Published online August 31, 2007
PEDIATRICS Vol. 120 No. 3 September 2007, pp. e454-e460 (doi:10.1542/peds.2006-3171)
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Clinical Manifestations and Predictors of Severe Malaria in Indian Children

Radha Tripathy, MDa,b, Sailajanandan Parida, MDa,b, Leena Das, MDa,b, Debi Prasad Mishra, MDc, Diptimayee Tripathy, MDd, Mangala Charan Das, MDe, Hegang Chen, PhDf, James H. Maguire, MD, MPHg and Pinaki Panigrahi, MD, PhDg,h

a Center for Research on Maternal and Childhood Malaria, Departments of
b Pediatrics
d Medicine
c Pathology, SCB Medical College, Cuttack, Orissa, India
e Department of Pharmacology, MKCG Medical College, Berhampur, Orissa, India
f Divisions of Bioinformatics and International Health, Departments of
g Epidemiology and Preventive Medicine
h Pediatrics, University of Maryland, Baltimore, Maryland


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
OBJECTIVE. Although the greatest morbidity and mortality attributable to malaria occurs among children in Africa, up to one third of the world's malaria burden is borne by non-African countries, where levels of endemicity are lower. Because there are few published criteria for managing life-threatening malaria in children in these countries, we conducted a study of major syndromes and predictors of death among critically ill Indian children to identify factors that could be used to improve the approach to their treatment.

METHODS. A prospective study was conducted at the pediatric ward of SCB Medical College in eastern India (Orissa). Baseline demographic data were collected on all of the patients with confirmed slide-positive falciparum malaria. Patients satisfying any 1 of the 2000 World Health Organization criteria for severe malaria were included in the analysis. Prevalence of and mortality as a result of major symptoms were calculated followed by multiple regression modeling to identify major predictors of death.

RESULTS. Of 1682 confirmed cases of malaria during a 32-month period, 374 subjects met the World Health Organization criteria for severe malaria. The case fatality rate was 12% in this series. Multiple regression analysis identified respiratory distress, coma, multiple organ dysfunctions, and hyperparasitemia as major predictors of death. Anemia and jaundice did not emerge as important markers of mortality. Many patients presented with multiple major complications, and the mortality rate was consistently high when >1 major predictor was present in a patient.

CONCLUSIONS. Clinical features in Indian children differed from those reported in most studies that involved an African population. Multiple organ dysfunctions emerged as an important presenting feature and a new predictor of death in childhood malaria.

Key Words: malaria • children • MODs • falciparum • clinical features

Abbreviations: WHO—World Health Organization • MOD—multiple organ dysfunction • RD—respiratory distress

Infection resulting from malaria accounts for >1 million child deaths globally every year1 at a rate of ~1 death every 30 seconds.2 Data from the 1990s suggested that as many as 90% of all malarial cases and 90% of deaths take place in sub-Saharan Africa, where levels of endemicity are high, and severe disease and mortality occur primarily during infancy and early childhood.3 More recent data-driven models indicate that up to one third of the global incidence may occur outside of Africa and that 25% of the world's clinical cases in 2002 occurred in South and Southeast Asia, where passive reporting may significantly underestimate the disease burden.4 India is one of the major contributors to malarial morbidity and mortality in this part of the world.5 Although malaria in children is now a well-known cause of mortality and morbidity in Asia,6 few studies from this region have described the predictors of life-threatening malaria in this population. The current prospective study was undertaken in the eastern Indian state of Orissa, which reports 29% of all malaria cases7 and >60% of total malarial deaths in the country.8


