 0.40, 0.64 ]
465
121
100.0 %
0.52 [ 0.45, 0.59 ]
5/45
22/29
72.6 %
0.15 [ 0.06, 0.34 ]
2/183
13/288
27.4 %
0.24 [ 0.06, 1.06 ]
228
317
100.0 %
0.17 [ 0.08, 0.36 ]
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
1 Convalescent serum
Total events: 33 (Immunoglobulin), 106 (No treatment)
Heterogeneity: Chi2 = 2.11, df = 2 (P = 0.35); I2 =5%
Test for overall effect: Z = 9.59 (P < 0.00001)
2 Adult serum
Morales 1930
Salomon 1923
Subtotal (95% CI)
Total events: 202 (Immunoglobulin), 104 (No treatment)
Heterogeneity: Chi2 = 0.02, df = 1 (P = 0.88); I2 =0.0%
Test for overall effect: Z = 10.14 (P < 0.00001)
3 Gamma globulin
Ordman 1944
Sheppeard 2009
Subtotal (95% CI)
Total events: 7 (Immunoglobulin), 35 (No treatment)
Heterogeneity: Chi2 = 0.34, df = 1 (P = 0.56); I2 =0.0%
Test for overall effect: Z = 4.63 (P < 0.00001)
Test for subgroup differences: Chi2 = 32.43, df = 2 (P = 0.00), I2 =94%
0.005
0.1
1
Favours immunoglobulin
Post-exposure passive immunisation for preventing measles (Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
10
200
Favours no treatment
52
Analysis 1.4. Comparison 1 Immunoglobulin versus no treatment, Outcome 4 Mortality due to measles.
Review:
Post-exposure passive immunisation for preventing measles
Comparison: 1 Immunoglobulin versus no treatment
Outcome: 4 Mortality due to measles
Study or subgroup
Immunoglobulin
No treatment
n/N
n/N
Morales 1930
0/120
1/92
4.1 %
0.26 [ 0.01, 6.22 ]
Morales 1930
0/393
1/91
5.9 %
0.08 [ 0.00, 1.90 ]
Salomon 1923
4/25
17/30
37.5 %
0.28 [ 0.11, 0.73 ]
Salomon 1923
5/36
18/30
47.6 %
0.23 [ 0.10, 0.55 ]
Wesselhoeft 1928
0/51
1/25
4.9 %
0.17 [ 0.01, 3.95 ]
625
268
100.0 %
0.24 [ 0.13, 0.44 ]
Total (95% CI)
Risk Ratio
Weight
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
Total events: 9 (Immunoglobulin), 38 (No treatment)
Heterogeneity: Chi2 = 0.65, df = 4 (P = 0.96); I2 =0.0%
Test for overall effect: Z = 4.67 (P < 0.00001)
Test for subgroup differences: Not applicable
0.005
0.1
Favours immunoglobulin
1
10
200
Favours no treatment
Post-exposure passive immunisation for preventing measles (Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
53
Analysis 1.5. Comparison 1 Immunoglobulin versus no treatment, Outcome 5 Complications due to
measles.
Review:
Post-exposure passive immunisation for preventing measles
Comparison: 1 Immunoglobulin versus no treatment
Outcome: 5 Complications due to measles
Study or subgroup
Immunoglobulin
No treatment
n/N
n/N
Morales 1930
0/393
2/91
27.6 %
0.05 [ 0.00, 0.96 ]
Morales 1930
0/120
2/92
19.3 %
0.15 [ 0.01, 3.16 ]
Ordman 1944
0/17
6/43
25.7 %
0.19 [ 0.01, 3.17 ]
Wesselhoeft 1928
2/51
3/25
27.4 %
0.33 [ 0.06, 1.83 ]
581
251
100.0 %
0.18 [ 0.05, 0.60 ]
Total (95% CI)
Risk Ratio
Weight
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
Total events: 2 (Immunoglobulin), 13 (No treatment)
Heterogeneity: Chi2 = 1.23, df = 3 (P = 0.75); I2 =0.0%
Test for overall effect: Z = 2.81 (P = 0.0049)
Test for subgroup differences: Not applicable
0.005
0.1
Favours immunoglobulin
1
10
200
Favours no treatment
Post-exposure passive immunisation for preventing measles (Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
54
Analysis 2.1. Comparison 2 Gamma globulin versus serum, Outcome 1 Measles cases.
