The diagnosis of malaria in children attending a tertiary unit in an endemic area is not straightforward. Clinical manifestations of malaria overlap with those of other common infections, making definitive diagnosis difficult.1–5 6 7–9
The practice of diagnosis and treating children presumptively for malaria can result in excessive reporting of malaria cases,7 10 6 11
To assess how mortality differs in children with a diagnosis of malaria according to status of microscopy testing for P. falciparum , we analyzed by retrospective chart review the differences in inpatient mortality between clinically and microscopically diagnosed malaria in all malaria-related admissions in children in the national referral hospital in Uganda during a 3½ year period.
MATERIALS AND METHODS
Study Type
A retrospective chart review was conducted of all malaria-related pediatric admissions aged 0–15 years to Mulago Hospital, Kampala, Uganda between January 2002 and July 2005.
Study Site
Mulago hospital is a 1500 bed national referral hospital in Uganda and a teaching hospital for Makerere University Medical School. It serves Kampala, the capital city, and surrounding districts in the central region of Uganda, which is an area of seasonal malaria transmission.12 children are admitted to Mulago Hospital annually, of whom about 30% are treated for malaria.13
Data Collection
All inpatient charts of children up to 15 years of age with a diagnosis of malaria were retrieved using the International Classification of Diseases (ICD 9) record codes and reviewed. The diagnoses recorded on the files are the final diagnoses for which the patient was treated during hospitalization. Information was collected from the patient's charts on the child's age, whether diagnostic microscopy for malaria had been performed (and if so, the results of microscopy), type of malaria complication, if any, other listed diagnoses, and outcome of hospitalization. Clinical diagnoses were recorded as listed in the chart (eg, cerebral malaria, severe malarial anemia, pneumonia), with or without supporting laboratory data. Accordingly, for these clinical data, WHO criteria might not be met (eg, cerebral malaria might be recorded in children with impaired consciousness rather than coma, and severe malarial anemia might be recorded without laboratory measurement of hemoglobin level). Although this means that not all clinical diagnoses are supported by strict inclusion criteria, our data do reflect the practice and diagnostic categorization in many hospitals in sub-Saharan Africa, where lack of resources and other factors often translate into diagnoses based purely on clinical criteria. Microscopy results were recorded as either not done, or negative or positive for Plasmodium species. The side-laboratory where all the malaria microscopy is done uses Field's Method.14 Plasmodium parasite cannot be identified on thick films, malaria causing admission in this area is overwhelmingly caused by P. falciparum , so all cases are reported and treated as cases of P. falciparum malaria. The laboratory is open from 7 am to 10 pm, during which period the majority of patients are admitted. Patients admitted after 10 pm have malaria blood smears done the next morning. In addition to the side-laboratory the hospital has a main laboratory that is capable of doing other diagnostic tests like blood counts, urinalysis, blood cultures and analysis of cerebral spinal fluid.
This study was approved by the Institutional Review Boards for Human Studies at Makerere University Faculty of Medicine, Case Western Reserve University and the University of Minnesota.
Data Analysis
Data entry was done in Filemaker Pro 7. Analysis was done with STATA 9.2 (Stata Corporation, Austin, TX). Frequencies were compared using the χ2 test or the χ2 test for trend, as appropriate. Multivariate logistic regression was used to assess the risk of mortality for specific malaria complications, comorbid diagnoses, and microscopy testing status. P values of <0.05 were considered significant.
RESULTS
Malaria Admissions and Microscopy Testing.
A total of 23,342 children 15 years of age and under were admitted with a diagnosis of malaria. A peripheral blood smear for malarial parasites was done in 18,536 of these children (79%), of whom 12,256 (66%) had a positive result. Mean age did not differ between children who were microscopy positive [mean age, 2.6 years; standard deviation (SD), 2.7], and those who were microscopy negative (mean age, 2.6 years; SD, 2.8), but children who were not tested by microscopy were older (mean age, 3.1 years; SD, 3.6; P < 0.001 as compared with microscopy positive children ). Gender frequencies were similar in the 3 groups, with a slight preponderance of males in all the groups (54%, 53%, and 52% male for children who were microscopy positive, microscopy negative, and did not have microscopy testing for P. falciparum , respectively). Children who did not have a smear done on average died earlier after admission than those that had a smear done (1.9 days versus 2.6 days, P = 0.01).
