|Year : 2014 | Volume
| Issue : 2 | Page : 105-110
Prediction of outcome of severe falciparum malaria in Koraput, Odisha, India: A hospital-based study
Lalit Kumar Das1, Bishwanath Padhi2, Sudhansu Sekar Sahu1
1 Unit of Clinical Epidemiology and Chemotherapy, ? Vector Control Research Centre (Indian Council of Medical Research), Medical Complex, Indira Nagar, Puducherry, India
2 Department of Internal Medicine, District Headquarters Hospital, Koraput, Odisha, India
|Date of Acceptance||25-Mar-2014|
|Date of Web Publication||12-Aug-2014|
Lalit Kumar Das
Scientist F, Vector Control Research Centre, Medical Complex, Indira Nagar, Puducherry 605 006
| Abstract|| |
Background and Objectives: Infection with Plasmodium falciparum, caused 627,000 deaths in 2012 in the world. P. falciparum infection causes myriads of clinical manifestations. Exact clinical manifestation resulting in poor prognosis in hyper-endemic epidemiological settings need to be ascertained to save human lives. A hospital-based study was conducted to elucidate the different severe clinical presentations of falciparum malaria and to examine the critical clinical and laboratory parameters on the prognosis of these severe manifestations in a stable hyper-endemic falciparum area in the state of Odisha, India. Materials and Methods: Consecutive patients admitted in a tertiary care hospital with severe manifestations of malaria as per WHO criteria and confirmed by parasitological examination were included in the study. A detailed clinical and biochemical parameters were examined. Clinical data were reviewed before being double entered into a computer and analyzed. Statistical analyses were carried out using Epi Info 6.04. Continuous and normal distributed data were compared by two-tailed Student's t-test and proportions compared with χ2 tests with Yates' correction or Fisher's exact test. Results and Discussion: A total of 1320 patients with clinical malaria, diagnosed at outpatients' department were admitted in the hospital during the 1 year study period of which, 292 (22.1%) were children under 14 years of age. The major clinical categories on admission were hyperpyrexia (70.7%), cerebral malaria (9.4%), malarial anemia (7.7%), algid malaria (1.5%), and malaria associated categories were respiratory infection (2.2%), hepatitis (2.0%), urinary tract infection (1.8%), enteric fever (3.3%), and sickle cell disease (1.2%). The overall case fatality rate (CFR) was 4.3 (57/1320). The CFR in children 12.3 (36/292) was significantly higher when compared to adults, that is, 2.0 (21/1028). The major causes of death were cerebral malaria (45.6%), malaria along with a respiratory infection (19.3%) and anemia (10.5%). Malarial anemia along sickle cell disease accounted for 19.3% of all malaria related deaths. Proportion of mortality due to acute renal failure was higher in adults. Biochemical parameters suggest involvement of multiple organs. The findings suggest that the area can be effectively managed by sustained and continuous preventive and curative efforts.
Keywords: Falciparum malaria, severity, prediction, outcome
|How to cite this article:|
Das LK, Padhi B, Sahu SS. Prediction of outcome of severe falciparum malaria in Koraput, Odisha, India: A hospital-based study. Trop Parasitol 2014;4:105-10
| Introduction|| |
Approximately 3.3 billion people, living in 99 countries are at risk of malaria, of which, 207 million develop symptomatic malaria annually.  Majority of these are caused by infection with Plasmodium falciparum with an average of 650,000 deaths each year between 1980 and 2010.  About 60% of the clinical episodes and 86% of the 627,000 deaths in 2012 occurred in children <5 years in Africa, south of the Sahara, where malaria accounts for 25-35% of all out-patient visits, 20-45% of hospital admissions and 15-35% of hospital deaths. , India reported 1.3 million malaria cases of which 0.6 million P. falciparum cases and 754 deaths in 2011.  India contributes about 80% of all malaria cases in south-east Asia and based on model based surveillance data suggested that 12,000-38,000 malaria deaths occurred in India in 2010.  Reports from India describing the clinical pattern and squeal are scanty and inadequate due to several reasons: viz., nonavailability of diagnostic facility, lack of proper system of reporting, and lack of will power among the health care professionals to build-up a database.  Malaria risk and mortality have not shown significant reductions yet in spite of introduction of newer anti-malaria drug regimens like rapidly parasiticidal artemisinin derivatives, ,, personal protection measures with long lasting insecticide treated bed nets. Management of patients with severe malaria poses a great challenge given the complex pathology of the infection involving multiple organs. Many earlier studies related to epidemiology and clinical manifestations have shown variations. ,,, Therefore, there is a need for more site-specific data in order to appreciate the complete clinical and epidemiological picture for efficient testing of candidate malaria vaccines and other control tools in future in different endemic sites.  This study highlights the different categories of severe malaria, seasonal pattern of hospital admission of malaria cases, clinical management practices and the outcome in a major referral hospital situated in a tribal area endemic for falciparum malaria in Odisha state of India.
