Background About 90 percent of the deaths from malaria are inAfrican children, but criteria to guide the recognition andmanagement of severe malaria have not been validated in them.
Methods We conducted a prospective study of all children admittedto the pediatric ward of a Kenyan district hospital with a primarydiagnosis of malaria. We calculated the frequency and mortalityrate for each of the clinical and laboratory criteria in thecurrent World Health Organization (WHO) definition of severemalaria, and then used logistic-regression analysis to identifythe variables with the greatest prognostic value.
Results We studied 1844 children (mean age, 26.4 months) witha primary diagnosis of malaria. Not included were 18 childrenwho died on arrival and 4 who died of other causes. The mortalityrate was 3.5 percent (95 percent confidence interval, 2.7 to4.3 percent), and 84 percent of the deaths occurred within 24hours of admission. Logistic-regression analysis identifiedfour key prognostic indicators: impaired consciousness (relativerisk, 3.3; 95 percent confidence interval, 1.6 to 7.0), respiratorydistress (relative risk, 3.9; 95 percent confidence interval,2.0 to 7.7), hypoglycemia (relative risk, 3.3; 95 percent confidenceinterval, 1.6 to 6.7), and jaundice (relative risk, 2.6; 95percent confidence interval, 1.1 to 6.3). Of the 64 childrenwho died, 54 were among those with impaired consciousness (n= 336; case fatality rate, 11.9 percent) or respiratory distress(n = 251; case fatality rate, 13.9 percent), or both. Hence,this simple bedside index identified 84.4 percent of the fatalcases, as compared with the 79.7 percent identified by the currentWHO criteria.
Conclusions In African children with malaria, the presence ofimpaired consciousness or respiratory distress can identifythose at high risk for death.
Malaria remains a major cause of childhood morbidity and mortalityin the tropics. The World Health Organization (WHO) has workedto define standard criteria for the recognition and managementof severe malarial disease.1 However, although African childrenaccount for 90 percent of the mortality associated with Plasmodiumfalciparum worldwide,2 there have been no comprehensive clinicaldescriptions of severe malaria in this group. Although therehave been studies in other populations, there may be major differencesin the clinical manifestations of malaria at different agesand under different levels of endemicity. We report here theresults of a study of malaria in hospitalized Kenyan children.Our goal was to define the spectrum of severe disease and toassess the appropriateness of the current WHO criteria for severeand complicated malaria.1
Methods
Study Site
The study was carried out at Kilifi District Hospital, Kenya.A detailed description of the predominantly rural populationserved by this hospital has been published elsewhere.3 Approximately120,000 outpatients are seen each year, and an average of 3000children are admitted yearly to the 35-bed pediatric ward.
Data Collection
Since 1989 a research team from the Kenya Medical Research Institute(KEMRI) has been part of the pediatric inpatient service ofthe hospital. All children are seen on admission by a KEMRIclinician, and summary data are recorded for entry in a cumulativedata base. A blood sample is taken to determine the hemoglobinconcentration and the white-cell count (Coulter counter, CoulterElectronics), and to allow a quantitative examination of a bloodfilm for malarial parasites. Other studies — includingmeasurements of plasma creatinine, electrolytes, glucose, lactate,and blood gases, as well as radiographic and microbiologic studies— are performed as clinically indicated.
We have used data on all children admitted between may 1989and November 1991 with a primary diagnosis of malaria. Thisdiagnosis was made only when a child had peripheral parasitemiaand no other detectable cause for the clinical presentation,after a review of all the available data.
Clinical Assessment
All children were assessed according to the WHO criteria forsevere and complicated malaria,1 which consist of 10 definingclinical or laboratory criteria, supported by 5 additional,nondefining, criteria (Table 1). The state of the patients'consciousness was assessed with use of the Blantyre coma score,4,5which is designed for use in young children and is based onverbal, motor, and gaze responses to stimulation. To distinguishbetween coma and transient postictal phenomena, children whohad seizures were ascribed a definitive coma score one hourafter the termination of the seizure, or after six hours ifthe seizure was terminated with anticonvulsant drugs. Prostration1was determined by observing whether a sitting position couldbe maintained without support from an attendant. Since pulmonaryedema is undefined in the WHO criteria, we have substituteda more clinically useful criterion, which we have termed respiratorydistress. Respiratory distress was defined as the presence ofany of the following signs: alar flaring, chest recession (intercostalor subcostal), the use of accessory muscles of respiration,or abnormally deep (acidotic) breathing. The more restrictivecriterion of severe respiratory distress was satisfied onlyby the children with documented recession or abnormally deepbreathing. Other minor operational modifications of the WHOcriteria are described in Table 1.
