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ABSTRACT |
 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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It is estimated that 34 million individuals are at risk for malaria in highland or "epidemic-prone" areas.13 Although thousands of children and adults develop severe malaria in highland areas, there is only anecdotal information on the spectrum of clinical manifestations of severe malaria in the highlands and how this contrasts with what seen in lowland, high-transmission areas. To date, the only published studies on the clinical manifestations of SM in highland areas have focused exclusively on cerebral malaria14 or anemia.14–16 Knowledge of the major clinical manifestations of severe malaria in highland areas is important to appropriate diagnosis and treatment of malaria in these areas and to assessment of clinical problems that require further research in these areas. We therefore conducted a prospective study of the clinical manifestations of severe malaria (as defined by World Health Organization [WHO] 2000 criteria) at Kabale Regional Referral Hospital (KRH), Uganda, from March 2002 to July 2003.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Study area. Kabale district is about 400 km southwest of Kampala in Uganda. It is bordered by Rwanda to the south and the Democratic Republic of Congo to the West and is surrounded by volcanic mountains. It is situated at an altitude of about 2,000 meters, and the altitude of the hospital’s catchment area ranges from 1,600 to 2,400 m above sea level. The Bakiga are the predominant ethnic community, and horticultural farming is their main source of livelihood. KRH, with a 250-bed capacity, is the main hospital serving Kabale district offering specialist services in all the main fields of medicine. It acts both as a primary care center and receives referral patients from the surrounding health units. Kabale is prone to seasonal malaria epidemics,4 with recent outbreaks in 1998 and 2001. In nonepidemic periods, the area has extremely low malaria vector density, with estimated entomological inoculation rates of less than one infectious bite per person per year.17
Study participants.
All patients admitted to KRH during the study period with a clinical diagnosis of malaria were assessed for inclusion into this study. If a peripheral blood smear was positive for asexual forms of Plasmodium falciparum parasites and the patient had one or more of the WHO 2000 criteria for severe malaria,2 the patient was included in the study after informed consent was obtained from the patient or guardian. WHO criteria (2000) are listed in Table 1
. Specific definitions for the criteria include 1) prostration: unable to sit, drink, or breast-feed, but conscious; 2) respiratory distress: tachypnea with sustained nasal flaring, retractions, or deep (acidotic) breathing; 3) multiple seizures: 2 or more in seizures in 24 hrs; 4) severe anemia: hemoglobin < 5.0 g/dL.
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Thick and thin peripheral blood smears were performed to detect P. falciparum infection. Parasites were counted against 200 white blood cells (WBCs) and parasite density calculated against a WBC count of 8,000/µL. One hundred fields were examined before declaring a slide negative. In patients suspected of having malaria, absence of malaria was declared after 3 consecutive negative blood smears at 8 hourly intervals.
Medical care of patients with severe malaria. Uganda national treatment guidelines for SM management were used for treatment.18 All patients were given quinine intravenously, then orally when they could tolerate oral medication, for a total of 7 days. Those with temperatures > 38.5°C were given paracetamol. Hypoglycemic patients received 1 mL/kg of 50% dextrose as a bolus infusion. Severely anemic patients (Hb < 5 mg/dL) were transfused with whole blood, 20 mL/kg, and all anemic patients received folic acid and iron sulfate. Standard nursing care was offered. A daily assessment of consciousness and documentation of further seizures was done during admission, and a full neurologic assessment performed at discharge.
Ethical considerations. Ethical clearance was obtained from the Institutional Review Boards of Kabale Hospital, the Uganda National Council for Science and Technology, and Case Western Reserve University/University Hospitals of Cleveland, Cleveland, Ohio. Informed consent was obtained from all fully conscious adult participants and from parents or legal guardians of minors and unconscious patients.
Data management and statistical analysis. Data entry was done using Epi Data 2.1a (Epi Data Association 2000, Odense, Denmark) and analyzed with SPSS version 11.5 (SPSS 2003, Chicago, IL). Categorical variables were compared using Fischer’s exact test and continuous variables with Student’s t test. Odds ratios (OR) and P values were used as measures of significance, a P < 0.05 was considered significant. A multivariate logistic regression model was used to assess likelihood of specific manifestations of SM in study participants under 5 years of age as compared with those 5 years of age or older.
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Sixty-two percent of the 117 patients had received antimalarial medication prior to hospital evaluation. These drugs were obtained from small private clinics (21.2%), shops (17.8%), health centers (16.9%), a hospital (5.1%), or other sources. Chloroquine and sulfadoxine-pyrimethamine were the antimalarial medications most often used prior to hospital evaluation.
