International Journal of Epidemiology
© International Epidemiological Association
Vol. 15, No. 3
Printed in Great Britain
Risk Factors for Fatal Measles
Infections
PHILLIP NIEBURG AND MICHAEL J DIBLEY
Recent estimates by UNICEF suggest that measles is
responsible for more than 2.5 million childhood deaths
annually.' Despite this toll, some uncertainty persists
about the factors responsible for fatal outcomes in
measles.
Aaby et al have recently presented in this journal an
interesting re-analysis of data from a severe measles
epidemic that occurred in Sunderland, England, more
than a hundred years ago. 2 The 10% case-fatality rate
(CFR) reported in that epidemic is of the same
magnitude as CFR's reported recently from several
developing countries. 3
As in their earlier papers,4"7 Aaby el al discussed in
their Sunderland re-analysis the roles played in disease
severity by such factors as overcrowding, exposure
intensity, prior respiratory infections, intercurrent
infection; conversely, they 'de-emphasized' the
possible role of malnutrition. They found higher CFR's
in households with more than one measles case. They
felt this higher CFR was primarily due to the greater
frequency of severe complications and higher mortality
among children with secondary cases, who presumably
acquired their infection within their own household.
Children with severe complications had a greater
frequency of history of prior respiratory infection (of
unspecified type and severity) than other children. In
addition, these more seriously ill children were reported
to have had shorter incubation periods in their measles
infections.
The investigators have placed emphasis on speculative theories such as the role of the virus dose absorbed
at the time of infection, suggesting that a greater virus
dose absorbed by a child infected under crowded
conditions could have been the factor chiefly responsible for the shorter incubation period observed in
children with more severe disease.2'5 One might just as
easily have speculated that the shorter incubation
period reflects a more rapid and more extensive viral
Phillip Nieburg, Division of Nutrition, Center for Health Promotion
and Education, Centers for Disease Control, 1600 Clifton Rd, NE
Atlanta, GA 30333, USA.
multiplication (and thus an earlier and more clinically
severe secondary viremia) that could occur because of
depressed host immunity related to malnutrition. The
further observation of an apparent association between
prior respiratory infections and severe measles outcome
among the Sunderland patients may well reflect a predisposition to severe measles caused by the earlier
infection, as suggested by Aaby el al. However, this
association could also reflect confounding if, for
example, the respiratory disease and the severe measles
were both related to pre-existing malnutrition.
Aaby et al point out that Drinkwater, the original
investigator, attributed the severity of the Sunderland
epidemic to 'semi-starvation among the poor.' Because
objective data on nutritional status in the Sunderland
population are unavailable, the role of malnutrition in
this severe measles epidemic cannot be ruled out. In any
case, their analysis is of particular interest because it
calls attention to some of the important contemporary
issues in measles control and in approaches to improving child survival.
The issues raised by Aaby et al and other recent
investigators lead to several important generic
questions related to measles mortality risk in developing societies:
/. What is the magnitude of the increase in measlesrelated mortality risk associated with pre-existing
malnutritionl
As acknowledged by Aaby et al1 nutritional status has
up to now been considered to be one of several
important determinants of measles mortality in
developing countries.9-10 The evidence for this association is strongly suggestive. For example, Chen et al
. observed in a prospective community study in Bangladesh that a group of children with very low weight-forage KGSVo of the reference population median) prior to
infection had a measles mortality rate 2.3 times higher
than children above that threshold." The Kasongo
Project Team found that children whose weight-forage index was in the lowest \O"Io of the study population had a relative measles mortality risk of 2.93 (95%
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310
INTERNATIONAL JOURNAL OF EPIDEMIOI OGY
confidence intervals of 1.60-4.77) compared with the
rest of the population. 12 Additionally, severely malnourished children have been shown to excrete measles
virus for longer periods than better-nourished children,
indicating prolonged risk to themselves as well as a
possible increase in duration of infectiousness and of
intensity of spread to others. 13 Other supportive data
include studies indicating that malnourished children
have altered T-cell function, which might be expected
to put them at increased risk from measles.14
Less conclusive data on the role of malnutrition in
severe measles have generally come from investigations
that compared mean anthropometric indices of those
who died versus those who survived.4'15 However, the
indices for mortality-risk identified by Chen et aln and
others 16 appear to have thresholds below which the
mortality rates rise sharply. Because risk may increase
significantly only below a certain level of malnutrition,
comparisons of means may fail to detect real differences. In addition, because other risk factors for
measles mortality may sometimes have effects greater
than those due to malnutrition, one would not expect to
find clear evidence for an effect of malnutrition in
every setting.