Table 1. Prevalence of Conditions Included in the WHO Criteria for Severe Malaria among Kenyan Children Admitted to the Hospital, and Associated Mortality.
Management
All children with evidence of neurologic involvement or withother acutely severe features such as respiratory distress weretreated with parenteral quinine.6 Children able to take oralmedication received chloroquine until January 1990; thereafter,they received pyrimethamine–sulfadoxine (Fansidar) pluschloroquine. Acetaminophen syrup or suppositories were usedroutinely as antipyretic agents. The blood glucose concentrationsof children with disturbed consciousness were measured frequently(every one to four hours) at the bedside. Comatose childrenhad nasogastric tubes inserted and their stomach contents aspirated.Convulsions were controlled with either intramuscular paraldehydeor intravenous diazepam. Phenytoin — if necessary, withthe addition of phenobarbital — was used as the standardtreatment of children with uncontrolled seizures. All childrenwith evidence of neurologic involvement underwent lumbar punctureto exclude a diagnosis of meningitis; because we have seen raisedintracranial pressure in children with cerebral malaria,7 lumbarpuncture was delayed until the patient had regained consciousnessto the point of being able to localize a painful stimulus; meanwhile,the child was treated presumptively with benzyl penicillin andchloramphenicol, the standard regimen in Kenya for childhoodmeningitis. This treatment was discontinued once the possibilityof meningitis had been excluded. Blood transfusions for severeanemia (defined as hemoglobin concentrations <5 g per deciliter)were restricted to children with respiratory distress.8,9 Anexception was made for children with hyperparasitemia (>20percent) and low hemoglobin concentrations, in whom transfusionwas sometimes initiated to compensate for the anticipated rapidloss of red cells over the subsequent 24 hours.
Statistical Analysis
Analysis was carried out with the use of SPSS PC+ and EGRET.Initially, frequency distributions of all variables were producedto allow us to observe the spread and decide on suitable groupingcategories. In general, groups for continuous variables werechosen on the basis of accepted clinical cut-off points (e.g.,hypoglycemia: a glucose concentration of less than 40 mg perdeciliter [2.2 mmol per liter]; severe anemia: a hemoglobinconcentration of less than 5 g per deciliter).
With the use of EGRET, univariate logistic-regression modelswere fitted for all variables, with death as the outcome variable,and adjustment for age. Relative risks of dying were estimatedas odds ratios with 95 percent confidence intervals.
A relatively generous cut-off point was chosen in deciding whichvariables were important enough to merit inclusion in a multivariatemodel that would best explain the risk of death. All variableswith a P value of 0.10 or less were included in the first fitof the multivariate model. Each variable in turn was then removedfrom the model, and its effect on overall deviance and the associatedP value observed. All variables that had a significant overalleffect on the model (P<0.05) were then retained for inclusionin a minimal effects model, the one that best explained outcome.Age was again retained in the minimal-effects model. All possibletwo-way interactions were added to the model in turn to testsignificance.
Results
Between May 1989 and November 1991, 7538 children were admittedto Kilifi District Hospital. P. falciparum was detected in theperipheral-blood films of 3014 children (40 percent), of whom1866 had a primary diagnosis of malaria. The mean age of childrenadmitted with a primary diagnosis of malaria was 26 months,and 86 percent were under 4 years of age. There was no predominanceof either sex at any age. Eighty-six children died (case fatalityrate, 4.6 percent; 95 percent confidence interval, 3.7 to 5.6).Eighteen children arrived in a moribund state and died duringinitial attempts at resuscitation and before the admission procedurecould be completed. An additional four children died later,not primarily because of malaria, although this had been theoriginal reason for admission to the hospital. The case fatalityrate in the 64 children with a primary diagnosis of malariawho completed the admission procedure (1844 children) was thus3.5 percent (95 percent confidence interval, 2.7 to 4.3 percent),with 84 percent of the deaths occurring within 24 hours of admission.The rest of the analysis presented in this paper is based ondata from these 1844 children. The incidence of severe malariaamong patients admitted to the hospital declined markedly afterthe age of four years, and there were only two deaths attributableto malaria in children over four years of age.