Most patients were less than 40 years of age, but there was a bimodal peak in cases from 0 to 8 years and 15 to 32 years of age, which mirrored the admission peaks for individuals evaluated for conditions other than malaria (Figure 1). Patients presented to the hospital throughout the year with peaks between November and January, and June to August. (Figure 2).
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) and in almost all cases marked the onset of illness.
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). However, the presence of cough was not associated with an increased frequency of respiratory distress, which was present in 23.9% of individuals with cough and 17.9% of individuals without cough (P = NS). Respiratory distress was termed mild if age-related tachypnea with nasal flaring was seen, and severe if deep/acidotic breathing or subcostal retractions were seen. Overall, respiratory distress was more common in children under 5 years than older children and adults (29.4% versus 15.2%, P = 0.07). Subcostal retractions and crackles on lung exam were rare physical findings (7.7% and 3.4%, respectively), suggesting that cough was not related to pneumonia in etiology. Although respiratory distress was also more frequent among patients with severe anemia (20.0% versus 8.6%), this difference was not statistically significant, P = 0.14. Gastrointestinal system. Vomiting and diarrhea were common symptoms in children under 5 years (61.2% and 38.8%, respectively) and individuals 5 years and older (61.8% and 32.4%), respectively.
Central nervous system (CNS).
CNS involvement included seizures, prostration, impaired consciousness, coma, abnormal postures and deep tendon reflexes, and brain stem abnormalities with evidence of raised intracranial pressure. Altered consciousness occurred in 11.1% of all patients (7.8% of children under 5 years, 13.8% of individuals older than 5 years). Abnormal posturing (decorticate, decerebrate, or opisthotonus) was seen in only three patients, of whom two in addition had irregular respiration. Three patients had neck stiffness and one had abnormal pupillary reflexes and absent corneal reflexes. Abnormal deep tendon reflexes were more frequent in individuals older than 5 years as compared with children under 5 years (18.8% as compared with 5.9%, P = 0.04, Table 2). Seizures were reported in only 15 (12.8%) patients at the time of admission, and only three patients had further seizures witnessed during the course of the admission.
Cardiovascular system. Eight patients had de-compensated anemia with features of cardiac failure. These patients improved clinically after blood transfusion. No other patients presented with features of circulatory decompensation.
Genitourinary system. Twenty-two percent of patients had trace proteinuria on urine dipstick testing, but none had > 1 + proteinuria. Four (3.4%) patients had hemoglobinuria, of whom three had red blood cells seen on microscopy. In all three of these patients, the microscopic hematuria cleared within two days. One patient had a serum creatinine of 3.5 mg/dL but never developed oliguria and improved on antimalarial medication.
Laboratory findings.
As compared with individuals 5 years and older, children under 5 years had lower mean hemoglobin and blood glucose but a higher geometric mean parasite density (Table 3). Overall, most patients had low parasite densities; 60 (51.3%) had a parasite density of <20,000/µL (< 0.4%), and only 7% had densities > 100,000/µL. We were only able to perform blood glucose tests in 86 patients. Hypoglycemia (blood glucose < 40 mg/dL) was uncommon occurring in only 4/86 (4.7%). Gametocytes were seen in 16.1% of the patients. Neither prior antimalarial drug therapy nor the duration of illness had any significant effect on the prevalence gametocytes.
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). Individuals older than 5 years more commonly had prostration than children under 5 years (68.2% as compared with 45.1%, P = 0.039), while children under 5 years of age were more likely than individuals over 5 years to present with respiratory distress (29.4% as compared with 15.2%, P = 0.07) and severe anemia (19.6% as compared with 4.5%, P = 0.016). Multivariate analysis including all manifestations revealed an increased risk of severe anemia and respiratory distress in children less than 5 years, and an increased risk of prostration and impaired consciousness in individuals 5 years or older (Table 4).
