ORIGINAL ARTICLE

Changing Profile of Severe Malaria in NorthIndian Children

Dinesh Yadav & Jagdish Chandra & Satinder Aneja &

Virendra Kumar & Praveen Kumar &

Ashok Kumar Dutta

Received: 1 July 2011 /Accepted: 20 October 2011 /Published online: 18 November 2011# Dr. K C Chaudhuri Foundation 2011

AbstractObjective To look for profile of severe malaria andcontribution of vivax infection to malarial morbidity in NorthIndian children.Methods Detailed clinical, biochemical and hematologicalcharacteristics of children hospitalized with severe malariaover last 3 y were recorded. Presence of malarial parasite onperipheral smear and/or positive antigen test was consideredas diagnostic for malaria.Results A total of 131(55.3%) patients with Plasmodiumvivax (Pv), 79 (33.3%) with Plasmodium falciparum (Pf) and27 (11.4%) with mixed infections were admitted. Cerebralmalaria, severe anemia and shock were significantly morefrequently observed in Pf group, while hepatic, renal,respiratory, and bleeding complications were more commonlyseen in Pv patients. Malaria mortality was highest in mixedinfection (11.1%), followed by Pf (7.6%) and Pv (3%) group.Conclusions Severe and fatal vivax malaria is an emergingrecognized entity and challenges the perception of Pv as abenign disease. Further clinical studies and molecularresearch is required to understand emergence of severemalaria in vivax mono-infection.

Keywords Severe malaria . Plasmodium vivax .

Plasmodium falciparum

Introduction

Malaria is a disease of global importance and afflicts morethan ninety countries and territories in the tropical andsubtropical regions. The World Health Organization(WHO) estimates 300–500 million malaria cases annually,with estimated mortality attributed to malaria ranging from0.7 to 2.7 million/year globally [1]. Approximately 2.48million cases are reported annually from South-east Asia, ofwhich 75% cases are contributed by India alone. WHO hasreported malaria mortality rate 15000 per year from India;however, a recent study by “million death collaborators”suggest much higher annual malarial mortality from India(205,000 overall and 55,000 in children <14 y age) [2].

Traditionally Plasmodium falciparum (Pf) is consideredresponsible for severe malaria and malaria mortality inliterature. Hence, most of the published research andliterature focuses on Pf and much less on P.vivax (Pv).However, there is growing evidence that Pv is responsiblefor a significant burden of disease worldwide [3]. Theclinical paradigm of “benign tertian malaria” has also beenchallenged recently by numerous reports of severe diseaseand even deaths due to Pv monoinfection [4].

The relative contribution of Pv vs. Pf to severe morbidityhas not been properly assessed from India. Most of thepublished literature consists of case reports or smalldescriptive clinical series, that too mainly from adultpopulation. Therefore, present study was planned to lookfor profile of severe malaria and contribution of vivaxrelated morbidity in North Indian children.

Material and Methods

This retrospective observational study was conducted onchildren (<18 y age) diagnosed with severe malaria requiring

D. Yadav : J. Chandra : S. Aneja :V. Kumar : P. Kumar :A. K. DuttaDepartment of Pediatrics, Lady Hardinge Medical Collegeand Associated Kalawati Saran Children’s Hospital,New Delhi, India

D. Yadav (*)c/o Prof. Jagdish Chandra, Lecturer’s Flat no 5,Lady Hardinge Medical College Campus,New Delhi 110001, Indiae-mail: dineshmamc@gmail.com

Indian J Pediatr (April 2012) 79(4):483–487DOI 10.1007/s12098-011-0603-x

hospitalization at Kalawati Saran Children’s Hospital, NewDelhi from January 2007 through December 2009. KalawatiSaran Children’s Hospital is a tertiary care governmenthospital for children and caters to population from Delhi aswell as neighboring states. There is no defined geographicarea; hence, denominator population cannot be defined. Caserecords of all patients were retrieved and reviewed. Detailedclinical, biochemical and hematological characteristics wererecorded. Presence ofmalarial parasite on thick and thin smearand/or positive rapid malaria antigen test (parasite LDHbased) was considered as diagnostic for malaria. Patients weredivided in complicated Pv, Pf and dual infections. Categori-zation into severe malaria and their treatment was as perWHOguidelines [5]. Cerebral malaria was defined as patientshaving altered sensorium, seizures or other neurologicalsigns with normal CSF findings. Shock was defined assystolic blood pressure less than 5th percentile for age andsex matched controls. Patients having jaundice with normalor near-normal liver enzymes and negative serology for viralhepatitis were considered as malaria hepatitis. Only thosepatients who required renal replacement therapy (peritonealdialysis) were considered to have acute renal failure (ARF).All patients were investigated for sepsis and other co-existentinfections including dengue and enteric fever, wheneverdeemed relevant. Severe anemia and severe thrombocytopeniawere defined as hemoglobin <5 g/dl and platelet count<20,000/mm3, respectively [5]. Leukopenia and leukocytosiswere defined as per age and sex related reference range fortotal leukocyte counts. Patients received packed red cell andplatelet transfusions as per hospital policy. Statistical analysiswas done using chi-square test for comparing proportions. pvalue<0.05 was considered significant.

