Percentages are adjusted for sampling methods.
Odds are adjusted for sampling methods. Odds of syndrome is defined
as the probability of having the specified syndrome divided by the probability
of not having that syndrome. For definitions of severe anemia, cerebral malaria,
and repiratory distress, see “Methods” section of the text and Table 2. CI indicates confidence interval.
Reyburn H, Mbatia R, Drakeley C, Bruce J, Carneiro I, Olomi R, Cox J, Nkya WMMM, Lemnge M, Greenwood BM, Riley EM. Association of Transmission Intensity and Age With Clinical Manifestations and Case Fatality of Severe Plasmodium falciparum Malaria. JAMA. 2005;293(12):1461-1470. doi:10.1001/jama.293.12.1461
Author Affiliations: London School of Hygiene
and Tropical Medicine, London, England (Drs Reyburn, Drakeley, Carneiro, Cox,
Greenwood, and Riley and Ms Bruce); Kilimanjaro Christian Medical Centre,
Moshi, Tanzania (Drs Reyburn, Mbatia, Olomi, and Nkya); and National Institute
for Medical Research, Amani, Tanzania (Dr Lemnge).
Context There are concerns that malaria control measures such as use of insecticide-treated
bed nets, by delaying acquisition of immunity, might result in an increase
in the more severe manifestations of malaria. An understanding of the relationships
among the level of exposure to Plasmodium falciparum,
age, and severity of malaria can provide evidence of whether this is likely.
Objective To describe the clinical manifestations and case fatality of severe P falciparum malaria at varying altitudes resulting in
varying levels of transmission.
Design, Setting, and Patients A total of 1984 patients admitted for severe malaria to 10 hospitals
serving populations living at levels of transmission varying from very low
(altitude >1200 m) to very high (altitude <600 m) in a defined area of
northeastern Tanzania, studied prospectively from February 2002 to February
2003. Data were analyzed in a logistic regression model and adjusted for potential
clustering within hospitals.
Main Outcome Measures Specific syndromes of severe malaria; mortality.
Results The median age of patients was 1 year in high transmission, 3 years
in moderate transmission, and 5 years in low transmission areas. The odds
of severe malarial anemia (hemoglobin <5 g/dL) peaked at 1 year of age
at high transmission and at 2 years at moderate and low transmission intensities
and then decreased with increasing age (P = .002).
Odds were highest in infants (0-1 year: referent; 2-4 years: odds ratio [OR],
0.83; 95% confidence interval [CI], 0.72-0.96), 5 to <15 years: OR, 0.44;
95% CI, 0.27-0.72; ≥15 years: OR, 0.44; 95% CI, 0.27-0.73; P<.001) and high transmission intensity areas (altitude <600
m: referent; 600 m to 1200 m: OR, 0.55; 95% CI, 0.35-0.84; >1200 m: OR, 0.55;
95% CI, 0.26-1.15; P for trend = .03).
The odds of cerebral malaria were significantly higher in low transmission
intensity areas (altitude of residence <600 m: referent; 600 m to 1200
m: OR, 3.17; 95% CI, 1.32-7.60; >1200 m: OR, 3.76; 95% CI, 1.96-7.18; P for trend = .003) and with age 5 years and
older (0-1 year: referent; 2-4 years: OR, 1.57; 95% CI, 0.82-2.99; 5 to <15
years: OR, 6.07; 95% CI, 2.98-12.38; ≥15 years: OR, 6.24; 95% CI, 3.47-11.21; P<.001). The overall case-fatality rate of 7% (139 deaths)
was similar at high and moderate levels of transmission but increased to 13%
in low transmission areas (P = .03), an
increase explained by the increase in the proportion of cases with cerebral
Conclusions Age and level of exposure independently influence the clinical presentation
of severe malaria. Our study suggests that an increase in the proportion of
cases with more fatal manifestations of severe malaria is likely to occur
only after transmission has been reduced to low levels where the overall incidence
is likely to be low.