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Outcome. During the 17-month period of this study, mortality for patients with severe malaria was very low. Only two patients (1.7%) died, both within 24 hours of admission, from cerebral malaria. The two patients who died were a 7-month-old boy who presented with multiple seizures, deep coma, respiratory distress, and hyperparasitemia, and a 13-year-old girl who presented with respiratory distress, multiple generalized seizures, deep coma, hypertonia, and hypereflexia. Morbidity was also low. The only patient with significant neurologic sequelae was a 30-year-old lady with hypoglycemia, impaired consciousness, respiratory distress, hypertonia, and hypereflexia who developed ataxia after regaining consciousness and was still ataxic at discharge.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The bimodal age peak for severe malaria seen in this study has not, to our knowledge, been previously described. 56% of severe malaria cases occurred in children from 0 to 8 years of age, and 29% in individuals from 15 to 32 years of age. Thus, 85% of all cases of severe malaria occurred in these two age ranges. The complete lack of cases in individuals between the ages of 45 and 60 suggests a degree of immunity to severe disease in older adults (> 40 years) in this population. A small third "peak" of four cases was seen in individuals over the age of 70 years and may reflect a waning of immunity in older age or malaria as a complication of other underlying illness or debilitation in this age group. The adult to child ratio (ratio of individuals with disease 
15 years to those < 15 years), which is commonly used to define the community-wide level of antimalaria immunity in outbreak-prone areas,7 was 0.65 for individuals with severe disease and 1.15 for outpatients with uncomplicated malaria (unpublished observation), suggesting that individuals above 14 years of age in this population are more strongly protected against severe than mild malaria. Interestingly, very few cases of malaria were seen in children ages 9–14 years (6 cases, 5.1%), and when all admissions were analyzed, the same peaks from 0 to 8 years and 15 to 32 years were seen, with a drop in admissions for ages 9 to 14 years (Figure 2). In a review of malaria morbidity in areas of differing transmission, Snow and others estimated malaria attack rates in areas of stable, high transmission of 1, 0.25, and 0.4 per 1,000 persons per year in individuals aged 0–4, 5–14 and 15 years or older, suggesting that even in these areas, children aged 5–14 have lower frequencies of malaria attacks than adults.23 The reason for these age-related peaks and decreases in disease is unclear. In the current study area, potential reasons for the decrease in cases among children 9–14 years of age include the development of some degree of antimalarial immunity in childhood that wanes during adolescence and the attendance of some children in this age group at boarding schools in other areas. However, neither of these reasons seem sufficient to fully explain the lower frequency of cases in this age group. The presence of a second peak from ages 15 to 32 years in our study argues for new susceptibility factors in this age group, though the nature of these factors is unknown. HIV infection, which occurs most frequently in the 15–32 year age range, could be a potential explanation for part of the increase in admissions in this age group. HIV infected persons develop symptomatic malaria more frequently than HIV noninfected persons24 and may also develop severe malaria more frequently.25,26 In the current study, HIV status was not routinely tested because of the lack of freely available counseling, testing, or medications for HIV at the time of the study and inadequate study funding for provision of these interventions. No patient had clinical signs of AIDS. Lack of testing for HIV infection was a weakness of the present study, and in future studies we hope to assess the contribution of HIV to severe malaria in this population.
Prostration was by far the most common manifestation of severe malaria in all age groups. Although prostration has been described in similar frequencies in other areas of Africa with high27,28 and low28 malaria transmission, most large studies of severe malaria have not included assessment of the frequency of prostration.29,30 A "supporting" criterion in the WHO 1990 severe malaria definition but a defining criterion in the WHO 2000 definition, prostration appears to have a lower case fatality rate than some other manifestations of severe malaria (6.8–8.2% in Burkina Faso and Ghana27,28). However, because it is the main reason for hospital admission for patients with malaria in highland Uganda, it will be important to educate health care workers in this area about the characteristics and frequency of this presentation of severe malaria. Very little has been written about the pathogenesis of prostration in severe malaria, and although it is considered by some a sign of CNS disease, the mechanisms by which malaria leads to inability to sit, stand or feed are poorly understood.
The age-related differences in specific clinical manifestations are likely due to multiple factors, including differential parasite organ sequestration in younger children as compared with older children and adults,31 low levels of complement regulatory proteins leading to increased red cell destruction in young children,32 inadequate reticulocyte production in young children,33 and possibly the need for exposure to specific strains in cerebral malaria.34 The almost complete lack of cerebral malaria in this population was striking, since cerebral malaria has been described as a frequent complication in other areas of unstable transmission,35 including a highland area of Kenya.14 There are a number of possible explanations for this difference. A majority of patients in the current study received antimalarial treatment prior to hospital admission, and this may have decreased parasite load and risk of CNS complications. Hyperparasitemia was rare in the current study (< 1%) but common in the Kenyan study.14 Alternatively, a higher level of antidisease immunity in this highland community or a paucity of "cerebral malaria strains" of P. falciparum in nonepidemic periods in this community may have led to the low frequency of cerebral malaria cases in this area.