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Study Site and Patient Population
This study was undertaken between April 2001 and December 2003 at SCB Medical College Hospital, a 1250-bed tertiary care center in Cuttack, Orissa. This hospital caters to a diverse patient population coming from an unstable hypoendemic coastal area, as well as hyperendemic tribal areas. The annual parasite index for Orissa was 12.4 and 11.1 with a slide positivity of 10.3 and 9.5 in the years 2002 and 2003, respectively.9 The falciparum/vivax ratio in our population was 85:159. The pediatric service at SCB Medical College had 1682 admissions during the study period, with the primary diagnosis of falciparum malaria confirmed by thick blood smears. Study physicians evaluated these patients and completed predesigned data collection forms. Of this population, data of 374 patients were included in the analysis who met the 2000 World Health Organization (WHO) criteria for severe malaria.10 The remaining patients (n = 1308) were either discharged from observation rooms with oral antimalarial treatment or discharged from the inpatient ward in <24 hours after showing significant clinical improvement. Parents of these patients were advised to bring the children back to the hospital in the case of recurrence of symptoms or emergence of new illness. We excluded patients who died during resuscitation in the first hour before admission formalities were complete. Following local regulations, approval was obtained from the hospital superintendent of SCB Medical College and the ethical review committee of the state government Health and Family Welfare Department. Parental consent was waived, because the study was done in an emergency setting following standard hospital practice without introduction of any experimental procedures. Clinical and laboratory variables were collected on coded data collection forms without patient identifiers.

Clinical Assessment and Laboratory Investigations
Patients were evaluated and managed following standard hospital practice. Patient demographics and clinical details were recorded. The level of consciousness was assessed using the Blantyre Coma Scale.11 Routine laboratory investigations included a complete blood cell count, platelet count, blood glucose estimation, urine examination, hepatic and renal function tests, coagulation profile, cerebrospinal fluid study, chest radiograph, and blood culture when indicated. Admission laboratory values were used for patient classification and data analysis. Blood gas and pH analyses were done in only a small subset of patients because of limited access to instruments. In subjects with depressed levels of consciousness, lumbar puncture was deferred until the patient regained full consciousness, and empiric intravenous antibiotics were started as deemed appropriate by the attending physician. Different clinical syndromes were defined as in Table 1 following WHO classification guidelines of severe malaria.


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  		TABLE 1 Definitions of Clinical Syndromes Used in the Study

 
Clinical Management
All of the patients received treatment with intravenous quinine, based on a contemporary WHO recommendation as the first-line drug. Blood transfusions for severe anemia, intravenous glucose for hypoglycemia, acetaminophen for hyperpyrexia, oxygen by facial mask for respiratory distress (RD), antibiotics for possible bacterial infection, and other supportive therapy were given as appropriate. Intravenous diazepam was used to control convulsions, and phenobarbital was used for repeated and uncontrollable seizures. Hemodialysis was performed in patients with severe renal failure, and 2 patients with multiple organ dysfunctions (MODs) received exchange transfusion.

Statistical Analysis
Statistical analysis was performed by using SAS 8 (SAS Institute, Inc, Cary, NC). All of the clinical and pathologic variables associated with death were examined using descriptive statistics. Univariate logistic-regression models were fitted for these variables using pro logistic, with death as the outcome measure and adjusted for age. Relative risks of dying were estimated as odds ratios with 95% confidence intervals. This analysis allowed the examination of the overall effect of each variable and then selection of the important ones for multivariate analysis. All of the variables with a P value of ≤.10 were included in the first multivariate model. Using the stepwise option of pro logistic, all of the variables that had a significant overall effect on the model (P < .05), as well as age, were included in the final model. Shock and spontaneous bleeding were excluded from the final minimal effects model because of small numbers (n = 11 and 9, respectively). We also did not include acidosis because of a lack of data on blood gas and pH in the majority of the cases.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
General Clinical Description
The median age of the children with severe malaria was 8 years. The age distribution of 1308 cases of nonsevere slide-positive malaria and 374 cases of severe malaria is given in Table 2. Forty-five deaths were recorded in the series, with an overall mortality rate of 12%. Although patient fatality seemed to be slightly on the higher side (16%) in children <2 years old, age did not emerge to have any significance in predicting death (P = .95). In our patient population, the most common presentations were coma (n = 159), prostration (n = 154), convulsions (n = 111), anemia (n = 107), and impaired consciousness (n = 95; Table 3). There were 64 patients who had involvement of ≥2 organs systems (MODs). Nearly one quarter of patients had hyperparasitemia.