Clinical and Prognostic Features of the Group as a Whole
The prevalence of clinical features that either define or areassociated with severe disease in the WHO criteria is shownin Table 1. To assess the prognostic importance of clinicalfindings on admission, we first performed a univariate analysis,stratified by age, using the variables listed in Table 1. Thesevariables, with the exception of those that were too rare (shock,renal failure, spontaneous bleeding, and hemoglobinuria) weremodeled with the use of logistic-regression analysis. We alsoexcluded acidosis, since our sample was small and biased towardvery ill children, as a result of our not having the abilityto perform routine measurements during the whole study period,since we did not have a working pH and blood gas machine duringthe study. The full model could only be fitted with data onthe 673 children whose venous blood glucose concentrations weredetermined on admission and for whom no data were missing. Themodel was therefore refitted without blood glucose as a variable,allowing the inclusion of 1776 patients (96 percent) with aprimary diagnosis of malaria. The minimal-effect models withand without blood glucose values are shown in Table 2. Thisapproach identified four variables as key prognostic indicatorsin inpatients with malaria: impaired consciousness, respiratorydistress, jaundice, and hypoglycemia. These were used to constructsimple prognostic indexes, which are compared with the WHO criteriafor severe malaria in Table 3.
Table 3. Comparison of Alternative Prognostic Criteria for Severe Malaria.
Specific Clinical Subgroups
Impaired Consciousness
The definitions of impaired consciousness and cerebral malariaare controversial.9 We have limited the term cerebral malariato children who satisfy the strict WHO criteria of being ina deep coma, unable to make a localizing response. We used theterm impaired consciousness for those with a Blantyre coma scoreof 4 or less to allow comparison with other recent studies ofcerebral malaria.4,5
Three hundred thirty-six children had coma or impaired consciousnesson admission, with a mortality rate of 11.9 percent. One hundredeighty-five of these children were profoundly comatose and satisfiedthe stricter WHO definition of cerebral malaria, with a mortalityrate of 16.8 percent. These groups form a continuum; the conditionsof an additional 23 children deteriorated enough to satisfythe stricter definition at some point after admission. For somepurposes it may be desirable to widen the definition of neurologicinvolvement even further to include children who are prostrate.1They present a characteristic picture: although fully conscious,they are hypotonic and unable to sit up. There were 192 suchchildren, and the mortality rate was 5.2 percent. Many had otherfeatures of severe disease, particularly jaundice or hypoglycemia;such children need to be identified to receive more intensivetreatment.
Factors strongly related to mortality in children presentingwith neurologic involvement included respiratory distress (relativerisk, 3.7; 95 percent confidence interval, 1.7 to 8.0; P<0.001);hypoglycemia (relative risk, 3.6; 95 percent confidence interval,1.5 to 7.8; P = 0.001); and deep coma (relative risk, 4.8; 95percent confidence interval, 1.6 to 13.9; P = 0.008). Severeanemia (hemoglobin concentration, <5 g per deciliter) andjaundice were not significantly related to mortality.
Respiratory Distress
Two hundred fifty-one children were reported by the admittingclinician to be in some degree of respiratory distress; 35 ofthese children (13.9 percent) subsequently died. The more precisecategory of severe respiratory distress proved more useful inidentifying high-risk children: of 133 children so described,33 (24.8 percent) died. Of the 133 children with severe respiratorydistress, 63 also had impaired consciousness, and this grouphad a mortality rate of 31.7 percent, as compared with 18.6percent in the remaining children. Children with respiratorydistress were significantly younger (mean age, 19 months) thanchildren with impaired consciousness (mean age, 35 months);children with both conditions were of an intermediate age (26months). No level of respiratory rate (even when adjusted forage) proved as useful as either respiratory distress or severerespiratory distress as a prognostic indicator. Similarly, thepresence of auscultatory findings (crackles or wheezing) hadno relation to the outcomes either in the group of all patientsadmitted with malaria as a whole or in the children with respiratorydistress.
Plasma bicarbonate was not measured routinely throughout thestudy period; however, data were available on 38 of the childrenwith severe respiratory distress. Since the mortality rate wasnot significantly different between the group with and the groupwithout plasma bicarbonate data (22 percent vs. 26 percent),there seems to have been no obvious bias toward sampling sickerchildren. Of the children with severe respiratory distress inwhom plasma bicarbonate was measured, 81.4 percent had severeacidosis (plasma bicarbonate concentrations of <15 mmol perliter), and all 11 children who died had plasma bicarbonateconcentrations below 10 mmol per liter.