| Materials and methods|| |
The study was carried out in the District Headquarters Hospital (DHH), Koraput in Odisha State, India. Transmission of malaria is perennial with two peaks: First in rainy (July-August) when the vector, Anopheles culicifacies breed in rice fields and second in winter season (December-January) when the vector, Anopheles fluviatilis breeding in streams plays a role.  Malaria infection is mostly due to P. falciparum (80-90%) and the major vector is A. fluviatilis.  Chloroquine (CQ) was the first line treatment for P. falciparum until 2009. It was replaced with artemisinin combination therapy (artesunate, sulfadoxine + pyrimethamine) from 2010 due to the development of P. falciparum resistance to CQ. 
Study design and participants
Consecutive patients, admitted at the DHH with the clinical diagnosis suggestive of acute malaria, from April 2011 to March 2012 were screened for severe malaria following WHO criteria. , Physicians documented findings of clinical examination, including vital signs twice daily during the course of illness from the time of admission to the time of discharge from the hospital.
The criteria of severity were followed as per WHO guidelines  along with slide parasite positive were taken for the study and detailed analysis. Only those fulfilling the criteria were retained in the study. The respiratory distress due to malaria was diagnosed based on exclusion of other causes of respiratory distress and positive response to antimalarial treatment. Sickling test was done following the method Dacie and Lewis. 
At admission and enrolment, full blood count, blood urea, creatinine, bilirubin, random blood sugar level, and detection of malaria parasite by quantitative buffy coat technique were carried out. Whole blood specimens were analyzed for full blood count using automated ABX Micros 60-OT hematology analyzer; serum creatinine, bilirubin, and blood glucose levels were determined using Micro Lab 200 analyzer.
Clinical management of patients
Patients were treated using a uniform protocol based on standard recommendations  consisting of either parenteral artesunate (2.4 mg/kg body weight intravenous or intramuscular given on admission; then at 12 h and 24 h and then once a day) until the patient was able to swallow, at which point the patients were put on an oral dose of artesunate combination therapy for 3 days (or quinine at 20 mg/kg loading dose followed by 10 mg/kg maintenance dose every 8 h until the patient was able to swallow, at which point she or he was switched to oral dose of 10 mg/kg every 8 h to complete a 7 day course of treatment). In addition to the specific treatment for P. falciparum infection, symptomatic and supportive therapy in terms of hemotransfusion for severe anemia, intravenous glucose for hypoglycemia, intravenous fluid for severe dehydration, paracetamol for pyrexia, diazepam for seizures, antibiotics for bacterial infections, and nasal oxygen for respiratory distress as per standard clinical practice were carried out as and when needed.
Data and statistical analysis
All study data were captured on a structured case report form bearing patient demographic and identification numbers. All clinical data were reviewed before being double entered into a computer. Statistical analyses were carried out with Epi Info, version 6, statistics program for public health, center for Disease Control and Prevention, Atlanta, Georgia, USA, 1996). Continuous and normal distributed data were compared by two-tailed Student's t-test and proportions compared with χ2 tests with Yates' correction or Fisher's exact test. Basic statistics were calculated for the baseline characteristics: Gender, age group, weight, fever, presenting symptoms, point estimates using proportions and means, and 95% confidence intervals were computed for the clinical and laboratory features. Significant differences were tested using confidence intervals of the difference or odds ratio and the corresponding (95%) confidence intervals and P values. A P < 0.05 was considered as statistically significant.
Approval of the study
The project proposal was approved by the Scientific Advisory Committee and Human Ethics Committee of Vector Control Research Center (ICMR), Puducherry.
| Results|| |
Clinical categories with symptoms of malaria patients on admission
A total of 1320 patients with clinical malaria were admitted in the hospital during the 1 year study period of which, 292 (22.1%) were children under 14 years of age. Highest number of cases (200) was admitted in the month of July [Figure 1]. The average days of fever, headache, vomiting, and chill/rigor on admission were 5.7 (+4.1), 5.1 (+3.8), 3.8 (+4.4), and 6.5 (+5.5) respectively in adults and 4.9 (+3.9), 4.8 (+2.0), 3.1 (+2.1), and 5.2 (+2.8) in children. The major clinical categories were hyperpyrexia (70.7%), cerebral malaria (9.4%), malarial anemia (7.7%), algid malaria (1.5%), and malaria associated categories were respiratory infection (2.2%), hepatitis (2.0%), urinary tract infection (1.8%), enteric fever (3.3%), and sickle cell disease (1.2%). The proportion of children and adults admitted in each clinical category is given in [Table 1].