Review:
Post-exposure passive immunisation for preventing measles
Comparison: 2 Gamma globulin versus serum
Outcome: 1 Measles cases
Study or subgroup
Gamma globulin
Serum
n/N
n/N
Cockburn 1950
8/37
25/38
15.2 %
0.33 [ 0.17, 0.63 ]
Cockburn 1950
59/175
98/177
59.9 %
0.61 [ 0.48, 0.78 ]
Hartley 1948
24/139
40/136
24.9 %
0.59 [ 0.38, 0.92 ]
351
351
100.0 %
0.56 [ 0.46, 0.69 ]
Total (95% CI)
Risk Ratio
Weight
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
Total events: 91 (Gamma globulin), 163 (Serum)
Heterogeneity: Chi2 = 3.03, df = 2 (P = 0.22); I2 =34%
Test for overall effect: Z = 5.50 (P < 0.00001)
Test for subgroup differences: Not applicable
0.005
0.1
Favours gamma globulin
1
10
200
Favours serum
APPENDICES
Appendix 1. CENTRAL and MEDLINE (OVID) search strategy
1 exp Measles/ (12564)
2 exp Measles virus/ (5522)
3 measles.tw. (17121)
4 (rubeola or rubeolla).tw. (280)
5 or/1-4 (20953)
6 exp Immunoglobulins/ (703484)
7 (immunoglobulin* or immuno-globulin* or immun* globulin*).tw,nm. (282301)
8 (gammaglobulin* or gamma-globulin* or gamma globulin*).tw,nm. (24894)
9 exp Immunization, Passive/ (27269)
10 (passiv* adj2 (immunotherap* or immuni*)).tw. (4143)
11 (passiv* transfer* adj2 antibod*).tw. (294)
12 passive antibody transfer.tw. (35)
13 Post-Exposure Prophylaxis/ (255)
14 ((post exposur* or post-exposur* or postexposur*) adj2 (prophyla* or prevent*)).tw. (1708)
15 or/6-14 (755709)
16 5 and 15 (4922)
Post-exposure passive immunisation for preventing measles (Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
55
Appendix 2. Embase.com search strategy
#16 #5 AND #15 1938
#15 #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 298227
#14 ((postexposur* OR ’post exposure’ OR ’post-exposure’) NEAR/2 (prophyla* OR prevent*)):ab,ti 1589
#13 ’post exposure prophylaxis’/exp 279
#12 (passiv* NEAR/2 (immunother* OR immuni*)):ab,ti 3659
#11 ’passive antibody transfer’:ab,ti 35
#10 (antibod* NEAR/2 ’passive transfer’):ab,ti OR (antibod* NEAR/2 ’passively transferred’):ab,ti OR (antibod* NEAR/2 ’passively
transfer’):ab,ti 251
#9 ’passive immunization’/de 5281
#8 gammaglobulin*:ab,ti OR ’gamma-globulin’:ab,ti OR ’gamma-globulins’:ab,ti OR (gamma NEXT/1 globulin*):ab,ti 5413
#7 immunoglobulin*:ab,ti OR ’immuno-globulin’:ab,ti OR ’immuno-globulins’:ab,ti OR (immun* NEXT/1 globulin*):ab,ti 110314
#6 ’immunoglobulin’/exp 252149
#5 #1 OR #2 OR #3 OR #4 16468
#4 rubeola:ab,ti OR rubeolla:ab,ti 240
#3 measles:ab,ti 12401
#2 ’measles virus’/de 5656
#1 ’measles’/de 9241
Appendix 3. CINAHL (EBSCO) search strategy
S14 S4 and S13 108
S13 S5 or S6 or S7 or S8 or S9 or S10 or S11 or S12 8108
S12 TI (((post exposur* or post-exposur* or postexposur*) N2 (prophyla* or prevent*))) OR AB (((post exposur* or post-exposur* or
postexposur*) N2 (prophyla* or prevent*))) 413
S11 (MH “Postexposure Follow-Up”) 952
S10 TI passive antibody transfer OR AB passive antibody transfer 6