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  		TABLE 2 Age Distribution of Severe and Nonsevere Cases of Malaria

 

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  		TABLE 3 Prevalence of Major Clinical Criteria of Malaria and Associated Mortality in Indian Children

 
The age-adjusted mortality according to clinical syndrome at presentation is shown in Table 3 (univariate analysis). Although common, anemia by itself did not have any value in predicting death. Malnutrition, prostration, and gastrointestinal dysfunction resulted in mortality rates of 11.7%, 8.4%, and 4.2%, respectively. Renal failure was present in 53 subjects (14% of patients), a quarter requiring dialysis, and 10 of these patients with MODs died. Although renal failure was frequently accompanied by other features of severe malaria and other organ system involvement, we had 4 subjects who presented with renal failure alone. Jaundice (bilirubin range: 3–38 mg/dL) was noted in 20% of the population and did not predict death. It was associated with 13.5% overall mortality, which increased to 27% with concomitant cerebral malaria and renal failure. Thirty percent of the patients had repeated seizures (>3/day), of which 31% had unarousable coma and 7% had hypoglycemia. Peripheral circulatory failure (shock) was seen in only 11 moribund patients (2.9%) with a very high mortality rate (81%). Disseminated intravascular coagulation and spontaneous bleeding developed in 9 patients, also culminating in a relatively high mortality (33%).

We admitted 64 patients (17% of total population) with MODs. There were 20 deaths (mortality rate: 31%) in this group, despite providing necessary specialty care. Apart from having ≥2 major organ systems involved, several of these patients had other concomitant conditions, such as hypoglycemia (n = 13), hemoglobinuria (n = 9), shock (n = 9), and myocarditis (n = 1). Two MOD patients needed exchange transfusion; both survived.

Major Predictors of Death in the Patient Population
We used data of our univariate model and a generous cutoff to include all of the possible predictors in the multiple regression analysis. Shock and spontaneous bleeding were excluded from this analysis because of the very small number of patients in each group. Only RD, coma, MODs, and hyperparasitemia emerged as significant predictors of death (Table 4).


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  		TABLE 4 Major Predictor Multiple Logistic Regression Model for Malarial Deaths in Children

 
Overlapping Presentation of MODs, Coma, RD, and Hyperparasitemia
There were 159, 119, 64, and 27 cases of coma, hyperparasitemia, MODs, and RD, respectively. Of the 64 patients with MODs, 30 did not have RD or coma. In this 30-patient MOD subgroup, mortality was 13.3% compared with 8.06% in those without MODs, signifying MODs as an independent clinical entity of severe malaria in our population. In addition, we observed a clear overlap among the 4 major predictors of death. Twenty-five patients had MODs and coma, 15 had MODs and RD, and 36 had MODs and hyperparasitemia (Fig 1). The mortality rate increased in these major subgroups when >1 feature was present in the patient. Although coma alone had a mortality of 18.9%, it increased to 36% when concomitant MODs were present (9 of 25 died). Twenty-seven patients with RD had an overall mortality of 66.7%. Fifteen patients in the RD group had MODs, of which 13 died exhibiting an increase in the mortality rate to 87%. The mortality rate in hyperparasitemia was 23.5% (28 died of 119). Thirty-six patients had MODs and hyperparasitemia, with 15 deaths in this overlapping group (mortality increased to 42%). Six patients had all 4 of the major predictors; mortality was 100% in this group.


Figure 1
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  		FIGURE 1 Overlapping presentation of coma, RD, hyperparasitemia (HP), and MODs in children with severe malaria.

 

   DISCUSSION
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
In the current Indian study, there was a clear departure from the typical presentation of malaria in African children. Although several features common to the African children were seen in our population, we observed a wide variation in the overall picture of malaria, and there were major differences in features that predicted death.

Median age of the children in our study was 8 years, in contrast to the mean age of 26 months, with 86% of the population being <4 years of age in high-transmission areas in Africa.12 In lower-transmission areas of Africa, such as Senegal, the mean age seems to be higher (mean age: 6.2 years),13 a phenomenon closer to that seen in India. In our study, mortality was 12%, almost equally distributed among different age groups, with the exception of a slightly higher rate (16%) in children <2 years of age. In high-transmission areas of Africa, mortality seems to be very rare in patients >4 years old. However, a picture closer to the Indian setting with a mean age of dying at 7.5 years is seen in nonendemic regions of Africa.13 These differences seem to be directly related to the level of endemicity, age at first infection, reinfections, and the acquired immunity by the pediatric population.14,15