In sub-Saharan Africa, malaria continues to impose an enormous burden,
causing between 0.5 and 2 million deaths per year.1 The
Roll Back Malaria initiative aims to halve malaria mortality by 2010,2 with a strategy relying heavily on the use of insecticide-treated
bed nets (ITNs), which have been shown to reduce all-cause mortality among
children younger than 5 years by a mean of 17% in the first 2 years after
However, there have been concerns that the delay in the acquisition
of functional immunity to Plasmodium falciparum and
the increase in the mean age of susceptibility to severe malaria that result
from use of ITNs could increase the more fatal forms of the disease.4,5 This effect would not be apparent initially,
when children benefit from both reduced exposure and the partial immunity
gained from previously high levels of exposure. However, the next generation
of children growing up under conditions of reduced exposure might be vulnerable
to a rebound in mortality as they become older.
These concerns are supported by evidence that hospital admission rates
for severe malaria may plateau at moderate levels of transmission,5- 9 that
cerebral malaria becomes increasingly prevalent as transmission intensity
declines, and that, in any given area, the mean age of children with cerebral
malaria is higher than that of children with severe malarial anemia.5,7,10,11 Because
the case-fatality rate associated with cerebral malaria has consistently been
observed to be 2 to 5 times higher than that associated with severe anemia,12,13 ITN use could result in a paradoxical
increase in mortality. However, the evidence for this concern is indirect,
being based on comparisons of hospital admissions for malaria between distant
populations or where the prevalence of syndromes of severe malaria has been
used as a proxy for expected mortality.
Recently, Lindblade et al14 reported
that the reduction in all-cause mortality associated with ITN use in the first
year of life was sustained for up to 6 years in western Kenya with no evidence
of rebound mortality compared with controls, although controls were given
ITNs after the second year of the study and subsequent mortality among them
was predicted from age-specific mortality in controls in the first 2 years
of the trial. These findings are consistent with at least 2 other studies;
Binka et al15 reported no evidence of increased
mortality 7 years after the end of a randomized trial of ITNs in Ghana, and
Diallo et al16 found no evidence of a shift
of mortality to older ages after 6 years of following a randomized trial of
insecticide-treated curtains in Burkina Faso.
An explanation for this difference between what might be expected from
studies of hospital admissions for severe malaria at differing levels of P falciparum transmission and the results of long-term
follow-up of populations following widespread introduction of ITNs is unclear.
One possibility is that much of the reduction in mortality attributed to ITNs
might be due to a reduction in indirect malaria mortality; ie, deaths not
directly due to malaria but that would not have occurred without previous
episodes of malaria.17 Another possibility
is that studies of how the manifestations of severe malaria vary with different
levels of P falciparum transmission have been unable
to determine the independent effects of different transmission rates, age,
and exposure, to study sufficient numbers of patients to analyze mortality
as an outcome measure, or to avoid confounding arising from comparisons of
Comparing the patterns of severe malaria in stable populations living
under different levels of exposure can provide an estimate of the likely long-term
impact of malaria control on the type and severity of clinical malaria, with
the caveat that human (eg, hemoglobin polymorphisms) and parasite (eg, genetic
diversity) factors associated with high malaria transmission may persist for
many years following reductions in P falciparum transmission.
We have thus carried out the first large-scale prospective study, within a
single area, of the clinical pattern, age, and outcome of admissions to hospital
for severe malaria at different intensities of transmission of P falciparum.
The study was conducted in northeastern Tanzania, an area characterized
by the Eastern Arc of mountains, where a culturally and ethnically similar
population lives at altitudes ranging from sea level to approximately 1800
m and where altitude has been shown to be a valid proxy for the intensity
of P falciparum transmission.20 Malaria
transmission is seasonally endemic across the region, and the mean number
of infected bites per person per year (entomological inoculation rate) varies
from 100 to more than 500 at altitudes below 600 m, from 2 to 34 at altitudes
from 600 through 1200 m, and from 0.03 to 2 at altitudes above 1200 m.20,21 These 3 bands of altitude were selected
as proxy measures of high, moderate, and low transmission, respectively.
Sulphadoxine-pyrimethamine is the first-line antimalarial treatment
in the study area. At low altitude, 7-day parasitological failure rates have
been reported to exceed 40%22 and genetic markers
of high-level sulphadoxine-pyrimethamine resistance have been found to be
equally prevalent at different altitudes in the study area.23 Data
suggest that nutritional status in children younger than 5 years may vary
with altitude in the study area24; thus, nutritional
data were collected and have been controlled for in the analysis.