Cough was a common symptom of malaria in this community, occurring in frequencies higher than those reported in other studies.36 In addition, respiratory distress was a common manifestation of severe malaria, particularly in younger children. Studies have documented airflow and gas transfer abnormalities in individuals with malaria, particularly those with respiratory symptoms,37,38 and several studies have documented overlap between pneumonia and malaria diagnoses when WHO Integrated Management of Childhood Illness (IMCI) guidelines are used in malaria endemic areas.39,40,41 Only a few individuals in the current study with signs of respiratory distress had crackles on auscultation, and all but one recovered without antibiotic treatment. Thus their pulmonary signs and symptoms were likely due to malaria alone.29,42 Algorithms from other areas of unstable transmission, which include "absence of cough" as a criteria,43 would exclude the majority of patients with malaria in this highland area. The frequency of cough as a symptom and of respiratory distress as a clinical manifestation of severe malaria should prompt reassessment of IMCI guidelines in this area for both pneumonia and malaria, as it has in other areas.40
Outcome in patients with severe malaria over the seventeen-month period was excellent, with a very low mortality rate (2 of 117 individuals, 1.7%) and little long-term morbidity. There are several possible reasons for this. First, no epidemic occurred during this time period, so hospital resources were not overwhelmed and overall severity of disease may have been lower. Second, most patients were treated with antimalarial medications as outpatients, which may have decreased parasite burden and reduced the risk of complications. Third, the frequency of cerebral malaria, which has a high case fatality rate,27,28,44 was very low, and some of the other manifestations with high case fatality rates (e.g., circulatory collapse, abnormal bleeding, pulmonary edema) were not seen. Fourth, this community is exceptional in its commitment to getting sick patients to the hospital, even from very far distances.17 In addition, the use of WHO 2000 definition likely led to inclusion of less severely ill patients and a lower case fatality rate than if the WHO 1990 definition had been used.27 Nonetheless, more than half the patients seen did have manifestations associated with case fatality rates of 9–37% in other studies,27,28 and the low mortality rates even in these patients suggests that good clinical care was an important factor in the excellent outcome of these patients.
The findings of the current study emphasize the importance of carefully defining clinical characteristics in areas of differing malaria transmission and provide important baseline information about how severe malaria presents in an epidemic-prone highland area. Future studies will focus on the relationships between immune responses to P. falciparum and the different clinical manifestations of malaria in this highland area.
Received November 5, 2004. Accepted for publication December 15, 2004.
Acknowledgments: We are indebted to the medical, nursing, laboratory, and records staff of Kabale Regional Referral hospital for their service in the recruitment, records, and management of patients, the study participants, and their parents/guardians.
Financial support: This study was supported by a Children’s Research Foundation Faculty Grant from Rainbow Babies and Children’s Hospital, Cleveland, Ohio.
Authors’ addresses: Richard Idro, Department of Pediatrics and Child Health, Makerere University Medical School/Mulago Hospital, P.O. Box 7051, Kampala, Uganda, Telephone: + 256-41-531875, Fax: + 256-41-530022. Edward Bitarakwate, Kabale Regional Referral Hospital, P.O. Box 7, Kabale, Uganda, Telephone: +256-486-22006, Fax: +256-486-22727. Sam Tumwesigire, Kabale Regional Referral Hospital, P.O. Box 7, Kabale, Uganda, Telephone: +256-486-22006, Fax: +256-486-22727. Chandy C. John, Rainbow Center for International Child Health, RBC 487, 11000 Euclid Ave., MS6008, Cleve-land, OH, 44113, Telephone: (216) 844 3645, Fax: (216) 844-8362, E-mail: chandy.john{at}case.edu.
Reprint requests: Chandy C. John, Rainbow Center for International Child Health, RBC 487, 11000 Euclid Ave., MS6008, Cleveland, OH, 44113, Telephone: (216) 844 3645, Fax: (216) 844-8362, E-mail: chandy.john{at}case.edu.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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This article has been cited by other articles:
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  D. Zurovac, B. A. Larson, J. Skarbinski, L. Slutsker, R. W. Snow, and M. J. Hamel Modeling the Financial and Clinical Implications of Malaria Rapid Diagnostic Tests in the Case-management of Older Children and Adults in Kenya Am J Trop Med Hyg, June 1, 2008; 78(6): 884 - 891. [Abstract] [Full Text] [PDF]
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