In African children from a high-endemicity area, impaired consciousness, jaundice, RD, and hypoglycemia are important predictors of death.12 Renal failure is uncommon, and multiple organ failure has not been described.12 In our series, there were 4 major predictors of mortality; RD, cerebral malaria, MODs, and hyperparasitemia. RD and hypoglycemia were seen in small subsets of patients, in 7.2% and 6.4% of the total population, respectively. Involvement of multiorgan systems emerged as an important clinical presenting feature in our study population and stood out as a key predictor of severe malaria and death. We found MODs to be overlapping with RD and coma in moderately high numbers, and in each case, mortality was higher when MODs were present as a concomitant feature with another major predictor. In the Indian subcontinent context, Bag et al16 studied 50 subjects with complicated falciparum malaria and reported 30% of children to have extracerebral features, including involvement of other organ systems. Mortality was higher in extracerebral form (33.3%) compared with cerebral malaria (22%). Huda et al,17 from Northern India, described 56.5% of their pediatric patient population to be presenting with >1 manifestation of severe malaria, including 8.7% with renal failure. High rate of MODs and cerebral malaria have been reported in adults from Dakar, Senegal,18 a seasonal endemic area, and is recognized as an important terminal sequel in adults with severe malaria.19,20 However, it is quite difficult to categorize the disease as mild versus severe, and there is always a continuum between the 2, where patients can go from mild to severe quickly (especially children), with serious implications.21 These observations point to the complex pathogenesis of this disease in nonimmune patients and to the fact that a similar spectrum of symptoms can be seen in patients coming from a wider age group. The current WHO recommendation6 for Southeast Asian countries does not consider impending or overt MODs to have specific diagnostic or prognostic value in childhood malaria.

Under-5 anemia has been proposed as a surrogate of malaria burden in endemic areas of Africa.22 In our study, anemia was present in 28.6% of the patients with 14% mortality but did not have an independent value in predicting deaths. Better survival in this group may be because of prompt blood transfusion available at our center. It may also suggest that other concomitant features were responsible for the deaths in this group. Other smaller studies from Orissa have described a similar, albeit slightly lower, prevalence of anemia in pediatric patients.16,23 Marsh et al12 reported 27.5% of the African population to have severe anemia, with a low 1.3% mortality that increased to 4.7% with impaired consciousness or RD. In the low-transmission area of Senegal, Imbert et al13 studied 161 children and reported severe anemia in 73%, 52%, and 26% of patients in age groups 0 to 3 years, 4 to 7 years, and 8 to 15 years, respectively, with a case fatality rate of 3%. In this study, prevalence of severe anemia depended on age and parasitemia rather than on transmission level.13 In northern Ghana, although severe anemia was present in 55% of the patients, it did not serve as a predictor of death.24 Our results seem to be similar to other nonendemic areas of the world and signify the burden of anemia in childhood malaria and the importance of this important childhood ailment that may manifest as a disease complex with other factors, such as nutritional deficiencies (iron, folic acid, or other micronutrients), helminth, and other infections.

RD, another key presenting feature of childhood malaria, was seen in 7.2% of our patient population. Although small, this group showed a very high mortality rate (66.7%). In African children, RD is common in younger children (13.7% prevalence).12 The relatively low mortality rate of 13.9% in RD increases to 24.8% when a more precise definition is used.12 Approximately half of the patients in this study who had concomitant impaired consciousness showed an even higher mortality rate of 31.7%.11 In Malawian25 and Gambian26 children, severe anemia results in impaired tissue oxygenation and metabolic acidosis, an analogous presentation of RD. With a small patient group and without measurement of plasma bicarbonate, it is difficult to comment further on the pathogenesis of this syndrome in our patients. From the point of view of early diagnosis and estimation of severity, it is safe to say that bedside recognition of RD may independently yield valuable information without blood gas measurement.11

Results of our study also describe other common features, such as malnutrition, convulsions, impaired consciousness, shock, and spontaneous bleeding/disseminated intravascular coagulation that need reiteration in the childhood malaria literature. African studies have reported malnutrition to be a key predictor of death.24 Interestingly, malnutrition did not come out as a significant predictor of death in our study, although 71% of our patients were malnourished. Similarly, impaired consciousness without coma was present in 25% of our patients, with a case fatality rate of 15.8%. These features, although not uniquely significant for predicting death, carry important public health messages.