S9 TI passiv* transfer* N2 antibod* OR AB passiv* transfer* N2 antibod* 11
S8 TI (passiv* N2 (immunotherap* or immuni*)) OR AB (passiv* N2 (immunotherap* or immuni*)) 82
S7 TI (gammaglobulin* or gamma-globulin* or gamma globulin*) OR AB (gammaglobulin* or gamma-globulin* or gamma globulin*)
97
S6 TI (immunoglobulin* or immuno-globulin* or immun* globulin*) OR AB (immunoglobulin* or immuno-globulin* or immun*
globulin*) 3229
S5 (MH “Immunoglobulins”) 5000
S4 S1 or S2 or S3 1902
S3 TI ( rubeola or rubeolla ) OR AB ( rubeola or rubeolla ) 17
S2 TI Measles OR AB Measles 1512
S1 (MH “Measles”) 1276
Appendix 4. EMBASE and MEDLINE filter for study type
We combined the following filter for non-randomised prospective intervention studies (not before and after and not time series studies)
with the Cochrane Highly Sensitive Search Strategy for identifying randomised trials (Higgins 2011).
1. exp Cohort Studies/
2. Epidemiologic Studies/
3. Intervention Studies/
4. Evaluation Studies/
5. Program Evaluation/
6. Random Allocation/
7. Clinical Trial/
8. Single-Blind Method/
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9. Double-Blind Method/
10. Control Groups/
11. Pilot Projects/
12. controlled clinical trial.pt.
13. clinical trial.pt.
14. comparative study.pt.
15. multicenter study.pt.
16. evaluation studies.pt.
17. Comparative Study/
18. Multicenter Study/
19. Follow-Up Studies/
20. Prospective Studies/
21. (cohort adj (study or studies)).tw.
22. cohort analy*.tw.
23. cohort*.tw.
24. ((“follow up” or follow-up) adj (study or studies or assessment)).tw.
25. (observational adj (study or studies)).tw.
26. longitudinal.tw.
27. prospective.tw.
28. ((single or double* or triple* or treb*) and (blind* or mask*)).tw.
29. trial*.tw.
30. placebo.tw.
31. groups.tw.
32. (“pre test” or pretest or pre-intervention or preintervention or “pre intervention” or “post test” or posttest or post-intervention or
postintervention or “post intervention”).tw.
33. (pre adj5 post).tw.
34. ((evaluat* or intervention or interventional or treatment) and (control or controlled or study or studies or program* or comparison
or comparative or “usual care”)).tw.
35. ((intervention or interventional or process or program) adj8 (evaluat* or effect* or outcome*)).tw.
36. (program or programme or secondary analyse*).tw.
37. (quasi-experiment* or Quasiexperiment* or “quasi random*” or quasirandom* or “quasi control*” or quasi control* or ((quasi* or
experimental) adj3 (method* or study or studies or trial or design*))).tw.
38. random*.tw.
39. (study adj3 aim*).ab.
40. “our study”.ab.
41. multivariate.ab.
42. compared.ab.
43. intervention*.ti.
44. pilot.ti.
45. (multicentre or multicenter or multi-centre or multi-center).ti.
46. controlled.ti.
47. (rat or rats or cow or cows or chicken* or horse or horses or mice or mouse or bovine or animal*).ti.
48. exp animals/ not humans.sh.