Severe Anemia
There were 508 children (27.5 percent) with a primary diagnosisof malaria who had venous hemoglobin concentrations of lessthan 5 g per deciliter on admission. Of these, 320 had peripheralparasitemia with counts of 10,000 per cubic millimeter or more,thereby satisfying the WHO criteria for severe malarial anemia.1There was some overlap with other clinical groups: 28 childrenwith severe malarial anemia also satisfied the WHO criteriafor cerebral malaria, 59 satisfied the broader criteria of impairedconsciousness, and 53 satisfied the criteria for severe respiratorydistress. A total of 181 children with severe anemia (35.6 percent)received blood transfusions. The mortality rate in the groupwith severe malarial anemia as a whole was 4.7 percent, butin the majority, who had neither impaired consciousness norsevere respiratory distress, it was only 1.3 percent.
Discussion
In many African hospitals, P. falciparum malaria is a leadingcause of admission of children and the chief cause of theirdeaths. Surprisingly, there have been no comprehensive clinicaldescriptions of these patients, and the current definitionsof severe and complicated malaria have not been validated inthis group most at risk. Our starting point was with childrenadmitted from among outpatients by clinical officers not involvedin the study. During a concurrent study of nonsevere malariatreated in outpatient settings, no deaths occurred within oneweek of treatment in 504 patients, and we are therefore confidentthat our findings do describe the complete spectrum of life-threateningdisease presenting to health services in this setting.
A striking picture emerged from our analysis. Despite its pathophysiologiccomplexity,10 life-threatening malarial disease in African children,as defined by poor outcome in the presence of good standardmanagement, fell into two overlapping clinical syndromes: malariawith impaired consciousness and malaria with respiratory distress.Malaria with impaired consciousness is, of course, a well-recognizedsyndrome, although the exact definition of cerebral malariais controversial.9 By contrast, respiratory distress has receivedlittle attention as a feature of life-threatening malaria inchildren, although milder respiratory signs and symptoms arecommon in less severe malaria.11 Recently, respiratory distresshas been reported to be of prognostic importance in Africanchildren with malarial anemia.8
Respiratory distress could potentially result from several underlyingprocesses acting alone or in combination. In nonimmune adultswith severe malaria, respiratory distress is a grave sign, oftenreflecting the development of pulmonary edema, which may leadto the adult respiratory distress syndrome.12 This does notseem to be the case in African children. The acute severe dyspneathat we observed in young children with malaria would, in manycases, probably be considered typical of heart failure due tosevere malarial anemia.8,13 However, several factors lead usto question the assumption that this is the principal or onlycause. First, the clinical signs commonly used to identify cardiacfailure in young children are nonspecific; tachycardia, tachypnea,and hepatic enlargement are common in febrile children withmalaria. Second, no studies documenting pulmonary edema or impairedcardiac function have been performed in children with malaria.Third, as can be seen in Figure 1, many children with severerespiratory distress were not severely anemic, and the outcomedid not appear to depend on whether they were or not.
Figure 1. Prevalence, Overlap, and Mortality for Major Clinical Subgroups of Severe Malaria.
Total numbers are given in parentheses, and mortality is given as a percentage. Slight discrepancies between totals in the figure and in the text are due to missing values, as indicated in Table 1. Thus, 26 children did not have their hemoglobin concentrations recorded on admission; of these, 1 had severe respiratory distress and 4 had disturbed consciousness. Two children for whom hemoglobin concentrations were recorded did not have the severity of their respiratory distress recorded.
The predominant finding in children with respiratory distress,regardless of hemoglobin concentration, was severe metabolicacidosis. Taylor et al. have recently documented the prognosticimportance of metabolic acidosis in Malawian children with malaria,14and Krishna et al. have reported that persisting lactic acidemiais a predictor of death in Gambian children with severe malaria.15We hypothesize that the development of metabolic acidosis isa fundamental process in severe malaria that cuts across otherdiagnostic categories, and that respiratory distress is commonlyits most obvious clinical manifestation. By impairing tissueoxygenation, severe anemia is one factor likely to contributeto the development of acidosis, and in areas of high transmissionwhere anemia is the dominant feature of malaria, it may becomethe chief factor. Nonetheless, it is vital that the relativeroles of primary cardiac failure and acidosis in producing theclinical syndrome of respiratory distress in children with malariabe distinguished, since the implications for management arequite different. If acidosis is the principal problem, thenthe current practice of slow blood transfusion, often with diureticagents, would amount to serious undertreatment, especially sincesuch a large proportion of deaths occur in the first six hoursafter admission. On the other hand, rapid volume expansion,a rational part of the management of severe acidosis, couldbe disastrous if there is genuine impairment of cardiac function.