Malaria Seasonality and Overall Malaria-Attributed Morbidity and Mortality.
From January 2002 to July 2005, malaria-related admissions accounted for 30.4% of hospital admissions in children 15 years of age and younger and malaria-related deaths accounted for 18.1% of total inpatient pediatric deaths. There was a significant increase in the proportion of admissions with a diagnosis of malaria from 2002–2004, but there was no significant increase in the proportion of inpatient deaths attributed to malaria during that period (Table 1 ).
TABLE 1: Children 15 Years of Age and Younger in Mulago Hospital, Kampala, Uganda, January 2002–July 2005
Case Fatality Rates for Malaria Complications and Comorbid Conditions.
The 3 most common complications of malaria were severe malaria anemia (SMA), cerebral malaria (CM), and malaria associated with convulsions (Table 2 ). Pneumonia and acute diarrhea were the 2 most common comorbid diagnoses in children with malaria-related admissions (Table 2 ). Other comorbid conditions occurring in >1% of children included upper respiratory tract infection (1.3%), urinary tract infection (1.1%), and sickle cell disease (1.1%). The overall case fatality rate of malaria-related admissions during the study period was 4.2%. SMA and CM accounted for 72% of all malaria-related deaths.
TABLE 2:
Malaria-Associated Mortality According to Microscopic Confirmation of Diagnosis.
Case fatality rate (CFR) was assessed according to microscopy testing: blood smear for P. falciparum positive, negative, or not performed. The CFR for children with no microscopy performed was more than twice that of children who were smear positive (7.5% versus 3.2%, respectively; P < 0.001), and children with no microscopy performed had higher CFR for each malaria complication and comorbid diagnosis than children who were smear positive (Table 3 ). Similarly, among children in whom microscopy was performed, the CFR overall was higher in children who were microscopy negative than microscopy positive (3.8% versus 3.2%; P = 0.03). This was largely because of a greater CFR for CM in microscopy negative as compared with microscopy positive children (17.7% versus 12.1%; P = 0.01; Table 3 ).
TABLE 3: Plasmodium falciparum
An increased risk of death was seen in children with CM in all 3 groups, and an increased risk of death for SMA was seen in children who were microscopy positive compared with children without these diagnoses. In addition, increased mortality was seen in children with a diagnosis of pneumonia in all 3 groups and with a diagnosis of acute diarrhea in children who were smear negative or who did not have microscopy testing performed (Table 4 ). After adjustment for age, malaria complications and comorbid conditions, lack of microscopy testing and negative microscopy testing remained highly significant independent risk factors for death in children admitted with a diagnosis of malaria (OR for no microscopy testing: 3.49, 95% CI: 2.88–4.23, P < 0.001; OR for microscopy negative: 1.59, 95% CI: 1.29–1.96, P < 0.001; both as compared with children who were microscopy positive).
TABLE 4: Plasmodium falciparum
DISCUSSION
In malaria endemic regions, there is a tendency to treat all fevers as malaria, particularly in high risk groups such as young children . The World Health Organization (WHO) guidelines for diagnosis and management of severe falciparum malaria,15 children who were given a diagnosis of malaria without microscopy testing for P. falciparum compared with children who were microscopy positive for P. falciparum . Furthermore, when microscopy was performed on children suspected for malaria, more than a third of children were microscopy negative but were still diagnosed and treated for malaria, and these children also had a 1.5-fold increased risk of mortality as compared with microscopy-positive children .