Ten of the 13 district, regional, or referral hospitals that served
the area were selected on the basis that they routinely provided the standard
of care defined in Tanzanian national guidelines for the treatment of severe
malaria25 and were willing to participate in
the study. Six were district hospitals situated at altitudes from 940 to 1450
m, 2 were a regional and a referral hospital serving a semiurban area of 141 500
people at an altitude of 900 to 970 m, and 2 were district hospitals situated
on the coastal plain at 320 and 198 m, respectively (Figure 1).
The study took place at 9 hospital sites for 1 year starting in February
2002 and at 1 hospital for 6 months starting in August 2002. Because of the
large number of admissions to the district hospital at lowest altitude, cases
under the age of 13 years were recruited on alternate calendar days; alternation
was consistent throughout the study to avoid overrepresentation of any day
of the week. A 4-month pilot study was conducted during which training sessions
were held for hospital staff, with particular attention paid to the consistency
of application of clinical definitions and assessments. Consistency checks
were made regularly throughout the study. At the 3 busiest hospitals, a research
team was based in the pediatric ward and visited other wards 2 to 3 times
per day. In each of the remaining 7 district hospitals, a study clinician
and a team of hospital staff collected data in the course of their usual work,
supported by twice-weekly supervisory visits by a senior project clinician.
All nonpregnant patients admitted with an intention to treat for malaria
were eligible for inclusion and no patient refused participation. Signed (or
thumbprint) informed consent to participate was obtained from patients or
their relatives in every case. Age, sex, brief clinical history, and village
of residence were recorded, followed by an assessment for criteria of potentially
severe disease based on World Health Organization criteria and previous studies
of severe malaria in African children.12,13,26 Patients
with moderate anemia (defined as hemoglobin 5 to <8 g/dL) were also eligible
for inclusion. The criteria for inclusion in the study were therefore (1)
severe anemia (hemoglobin <5 g/dL) or moderate anemia (hemoglobin 5 to
<8 g/dL) (HaemoCue AB, Ängelholm, Sweden); (2) prostration, defined
as inability to sit unsupported (observed) if aged 1 year or older or inability
to suck or drink (observed) if younger than 1 year; (3) impaired consciousness,
defined as unresponsiveness to pain (sternal rub) if younger than 1 year or
inability to localize pain if 1 year or older; (4) confusion, defined as disorientation
in time or place for those aged 5 years or older; (5) respiratory distress,
defined as the presence of lower chest wall inspiratory recession or abnormally
deep respiration; and (6) any degree of jaundice, judged by inspection of
If any of these 6 criteria were present, additional data were collected
on axillary temperature, skin turgor, height and weight if younger than 5
years, history of convulsion or use of anticonvulsant medication, and, if
there was a reduced response to pain, blood glucose level (Accu-Check Active,
Roche Diagnostics, Mannheim, Germany). Cerebral malaria was considered synonymous
with “malaria with impaired consciousness”7 and
was defined as impaired consciousness with any malaria parasitemia (defined
below), blood glucose level greater than 38 mg/dL (2.1 mmol/L), no convulsions
within 1 hour of diagnosis, and no anticonvulsants administered within 6 hours
of diagnosis. Outcome and treatment given were recorded at discharge or death.
Nutritional status was assessed using z scores
for weight and age.
The number of P falciparum asexual parasites
per 200 leukocytes was counted on Giemsa-stained thick blood films. A slide
was considered negative only after scanning 100 high-power fields. All slides
were read twice independently. A third reading was performed if there was
discrepancy between positivity and negativity or if there was more than a
33% difference in parasite count and a difference of more than 10 parasites
per 200 leukocytes. According to this definition, discrepancies were observed
for 706 (15.5%) of 4547 slides, which were then read by a third expert slide
reader. The majority result was accepted for positive/negative discrepancies
and the geometric mean density of parasites was calculated assuming a white
blood cell count of 8000/μL. The findings on cases with negative slide
results have been reported elsewhere.27
Using principal components analysis,28 a
socioeconomic score was generated for each individual based on the number
of occupants and rooms in households, roof construction, and access to electricity.