A major aim of this study was to validate the current criteriafor severe and complicated malaria. In applying these criteriait became clear that in some cases definitions are either inapplicableor inappropriate. For the purpose of identifying children athigh risk for death, we found that the WHO criteria can be simplifiedto require only simple bedside assessments of neurologic involvementand respiratory distress.
The effect of using different definitions of neurologic involvementor respiratory distress on the proportions of all hospital patientssingled out for more intensive treatment and the value of thecriteria for predicting deaths are shown in Table 3. In eachcase it is clear that the more stringent a definition the greaterthe predictive value for poor outcome. For the clinical purposeof identifying children requiring more intensive treatment,the broadest definition is necessary; for specific therapeuticor epidemiologic studies, a more restrictive definition maybe more appropriate. For example, the use of severe respiratorydistress as a criterion rather than simply any respiratory distressallowed a marked increase in selectivity (133 instead of 251children identified, with only two deaths not included), butit is very likely that action taken as a result of applyingthe broader classification (usually blood transfusion or rehydration)averted a number of deaths.
This approach has obvious advantages for most centers managinginpatient malaria: it is simple, rapid, easily taught, and avoidsreliance on laboratory measurements, which are often unavailableor unreliable. Clearly, children without the poor prognosticfeatures may nonetheless have benefited from the extra attentionthey received in this study. However, we doubt that this detractsfrom the general applicability of the approach. Since the endof the study these criteria (number 4 in Table 3) have beenused at Kilifi District Hospital to identify children to bereferred for parenteral therapy and close monitoring. The other70 percent of young patients with malaria receive simple careon the general ward at a level typical of that at any busy districthospital. Case fatality rates in the two groups remain unchangedfrom those observed during the study period.
We draw several major conclusions from this study. First, mostchildren who die of malaria in hospitals fall into two easilydefined groups, one of which — those with respiratorydistress — has not been adequately recognized previously.The fact that most deaths occur within 24 hours of admissionimplies that efforts to lower the case fatality rate shouldfocus on understanding the pathophysiologic processes underlyingthese syndromes. Second, we concur with the authors of the WHOguidelines on severe malaria that no single definition of severedisease will be satisfactory or relevant in all situations.Two sorts of definitions are now required for African children:the first should aim to define in detail the pathophysiologicelements of severe disease, and will be used primarily for researchpurposes. A second definition is required for clinical management,therapeutic studies, and epidemiologic surveillance; here thecriteria need to be simple, robust, and capable of identifyinghigh-risk groups. In our experience, bedside observation ofneurologic involvement and respiratory distress fulfills theserequirements.
Supported by the KEMRI–Oxford–Wellcome Trust ResearchProgramme at Kilifi and by the special program of the UnitedNations Development Program, the World Bank, and the World HealthOrganization for research and training in tropical diseases.Dr. Marsh is a Wellcome Trust Senior Clinical Research Fellow.Dr. Newton holds a Wellcome Trust Advanced Training Fellowship.Dr. Snow is a Wellcome Trust Senior Fellow in Basic Science.
We are indebted to Dr. D. Koech, the director of KEMRI, forpermission to publish these results; to all our colleagues atthe KEMRI unit, Kilifi, and at the Kilifi District Hospital,particularly nursing and laboratory staff, for their skilledwork and collaboration; and to the many colleagues who haveprovided helpful advice and comments, in particular Dr. J. Crawley,Dr. S. Murphy, Dr. M. English, Dr. C. Nevill, and Prof. D. Warrell.
Source Information
From the Kenya Medical Research Institute–Clinical Research Centre, Kilifi Unit, Kilifi, Kenya (K.M., D.F., C.W., I.M., M.W., V.M., C.N., P. Winstanley, P. Warn, N.P., G.P., R.S.); and the Nuffield Department of Clinical Medicine (K.M., D.F., P. Winstanley, P. Warn, G.P., R.S.) and the Department of Paediatrics (C.N.), Oxford University, John Radcliffe Hospital, Headington, Oxford, United Kingdom.
Address reprint requests to Dr. marsh at the KEMRI Unit, P.O. Box 230, Kilifi, Kenya.
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