|Figure 1: Month-wise number of malaria patients admitted in the district hospital, Koraput|
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|Table 1: Categories of confirmed severe malaria in children and adults in admitted malaria patients |
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Detailed clinical examination and laboratory investigations
Out of 1320 patients admitted, a total of 641 consecutive patients (533 adults and 108 children) confirmed clinically and parasitologically were subjected to detailed clinical examination and laboratory investigations in the hospital wards. Though hyperpyrexia, cerebral malaria, malarial anemia, and malaria along with a respiratory infection are the major complications both in adults and children, the proportions of these complications are significantly higher in children. However, no significant difference was observed in adult and children patients having malaria with other associated disease such as sickle cell disease, urinary tract infection, algid manifestation, hepatitis, and enteric fever [Table 1].
Major clinical and prognostic features
Hyperpyrexia in children and adults
Hyperpyrexia was the predominant clinical manifestation both in children and adults. The mean hemoglobin (Hb) concentration, total leucocyte count, blood urea, and serum creatinine, and random blood sugar levels were within normal range, whereas serum bilirubin was above the normal values in adults. The mean values of Hb concentration (8.7 g/dL) and serum bilirubin (0.2 mg/dL) were below the normal values in children with hyperpyrexia [Table 2].
Cerebral malaria in children
In all, 20 children (18.5%) below 14 years of age had cerebral malaria (Blantyre coma score <3) on admission. The frequency of cerebral malaria in 0-5 years old was 35.0% only. Only one infant of 6 months of age showed signs of cerebral involvement. There was no significant difference of this manifestation between male and female children. The mean values of serum creatinine, serum bilirubin, and random blood sugar were above the normal values [Table 2].
Cerebral malaria in adults
A total of 53 (9.94%) had cerebral malaria on admission. The clinical picture varied from altered consciousness, abnormal behavior to unrousable coma. The mean values of serum bilirubin, blood urea, serum creatinine, and random blood glucose level were above normal range [Table 2].
Malarial anemia in children
In all, 14 children (13.0%) below 14 years of age had malarial anemia. The mean Hb level was 7.8 g%. About 19% of children with anemia had Hb concentration of <7 g% requiring blood transfusion. Children with malarial anemia had severe anemia when associated with sickle cell disease. Children with severe anemia had more respiratory distress than those without [Table 3].
|Table 3: Causes of deaths in malaria patients admitted in the district hospital, Koraput |
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Malarial anemia in adults
A total of 21 (3.9%) of adults had malarial anemia. The mean of Hb was 8.7 g%. Serum bilirubin and serum creatinine, whereas random blood sugar, blood urea were within normal limits. Around 11% of cases had severe anemia with Hb concentration <7 g/dL [Table 2].
Respiratory infection in children and adults
A total of 18 (3.4%) adults had respiratory infection of which 5 had acute respiratory distress syndrome (ARDS). The mean of Hb concentration, total leucocyte count (7808/μl), blood urea (32.8 mg/dL), serum creatinine (0.77 mg/dL) and random blood glucose (118 g%) were within normal range. Serum bilirubin (3.06 mg/dL) was above normal values. A total of 11 (10.2%) children had respiratory infection of which 8 had ARDS [Table 2].
|Table 2: Biochemical parameters in major clinical categories of severe malaria cases in adults and children |
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Duration of hospital stay
The duration of hospital stay varied between 2 and 10 days, the lowest being in cases of malaria with urinary tract infection and highest in cases of malaria with respiratory tract infection [Figure 2].
|Figure 2: Average number of days of hospital stay of different severe malaria cases admitted in the district hospital, Koraput|
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Of the 1320 cases of severe malaria enrolled during the 1 year study period (April 2012 to March 2013), 47.6% were enrolled in June-September (rainy season), 31.4% in February-May (summer season), and 21% in October-January (winter season) [Figure 1].