Altitude of residence was calculated from a global positioning system reading
(Trimble Navigation Ltd, Sunnyvale, Calif) taken from the center of each village
from which cases had been admitted. Tanzanian National Census data (2002)
from districts in the study area suggest that 14.4%, 13.2%, and 14.8% of the
population were younger than 5 years in areas below 600 m, between 600 and
1200 m, and above 1200 m, respectively.29 In
the same study area, Drakeley et al (unpublished data) found that 28% of children
younger than 5 years used bed nets, 6% of which had been impregnated with
insecticide in the previous 6 months; these prevalences did not vary by altitude.
We estimated that 8% of cases at high transmission would be fatal and
that 1230 cases would be sufficient to detect a 50% difference in case fatality
between high and moderate transmission bands with 80% power and 95% confidence.
Data were double-entered in Access 2000 (Microsoft Corp, Redmond, Wash), and
statistical analysis was performed using STATA, version 8 (Stata Corp, College
Station, Tex). Initial survey tabulations and univariate analysis examined
the distribution of cases and case fatality overall and within categories
of various factors. A logistic regression model with weighted estimates and
robust standard errors was used to assess the effect of various factors on
severe cases and mortality allowing for clustering within hospitals. An adjusted
Wald test was used to assess the fit of all models and interactions between
factors in the model. Collinearity diagnostics were used to assess intercorrelation
between predictor variables prior to modeling. Adjusted odds ratios (AORs)
quoted in the text have been adjusted for factors specified in the Tables.
The data were weighted to adjust for the sampling of children on alternate
days in 1 district hospital and stratified into two 6-month periods to allow
for the hospital that was included only for the latter 6 months. Weighted
counts are presented in the results. Weight-for-age z scores
for children were derived from Epi Info (Centers for Disease Control and Prevention,
Atlanta, Ga), which uses a reference population of US children.
Ethical approval for the study was granted by the ethical committees
of the National Institute for Medical Research, Dar es Salaam, Tanzania, and
the London School of Hygiene and Tropical Medicine, London, England.
During the year, 16 775 nonpregnant patients were admitted to the
study hospitals with an intention to treat for malaria. Of these, 12 327
did not meet the study criteria for severe disease, of whom 5076 had a positive
blood slide result for P falciparum at any density
and 47 (0.9%) died.
Of the 4448 patients (27%) who fulfilled the study criteria for severe
disease, blood slide results were available for 4261 (95%); 1984 (47%) were
positive for any density of P falciparum, among whom
139 (7%) died. The following analyses are based on these 1984 cases using
weighted estimates adjusted for the sample design.
Most cases (1560 [62%]) lived in an area of high transmission below
600 m; 830 (33%) lived between 600 and 1200 m and 113 (4.5%) lived above 1200
m (Table 1). Eighty-six percent of cases
were younger than 5 years and only 6.5% were aged 15 years or older. The median
age of cases increased with increasing altitude, and the age distribution
was highly skewed in the low and middle altitude bands
(Figure 2A); the median (mean) ages of cases were 1 (1.9), 3 (6.0),
and 5 (17.1) years for the altitude bands of lower than 600 m, 600 to 1200
m, and higher than 1200 m, respectively.
There was no significant variation by altitude in socioeconomic score
(P = .13), reported travel time to the
hospital (P = .92), mean reported number
of days of illness prior to admission (P = .32),
or use of antimalarial agents in the 48 hours prior to admission (41% overall; P = .20). Prior use of antimalarial agents was
significantly more likely if illness had lasted 3 or more days (P<.001) (complete data available from the authors).
Forty-nine percent of cases (and 78.9% of deaths) presented with cerebral
malaria, severe anemia, or respiratory distress; 218 cases (16.4%) experienced
more than 1 of these syndromes. The combination of respiratory distress and
anemia accounted for 64% of all cases with more than 1 syndrome.
The odds of having a particular clinical syndrome among the admissions
for severe malaria compared with baseline groups for age (≤1 year) and
altitude (<600 m) are shown in Table 2.