2. Is the additional risk associated with malnutrition
strictly the result of protein-energy malnutrition, or are
deficits of specific micronutrients (eg, vitamin A, zinc)
also involved1.
The role(s) of micronutrient deficiencies in measles
mortality may turn out to be far more important than
currently appreciated. Two leading contenders for such
roles are deficiencies of vitamin A, which has recently
been linked to child survival,17 and zinc, which has an
important role in maintenance of normal immunity.18
Tissue levels of these micronutrients have not been
found to correlate particularly well with anthropometric measurements so that these factors may operate
somewhat independently of protein-energy nutritional
status. In addition, interactions between these micronutrients may occur; zinc deficiency, for example, is
associated with inhibition of vitamin A release from
liver stores.21
3. Which other host or environmental factors can be
clearly linked to measles-related mortality']
An excellent review of risk factors for severe outcome
in measles has recently appeared. 10 In addition to nutritional status, age at infection, type and severity of
complications, and availability of appropriate medical
care have all been implicated as measles mortality risk
factors, at least in some circumstances. Infants have
repeatedly been shown to have higher measles CFR's
than older children. Measles-related diarrhoea,
pneumonia, and central nervous system disease have
each been associated with higher mortality in measles.
Finally, lack of access to appropriate health care has
been implicated as a risk factor in measles mortality,
probably because many of the more severe complications such as pneumonia, dysentery, and diarrhoea are
treatable.
Aaby et al4'1 and Smedman et als proposed other
factors related to crowding and to family structure as
having independent roles in measles mortality. Some of
these factors were suggested to have played important
roles in the Sunderland epidemic.2
It is important to remember that any specific factor
may be a marker for risk of measles mortality while not
being a true determinant of that mortality. A difficult
problem with each of these risk factors is determining
the strength of its causal effect while accounting for
confounding by other factors. Because so many of the
nutritional and health care access factors are related to
socioeconomic status, avoiding such confounding is
not simple. While some of the more recently proposed
measles mortality risk factors2'4"8 may act independently of any confounding by nutritional status or
other factors related to socioeconomic status, the data
currently available to support such contentions are still
limited. To properly clarify the roles in measles
mortality of each individual risk factor, future analyses
should permit control for confounding by other
factors.
4. What are the implications for measles vaccine use
as part of a strategy for improving child survival?
If we accept that measles plays a major role in child
mortality in the developing world, do we necessarily
agree that measles vaccine is the optimal prophylaxis?
It has been suggested that those children who are prevented from dying by measles vaccine are the ones who
remain at greatest risk of dying of other childhood
diseases, particularly diarrhoea, and that the benefits
conferred by measles immunization are thus eventually
decreased or lost entirely.20
The concern of Aaby et al seems to be that attribution of an important role in measles mortality to preexisting malnutrition will result in a greater focus of
attention on childhood malnutrition (a problem for
which simple yet successful long-term solutions are
difficult to design) to the detriment of measles control
programmes.6-7 However, their anxiety in this regard is
probably unjustified. Measles has been implicated by
several studies as a major precipitating factor in the
development of protein-energy malnutrition. 3 Morley
has called measles immunization 'the most significant
RISK FACTORS KOR FATAL MEASLES INFECTIONS
21
public measure available to the developing world.'
More recently, the Director of the Expanded Programme on Immunization of the World Health Organization cited measles control as 'a prerequisite for
primary health care.' 22 Finally, the vaccine has been
convincingly demonstrated to provide immunity to
even severely malnourished children.23 Prevention of
measles through widespread vaccine use is certain to
remain a high priority for those concerned with public
health programmes in developing countries.
The twin lessons from reconsidering the Sunderland
epidemic and from earlier studies by Aaby's group and
many other investigators are (1) that, in different
circumstances, risk factors for measles mortality may
play roles of varying importance and (2) that we still
have much to learn about the relationships between
measles outcome, pre-existing nutritional status, and
other risk factors. Continued careful attention to study
designs that can minimize confounding of outcomes by
interrelated social and biological processes will expedite
our learning process. In the interim, it is worth
remembering that, regardless of the importance of
specific risk factors for disease severity, measles vaccine
can effectively prevent much of the mortality and
morbidity due to measles.
1
2
3
4
3
6
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