Our study findings on mortality in microscopy negative as compared with positive children are similar to those of a prospective study conducted in Tanzania,8
The higher mortality in children diagnosed and treated for malaria without microscopic confirmation is likely due at least in part to misdiagnosis and a lack of treatment for conditions other than malaria. We were not able to record complete treatment details on the patients in this study, so we do not know how many of the children with a diagnosis of malaria received antibiotics in addition to antimalarials. At Mulago Hospital, antibiotics are usually given only to those with a listed diagnosis of a bacterial illness (eg, pneumonia or sepsis), so we suspect that most of the children with a clinical diagnosis of malaria were not treated with antibiotics. Other causes of febrile illnesses in children , like bacteremia, meningitis, encephalitis or other diagnoses, may be obscured by the focus on malaria. A recent study in post neonatal infants (1–12 months) in Nigeria reported that 38.2% of children presenting with febrile illness had bacteremia16 children with febrile illness who were smear negative had bacteremia compared with 12% in smear positives.17 children with febrile illnesses in malarial areas.
The risk of severe disease or death from malaria in children in malaria endemic areas supports the approach of presumptive treatment of febrile children in facilities where microscopy is not available.18,19 children who had no microscopy testing performed, mortality was particularly increased in children with cerebral malaria, with a case fatality rate of 33.6% and an almost 7-fold increase in the risk of death in this group as compared with a case fatality rate of 12.1% and a 6-fold risk of death in children with cerebral malaria confirmed by blood smear. A case fatality rate this high strongly suggests the possibility of misdiagnosis, and underscores the critical need for microscopy testing in children thought to have severe malaria.
Among children with a negative blood smear, there was only a minor increase in the case fatality rate compared with children with a positive smear (3.8% versus 3.2%, P = 0.03), but after controlling for other potential confounding factors such as age, type of malaria complication and comorbid diagnosis, the increased risk of death was highly significant (OR: 1.59, 95% CI: 1.29–1.96, P < 0.001). The increased risk of death in children with negative blood smears is also most likely the result of misdiagnosis and lack of treatment for the real cause of illness in these children . However, it is possible that true infection was undetected in some children because of prior antimalarial treatment. In Uganda antimalarials are often purchased from drug shops or pharmacies: a study conducted at 7 sites around the country found chloroquine metabolites in 32–80% of the general population.20 21,22 children who were smear negative. In addition, use of ineffective medications, even at the correct dose, may lead to persistent symptoms despite low level parasitemia. There is also a need for public health policy makers to enforce the dispensing and proper use of antimalarials by the public.21
The reliance on microscopy to make a diagnosis of malaria has been subject of much debate.11,23,24 25 26 27,28 29 11,30
Pneumonia and acute diarrhea were the most common comorbid conditions associated with malaria and were both strong predictors of mortality, as has been documented in previous studies.31,32 31 4 33
Drug resistance to the first-line drugs recommended for malaria at the time of this study (chloroquine and sulfadoxine-pyrimethamine) is the most likely cause of the increased frequency of malaria-related admissions in children from 2001–2004.34–36 37
The present study used the diagnoses assigned by the many different inpatient clinicians admitting these children . These diagnoses were not necessarily validated by rigorous or uniform criteria. For this reason, we cannot definitively conclude that all children with a diagnosis of cerebral malaria, for example, actually had cerebral malaria. Indeed, it is likely that a significant proportion assigned this diagnosis without blood smear confirmation had another cause of their coma. But the latter case points out the practical relevance of chart review study such as the present study: clinical diagnosis of malaria, often without microscopy confirmation, is not infrequent in hospitals and clinics throughout sub-Saharan Africa. Our study results provide evidence that lack of testing in children with a diagnosis of malaria is associated with significantly increased rates of death, and argue for microscopy or rapid diagnostic testing of all children admitted with a diagnosis of malaria and evaluation of other causes of disease in children with negative results. Based on the findings of previous studies, however, it is likely that reductions in mortality will only be accomplished with clinician education on the utility of these tests, the risks of specific malaria complications and the importance of evaluation for alternative diagnoses.
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