A significant reduction in the odds of severe anemia with increasing age group
(P<.001) and with increasing band of altitude
of residence (P = .03) was observed. In
addition, the odds of severe anemia adjusted for the factors listed in Table 2 were positively associated with respiratory
distress (AOR, 1.65; 95% confidence interval [CI], 1.17 to 2.33; P = .004), illness of 3 or more days (AOR, 1.73; 95% CI,
1.45-2.06; P = .007), increase in travel
time (per hour) to hospital (AOR, 1.2; 95% CI, 1.11-1.30; P<.001), and use of an antimalarial agent in the 48 hours prior
to admission (AOR, 1.34; 95% CI, 1.16-1.66; P = .001)
and were negatively associated with reported use of a bed net (AOR, 0.75;
95% CI, 0.64-0.91; P = .003).
The odds of having cerebral malaria increased significantly with both
increasing age group (P<.001) and increasing altitude
of residence (P = .003). Cerebral malaria
was also associated with respiratory distress (AOR, 3.32; 95% CI, 1.89-5.83; P<.001).
The odds of respiratory distress were higher among infants than those
older than 1 year (P = .03) but did not
vary with age after 1 year (P = .70). Cerebral
malaria (AOR, 4.0; 95% CI, 2.42-6.60; P<.001)
and severe anemia (AOR, 1.56; 95% CI, 1.03-2.38; P = .04)
were associated with an increase in the odds of respiratory distress, as was
an increase in travel time (per hour) to hospital (AOR, 1.13; 95% CI, 1.00-1.94; P<.001), while use of an antimalarial agent in the 48
hours prior to admission was associated with a reduced risk of respiratory
distress (AOR, 0.76; 95% CI, 0.61-0.94; P = .01).
Information on malnutrition (weight-for-age z score
<2 SDs below median of reference population) was available for 96% of patients
younger than 5 years and did not vary by altitude (P = .20).
In the models for children younger than 5 years, malnutrition was not a predictor
for any of the 3 severe disease syndromes or case fatality (complete data
available from the authors).
Although the odds of the 3 syndromes of severe malaria varied with age
and altitude (Figure 3), the overall
shape of the age distribution curve of odds for each syndrome was similar
at each band of altitude. Thus, the odds of admission with severe anemia were
highest in children younger than 2 years at all altitude bands and fell most
steeply between 2 and 4 years of age. Similarly, the odds of admission with
cerebral malaria were consistently low for those younger than age 4 years
at all altitude bands and increased in those aged 5 years or older, but with
a progressively steep gradient with increasing altitude.
Of the 1227 cases (48.0%) of severe malaria (by our criteria) without
severe anemia, cerebral malaria, or respiratory distress, 841 (68.5%) had
moderate anemia (hemoglobin level 5 to <8 g/dL) only, 120 (9.8%) had prostration
only, and 156 (12.7%) had a combination of prostration and moderate anemia.
The remaining 83 cases (6.8%) had combinations of moderate anemia or prostration
with confusion or jaundice. Prostration was more likely in the middle and
upper bands of altitude compared with the lowest band (P<.001) but did not vary by age among those older than 1 year. As
with severe anemia, the risk of moderate anemia (hemoglobin 5 to <8 g/dL)
decreased with age (P = .001) and decreasing
altitude (P = .03).
Case fatality by altitude is shown in Figure
2B; case-fatality rates were similar in the middle and lowest bands
of altitude (P = .40) but higher in the
highest band of altitude (altitude <600 m: reference; 600 m to 1200 m:
AOR, 0.39; 95% CI, 0.18-0.83; >1200 m: AOR, 0.69; 95% CI, 0.42-1.15; P = .05). Case fatality by age showed a J-shaped
pattern, being higher in those younger than 1 year, declining between ages
2 and 5 years, and then increasing progressively with increasing age (0-1
year: referent; 2-4 years: AOR, 0.28; 95% CI, 0.18-0.41; 5 to <15 years:
AOR, 0.71; 95% CI, 0.27-1.88; ≥15 years: AOR, 0.99; 95% CI, 0.37-2.62; P<.001). All other predictors from the case-fatality
model are shown in Table 3. Respiratory
distress was most strongly associated with a fatal outcome (AOR, 6.54; 95%
CI, 4.59-9.31; P<.001), followed by cerebral malaria
(AOR, 3.88; 95% CI, 1.67-9.09; P = .004).