In this study, aerobic blood culture was done, and antibiotics were given to a small subset of patients (n = 22) based on the clinician's judgment. Although it is a common practice in peripheral hospitals to use antibiotics along with antimalarials in severely sick patients, there is no consensus opinion on the utility of such treatment. However, septicemia itself can manifest with symptoms of MODs, and more comprehensive studies with blood culture are needed to discern the difference between these 2 entities.

It is possible that we did not capture the full burden of malaria and the complete spread of clinical symptoms in our hospital setting. It is speculated that many deaths take place at home in the villages in the developing world,27,28 and there is a possibility that we missed certain manifestations of malaria causing early deaths in children. Population-based surveillance is required for precise measurement of these variables. Nevertheless, we examined a large group of pediatric patients (1682 confirmed with slide positivity) with varying manifestation and severity of malaria during the study period. We enrolled 374 patients who met WHO criteria of severe malaria in our analysis, including patients with shock and spontaneous bleeding, and several moribund patients died during the first hour of presentation during the study period. These observations make us feel comfortable in that our data were not skewed toward certain symptoms and provide assurance against the possibility that we could have completely omitted other high-risk predictors.

Our results described in this study population bear high significance in shaping the guidelines in the diagnosis and treatment of malaria in children worldwide, especially in the non-African setting. The WHO guidelines continue to draw from the African experience and list cerebral malaria, anemia, RD (acidosis), and hypoglycemia to be key determinants of pediatric malaria.3,5,29 Renal failure is described to be uncommon. The 2005 rollback malaria initiative5 and the 2006 treatment guidelines by the WHO30 recognize the high disease burden and mortality in children in Southeast Asian countries but fall short of describing specific or new predictors of severity or death for the pediatric population in this region. The WHO- South East-Asia Regional Office regional guidelines6 continue to list severe anemia, convulsions, hypoglycemia, and metabolic acidosis to be the most common manifestations in the pediatric population and cerebral malaria to be common in older children. Multisystem involvement is described only in adults.6 The 2006 treatment guidelines of the WHO list cerebral malaria, metabolic acidosis, severe anemia, and hypoglycemia to be the key common features and renal failure and acute pulmonary edema in adults.30 This recent report does recognize that the disease manifestation may be different in areas of unstable malaria in much of Asia and Latin America and the remaining parts of the world where malaria is endemic.30


   CONCLUSIONS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
Malaria is no longer a disease of just sub-Saharan Africa.5 Apart from an increase in the incidence,31 the United States had 63 outbreaks of malaria between 1957 and 2003.31 A recent report of 30 GeoSentinel sites involving 17553 travelers described malaria to be 1 of the 3 most frequent causes of systemic febrile illness and reported 269 cases of malaria in 1069 patients returning from Southeast and South Central Asia.32 With the unprecedented increase in travel and commerce around the world, trends in the incidence will only increase, and the clinical picture will change in the coming years. At this juncture, results of our study indicate that it is not appropriate to propose a "one-size-fits-all" set of criteria for diagnosing or treating severe malaria. Country-specific and region-specific studies are critically warranted to develop guidelines for management of this disease. These guidelines should be treated as living documents accepting major changes as malaria changes its clinical face, sensitivity to drugs, and immune response in the host.


   ACKNOWLEDGMENTS
 
This study was funded in part by National Institutes of Health (Fogarty) grant TW 00601. We are grateful to Bijay Shri Routray, minister of health and family welfare, Government of Orissa, for providing necessary support for this study.

We thank the medical superintendent of SCB Medical College for permission to conduct this study and for providing all of the logistic assistance during the study.


   FOOTNOTES
 
Accepted Feb 16, 2007.

Address correspondence to Pinaki Panigrahi, MD, PhD, Departments of Pediatrics and Epidemiology and Preventive Medicine, Division of International Health, University of Maryland School of Medicine, 22 S Greene St, N5W68, Baltimore, MD 21201. E-mail: ppanigrahi{at}pol.net

The authors have indicated they have no financial relationships relevant to this article to disclose.


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

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