Factors associated with malaria death
The overall case fatality rate (CFR) (adult and child combined) was 4.3 (57/1320) during the 1 year study period. The ratio was similar in male and female. The major cause of death was cerebral malaria (45.6%). This could be due to late arrival of patients to the hospital from rural areas. The second most important cause of death was malaria along with respiratory infection (19.3%) and anemia (10.5%). However, malarial anemia along with sickle cell disease accounted for 19.3% of all malaria related deaths [Table 3]. The CFR in children (12.3) (36/292) was significantly higher (P < 0.05) than adults (2.0) (21/1028). The proportions of deaths due to malaria associated respiratory infection and sickle cell disease in children were significantly higher when compared to adults. However, proportion of mortality due to acute renal failure was higher in adults. Though cerebral malaria and malaria related respiratory infection were the leading cause of mortality in children, the effect of malaria related anemia and sickle cell disease also played a major role in poor prognosis in children. Therefore, children with severe anemia (<7 g/dL) due to cause cited above could not be saved in spite of a blood transfusion.
| Discussion|| |
The results showed that a large number of cases of P. falciparum malaria with severe manifestations are reported in this tribal district of the state. The hospital admissions may be a small proportion of cases in comparison to incidence in the community. Incidence of severe malaria can be a good indicator to assess the effectiveness of malaria control activities or success of a vaccine. , At present, mortality impact is the most important public health measure, but it represents a smaller proportion of the disease burden and will, thus, require large sample size for any meaningful conclusion.  In many malaria endemic areas, as the present study area, assignment of causes of deaths may present sensitivity and specificity problems that may lead to misclassification, over or underestimation and reduction of the statistical power of any study with mortality as an end point. ,, Clinically it is easier to define severe malaria as the endpoints are better defined than in mild disease from many of the other common febrile illnesses in most endemic areas. Again, the comparative ease of using the established case definitions of severe malaria and the fact that most malaria patients diagnosed as having the disease with worse prognoses than those with mild disease makes severe malaria a better endpoint. Well-defined severe malaria, therefore, bridges the gap of being a measurable parameter and can be common enough and as important as malaria-associated mortality indicator in endemic areas. 
The present study area with overall malaria CFR of 4.3 and child CFR of 12.3 and no significant difference between the genders could be a suitable site for drug and vaccine efficacy trials. This study indicates that cerebral malaria and severe anemia are the major causes of mortality. These two independent clinical entities confirms the fact that severe anemia due to chronic blood loss and cerebral involvement are the factors that are most associated with poor outcome. Sickle cell disease also resulting in anemia could be an added factor in precipitation of poor prognosis of severe anemia cases. The observation that six cases (four children and two adults with severe anemia with Hb concentration <7 g/dL) could not be saved in spite of blood transfusion suggest that it can be important indicator especially in children to evaluate malaria control program because of its frequency, especially in children and ease with which it can be measured with certainty in field situations. Respiratory infection, though the most frequent associated clinical feature, was a poor predictor of death independently, perhaps because most of cases might have received some form of antibiotic therapy before admission at the hospital. Acute renal failure, probably as a result of electrolyte imbalance due to severe dehydration prior to hospitalization has poor prognosis in cases of adult patients. Increase in serum bilirubin in cases of hyperpyrexia, cerebral malaria, and malaria associated with respiratory infection both in adult and children patients suggest derangement of liver function. Increase in blood urea, serum creatinine, serum bilirubin, and random blood sugar level in cerebral malaria cases both in children and adults indicate involvement of multiple organs. The clinical and laboratory manifestations were also consistent with reports in other endemic settings. This study represents only hospital admitted cases instead of community data suggesting that this finding may be an underestimation, as some cases might have died at home during the period since almost all cases of untreated severe and complicated malaria are potentially fatal.
Significant seasonal variations of incidence of severe malaria were recorded in 1 year study period. The highest (47.5%) occurred in the months of June-September (rainy season). The observed pattern points to the fact that increase in vector breeding during the rainy season is responsible for the upsurge in the malarial cases. Other bacterial and viral infections during rainy season may be contributing for more hospital admissions. Our earlier studies in southern parts of the district had shown higher peak of malaria incidence in winter months (October-January).  The temperature of the present study area (2900 ft. MSL) during winter months could fall to 12°C or below and result in use of winter cloths and fire in the night. In malaria endemic areas, majority of malaria death and morbidity occur during the peak transmission seasons. As such, enhanced preventive treatment approaches during this intense transmission period could have a greater impact on reducing disease burden. Such preventive measures also could reduce the risk of severe malaria.
| Conclusion|| |
Severe forms of malaria in the study area occur frequently, the predominant feature being cerebral malaria and severe anemia. Though perennial, most of the severe malaria occurs during monsoon, high transmission season. The findings suggest that the area could be effectively managed by sustained and continuous preventive and curative efforts. Clinical signs suggest multi organ dysfunction (e.g. renal failure, pulmonary edema leading to respiratory distress syndrome, hepatic damage). Acute renal failure in adults and severe anemia with Hb concentration <7 g/dL and cerebral malaria had poor prognosis.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]