In addition to age, the risk of mortality was also strongly influenced by
prostration (AOR, 4.36; 95% CI, 2.30-8.26; P<.001),
convulsions while in the hospital (AOR, 2.90; 95% CI, 1.21-6.94; P = .02), and an increase in travel time (per hour) to the
hospital (AOR, 1.13; 95% CI, 1.05-1.21; P = .003).
Patients with combinations of severe anemia, altered consciousness,
or respiratory distress had particularly high case-fatality rates; the combinations
of cerebral malaria and respiratory distress, severe anemia and respiratory
distress, and severe anemia and cerebral malaria were associated with case
fatalities of 58%, 24%, and 16% respectively.
Among the 1227 cases without respiratory distress, severe anemia, or
cerebral malaria there were 40 deaths (3.3%); in this group, case fatality
did not vary between categories of moderate anemia, prostration, confusion,
or jaundice (P = .90). Although those with
hemoglobin levels between 5 and less than 8 g/dL did not meet World Health
Organization criteria for severe malaria, they had a significantly greater
case-fatality rate (3.1%) than those who did not have severe malaria or moderate
anemia (0.9%) (P<.001).
We have prospectively demonstrated differences in the pattern of severe
malaria at transmission intensities varying from hyperendemic to hypoendemic.
Although some of the findings (for example, the association between increasing
median age of severe disease and decreasing transmission intensity) are consistent
with several previous studies, our study, to our knowledge, is the first to
be able to evaluate separately the effects of age and transmission intensity,
with outcomes across the complete range of malaria transmission.
Currently there is no satisfactory method for characterizing the exposure
of large populations to P falciparum. Microvariation
of malaria transmission occurs for a variety of reasons. In addition, we estimate
that less than 3% of the study population may have been misassigned to a band
of altitude of residence because the village spanned more than 1 altitude
band. However, empirical data20,21 and
the increase in age of cases with increasing altitude in our study, consistent
with previous studies10,11 are
good evidence that altitude in the study area is a good proxy measure of transmission
intensity. Unlike other measures, altitude data have the advantage of availability
at a village level over a wide area.
Our analysis is based on proportions and risks of syndromes among cases
of severe malaria without reference to an estimate of incidence. Although
not ideal, estimates of incidence of severe malaria from hospital admission
rates have produced highly variable results5,6,30,31 that
can distort the true picture of how syndromes of clinical malaria vary with
transmission intensity. We have thus reserved estimates of incidence for a
separate analysis at a later date. The age distribution of severe malaria
cases and known entomological inoculation rate in our low transmission sites
suggest epidemic-prone, unstable malaria where hospital admission rates for
severe malaria have been found to be consistently low.5,9 In
addition, hospital admissions for severe malaria may not be representative
of all severe malaria cases, as an unknown proportion of cases never present
to the formal health care system.32 This inevitable
limitation of hospital studies is almost impossible to overcome because early
detection through community surveillance itself changes the probability of
progression to severe malaria, as suggested by our finding of the association
between duration of illness and fatal outcome of severe malaria. It seems
likely that failure to present to the hospital is more likely for infants
than for older children and adults since the signs of illness can be difficult
to detect and infants do not draw attention to their illness as do older children.
If this is true, our findings will have tended to underestimate syndromes
that are most frequent in infants, the commonest of which was severe anemia.
We were unable to determine whether cases occurred because of transfusion
or vertical transmission. However, in this highly endemic area, transfusion
is unlikely to be a common cause of transmission. Finally, about a quarter
of children younger than 5 years used bed nets. However, use of bed nets did
not vary by altitude and, therefore, was unlikely to confound our analysis.
Severe malarial anemia, although carrying a lower risk of death than
either cerebral malaria or respiratory distress, accounted for more than half
of the admissions meeting strictly defined World Health Organization criteria
for severe malaria26 and almost a third of
all such deaths. Severe anemia was strongly age-dependent, and this association
was similar at all levels of transmission, suggesting that age-related physiological
factors, independent of acquired immunity, modify the risk of severe anemia.