49. (or/1-46) not (47 or 48)
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Appendix 5. Companies manufacturing immunoglobulin products contacted for unpublished studies
•
•
•
•
•
•
•
•
•
•
•
•
•
Bayer Healthcare Pharmaceuticals
BDI Pharma (a business unit of Baxter Healthcare corporation)
Bio Products Laboratory*
CSL Behring
Grifols*
Haffkine Bio-Pharmaceutical Corporation Ltd
Kedrion Biopharma
LFB Biotechnologies
Link Medical Products Pty Ltd
Mirren*
Octapharma*
Sanofi Aventis*
Taj Pharmaceuticals Limited
Companies contacted using details available publicly on their websites in October 2012.
*Companies that responded indicated with an asterisk.
CONTRIBUTIONS OF AUTHORS
Dr Megan Young (MY) and Prof Graeme Nimmo (GN) obtained copies of the studies and selected studies for inclusion in the review.
MY and Prof Allan Cripps (AC) extracted the data and assessed the risk of bias in the studies.
MY and Dr Mark Jones (MJ) entered and analysed the data and interpreted the analysis.
All authors completed the final review.
DECLARATIONS OF INTEREST
Dr Megan Young is a public health physician in Queensland, Australia who is involved in the public health management of measles and a
PhD student whose thesis topic is the effectiveness and efficiency of passive immunisation with NHIG (normal human immunoglobulin)
for the public health management of communicable disease. She is collaborating with staff of CSL Biotherapies, Australia on a study
related to the review topic. She receives no financial benefits from CSL or any other pharmaceutical company.
Prof Allan Cripps and Prof Graeme Nimmo are PhD supervisors for Dr Megan Young.
Dr Mark Jones has no known conflicts of interest.
SOURCES OF SUPPORT
Post-exposure passive immunisation for preventing measles (Review)
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Internal sources
• Griffith University, Australia.
In-kind employee time
• The University of Queensland, Australia.
In-kind employee time
• Queensland Health, Australia.
In-kind employee time
External sources
• No sources of support supplied
DIFFERENCES BETWEEN PROTOCOL AND REVIEW
We had not identified in the protocol that we would search www.clinicaltrials.gov or WHO ICTRP.
We recognised during the search and retrieval of studies that a number of different sources of immunoglobulin had been studied in
the early practice of passive immunisation. GN and MY collectively decided to include only studies where the immunoglobulins used
were sourced from human sera or plasma and exclude studies of immunoglobulins from other sources. This decision was made as these
interventions were felt to be analogous to the current practice of using a blood product manufactured from human plasma, whereas
the other sources are not comparable to current practice.
We recognised during the application of the inclusion criteria, particularly to older studies where no further information was going
to be obtainable from authors, that we needed to increase the specificity of the criteria for inclusion so that they could be applied
consistently. GN and MY discussed the criteria and collectively determined that to be considered a prospective non-RCT (cohort)
study, the intervention and control groups of relevance needed to be recruited over the same (or similar and overlapping) timeframe
and from the same exposed population. Further, to be included, the study must specify that the intervention and control populations
of relevance had been exposed to measles and were susceptible to measles. If any of these points could not be determined from the
information available, either in the publication or from the authors, the study was excluded.
We found that in at least one study with multiple intervention groups the risk ratio for each intervention group compared to control
was clearly heterogenous. We therefore chose, for studies with multiple intervention groups, to split the control group and add each
pair-wise comparison to the relevant meta-analyses rather than calculate a weighted average of the relevant pair-wise comparisons as we
had outlined in the protocol.
We had not listed the secondary outcome ’complications from measles’ among the outcomes for meta-analysis in the protocol but
found this was warranted given the available evidence.
We undertook a number of sensitivity analyses that were not listed in the protocol in response to our inability to undertake subgroup
analyses that were specified in the protocol.
We made the decision to include ’Summary of findings’ tables in the review along with the eligible outcomes for the tables postprotocol.
Post-exposure passive immunisation for preventing measles (Review)
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INDEX TERMS
Medical Subject Headings (MeSH)
Cohort Studies; Immunization, Passive [∗ methods]; Measles [∗ prevention & control]; Post-Exposure Prophylaxis [∗ methods]; Randomized Controlled Trials as Topic; gamma-Globulins [administration & dosage]
MeSH check words
Humans
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