We also found, with borderline significance, that severe anemia was more common
at higher transmission intensities independent of age, probably related to
the more perennial pattern of malaria transmission in lowland areas.33 The duration of reported illness was longer for cases
of severe anemia than for other severe malaria syndromes. This finding, in
conjunction with evidence that in the community, anemia is much more common
in children younger than 2 years than in those 2 years or older,34 suggests
that severe malarial anemia is often an exacerbation of a chronic process
that has either gone undetected by caregivers or is the result of treatment
failure. Our findings suggest that there is an age-related “window of
vulnerability” to severe anemia and that protection of infants and young
children from severe malarial anemia is most unlikely to result in an increase
in this form of the disease in older age groups. Two-year follow-up of children
who were protected from severe anemia in infancy by intermittent presumptive
treatment tends to support this conclusion, in that these children did not
show any increased risk of severe anemia in the second year of life compared
with children who had not received intermittent presumptive treatment.35
In common with previous studies,8,10,11 we
have observed that the proportion of cases with cerebral malaria increases
with falling transmission intensity. However, we have also observed a consistent
association with age: cerebral malaria tends to be relatively uncommon in
children younger than 5 years at all transmission levels and then rises sharply
beginning at 5 years at low and moderate levels of transmission but remains
low at high transmission. The consistency of the finding suggests that (as
for severe anemia) age-dependent physiological factors that operate independent
of acquired immunity influence susceptibility to cerebral malarialike syndromes.
That cerebral malaria is relatively less common at higher transmission suggests
that frequent exposure to P falciparum in infancy
and early childhood allows the development of protective immune mechanisms
prior to the onset of physiological susceptibility to cerebral complications
of malaria. Our findings with regard to both age and altitude are consistent
with the theory that cerebral malaria is to at least some extent an immunopathological
syndrome mediated by adaptive immune responses primed by prior exposure to
malaria or to cross-reacting antigens.36 However,
not all studies have observed such a relationship among risk of cerebral malaria
syndromes, age, and exposure to infection,11,13 and
it seems likely that these relationships are complex and multifactorial, consistent
with evidence that cerebral malaria is a mixed pathophysiological entity.7,37
As in other studies,12,13 we
found that respiratory distress was associated with high case fatality but
that the odds for respiratory distress were generally low, and we found no
association between respiratory distress and age or transmission intensity.
Age-specific case fatality was J-shaped, reaching its lowest level between
the ages of 3 and 4 years; the initial decline is likely to be due to rapid
acquisition of immunity to severe disease among those living in areas of high
transmission, which may occur after very few infections,38 and
the subsequent increase in case fatality in children older than 5 years was
accounted for by the increasing proportion of cases with cerebral malaria.
A J- or U-shaped pattern of age-specific case fatality is in general agreement
with data amalgamated from multiple sites by Marsh and Snow,8 although
in their series, case fatality reached its lowest level between ages 1 and
2 years. The CIs around both these estimates are wide and there is a need
for a larger study to define this, since partial control of malaria, such
as can be achieved with use of ITNs, is likely to be associated with a relatively
small increase in mean age of severe malaria in children younger than 5 years.
Our data on severe malaria in adults are difficult to interpret because
despite the size of the study, the number of cases was small and the pattern
and severity of disease may have been confounded by human immunodeficiency
virus (HIV) infection, estimated to affect 17% of antenatal clinic patients
and 7% of blood donors in this part of Tanzania, but there are currently no
data on differential HIV prevalence in different altitude bands in the study
area.39 Nevertheless, case fatality among adults
with severe malaria was higher than among children, consistent with studies
of malaria among travelers40 and nonimmune
migrants in Asia.41
We have found evidence of a complex relationship between intensity of P falciparum exposure, age, clinical manifestations, and
fatality of malaria, suggesting that age-related factors influence susceptibility
to severe malaria independent of acquired immunity, an observation that might
provide valuable leads toward an understanding of the pathophysiological basis
of severe malaria. Our data are encouraging in that reduction in transmission
of P falciparum in highly endemic areas is likely
to increase the median age of severe malaria from around 1 year to 3 years
of age, an age at which severe malarial anemia becomes less likely, the risks
of cerebral malaria have not yet increased, and the overall case-fatality
rate was at its lowest. However, further reductions in P falciparum transmission are likely to result in a higher proportion
of cases with cerebral malaria, with a consequent increase in case-fatality
rates, but at these levels of transmission our data suggest that the incidence
of severe malaria is likely to be low. This would seem to be a price worth
paying for the benefits of malaria control.
Corresponding Authors: Hugh Reyburn, MD,
Joint Malaria Programme, PO Box 2228, Kilimanjaro Christian Medical Centre,
Moshi, Tanzania (firstname.lastname@example.org); Eleanor M. Riley,
PhD, Department of Infectious and Tropical Diseases, London School of Hygiene
and Tropical Medicine, Keppel Street, London WC1 E7HT, England (email@example.com).
Author Contributions: Dr Reyburn had full access
to all of the data in the study and takes responsibility for the integrity
of the data and the accuracy of the data analysis.
Study concept and design: Reyburn, Carneiro,
Nkya, Lemnge, Greenwood, Riley.
Acquisition of data: Reyburn, Mbatia, Drakeley,
Carneiro, Olomi, Cox, Nkya, Lemnge.
Analysis and interpretation of data: Reyburn,
Mbatia, Drakeley, Bruce, Carneiro, Nkya, Lemnge.
Drafting of the manuscript: Reyburn, Mbatia,
Drakeley, Bruce, Nkya, Lemnge, Riley.
Critical revision of the manuscript for important
intellectual content: Reyburn, Mbatia, Drakeley, Bruce, Carneiro, Olomi,
Cox, Nkya, Lemnge, Greenwood.
Statistical analysis: Reyburn, Bruce, Carneiro,
Obtained funding: Lemnge, Greenwood, Riley.
Administrative, technical, or material support:
Mbatia, Drakeley, Olomi, Cox, Nkya, Lemnge, Riley.
Study supervision: Reyburn, Mbatia, Drakeley,
Olomi, Lemnge, Riley.
Financial Disclosures: None reported.
Funding/Support: This study was funded by the
UK Medical Research Council grant 9901439.
Role of the Sponsor: The UK Medical Research
Council did not participate in the design and conduct of the study, in the
collection, analysis, and interpretation of the data, or in the preparation,
review, or approval of the manuscript. The manuscript was approved for publication
by the London School of Hygiene and Tropical Medicine and by the director
of the National Institute for Medical Research, Tanzania.
Disclaimer: The opinions contained in this
article are those of the authors and are not to be construed as official or
reflecting the views of the UK Medical Research Council. Use of trade names
is for identification purposes and does not imply endorsement by the UK Medical
Research Council or any organization involved in this study.
Acknowledgment: We thank the regional, district,
and hospital staff who assisted in this study, in particular William Mwengee,
Herbert Mbwhana, S. Mgema, Balthazar Ngoli, Charles Kifunda, Werner Shimana,
Cleopa Mbwambo, Justina Mushi, Sister Henrika, Christon Nkya, Alan Minja,
William Silayo, Sr Dr Safari, Richard Mcharo, Waziri Semarundu, Raymond Urassa,
Richard Collins, Francis Assenga, Hilda Mbakilwa, Sia Nelson, Nsia Muro, Elizabeth
Msoka, Theresa Mtui, Sarah Mushi, and Michael Irira. We also thank the laboratory
staff who read blood films: Esther Lyatu, Alutu Masokoto, Frank Magogo, Nico
Funga, Lincoln Male, William Chambo, and Zacharia Savaeli. We are grateful
for contributions to design and analysis from Thor Theander and Daniel Chandramohan.
We thank the patients and their relatives who agreed to participate in the
study. This study was conducted as part of the Joint Malaria Programme, a
collaboration between the National Institute for Medical Research, Tanzania,
Kilimanjaro Christian Medical Centre, London School of Hygiene and Tropical
Medicine, and Centre for Medical Parasitology, University of Copenhagen, Denmark.