Results

A total of 342 patients were admitted over 3 y with clinicaldiagnosis of severe malaria. Out of these, 237 cases hadmalaria confirmed by peripheral smear examination and/orrapid malaria antigen test, while remaining 105 had clinicalsuspicion of malaria where both peripheral smear and rapidantigen test were negative. Among confirmed cases, 131(55.3%) had Pv, 79 (33.3%) had Pf and 27 (11.4%) had mixedinfections, as shown in Fig. 1. Most of the patients in both thegroups belonged to Delhi and neighboring states (Haryana,Utter Pradesh and Rajasthan). Comparison of clinical andhematological characteristics of patients having Pv and Pfmonoinfection is presented in Table 1. Male–female ratiowas similar with male predominance in both the groups(2.97:1 in Pv and 2.76:1 in Pf). Pv patients had much widerage range compared to Pf though median age was similar inboth groups. However, proportion of patients from youngerage group (<5 y) was significantly higher in Pv group.

Duration of illness and hospitalization were also similar inboth groups with shorter median duration of symptoms in Pfgroup. Dengue, enteric fever and HIV co-infection were seenin 2, 1 and 1 patient, respectively in Pv group.

Among various clinical syndromes, severe anemia, cerebralmalaria and hepatitis were most common in both groups.Cerebral malaria, severe anemia and shock were morefrequently observed in Pf group and this differencewas statistically significant (p value<0.05). Hepatitis,ARF, acute respiratory distress syndrome (ARDS) andbleeding symptoms were more commonly seen in Pvpatients. However, this difference was statistically notsignificant (p value >0.05).

Among hematological parameters, severe anemia(Hb <5 g/dl) was significantly more common in Pf groupand more frequently required packed red cell transfusions (pvalue<0.05). Thrombocytopenia was significantly morecommon in Pv group (p value<0.05); though no significantdifference was observed in occurrence of severe thrombocy-topenia and platelet transfusion requirement in both groups.Leucopenia and leukocytosis were more frequently observedin Pf group (p >0.05).

Mortality was highest in mixed infection (11.1%),followed by Pf (7.6%) and Pv (3%) group. Most of thesepatients had 2 or more clinical syndromes simultaneously.Cerebral malaria was most common cause of mortality (4cases), followed by DIC (2), shock (2), ARF (1) andhepatitis (1) in Pf patients. In patients with Pv mono-infection, ARDS, ARF and hepatitis (2 each) were thecauses of mortality, followed by cerebral malaria and DIC(1 each).

Discussion

Malaria imposes great socio-economic burden on humanity,and with six other diseases (diarrhea, HIV/AIDS, tuberculosis,measles, hepatitis B, and pneumonia), accounts for 85% ofglobal infectious disease burden. Among cases with malaria,

342 Clinically suspected severe Malaria

237 +ve PS and/or Rapid Antigen Test

131 Pv 79 Pf 27 Dual Infection

26 (Pv + Pf) 1 (Pv + P malariae)

Fig. 1 Flow diagram of patients

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proportion of Pv and Pf varies in different parts of India with10-30% cases caused by Pf and remaining 70–90% by Pv inmost parts of the country. A continued rise in Pf has beenreported recently and its proportion has gradually risen tonearly 50% of total cases in recent years [6, 7]. Severe malariais classically associated with Pf infection. However, recentstudies from several countries including India have shownthat 21–27% of patients with severe malaria have Pvmonoinfection and clinical spectrum of these cases is broadwith an overall mortality of 0.8–1.6% [8]. More than half of

the cases with severe malaria in present series were due to Pvmonoinfection, while Pf contributed only one-third of totalcases. Similar higher proportion of severe Pv malaria (63.1%)has been reported from a study in children from Bikaner, innorthwest India [9].

Male predominance was seen in both Pv and Pf groups,which is possibly due to higher health seeking behavior formale children. Severe Pv malaria was more frequentlyobserved in younger children (<5 y age) in comparison to Pfmalaria, which affected more of older children. Similar higherproportion of severe malaria in children <5 y of ageattributable to Pv (67.4%) compared with Pf (30.4%), hasbeen reported by Kochar et al. [9]. Shorter median duration ofillness was seen in present study in Pf group, which ispossibly due to more severe presentation of the disease(cerebral malaria, shock, severe anemia). However, bothgroups had similar median duration of hospitalization,suggesting that even Pv patients took equal time torecover.

Very little information is available in literature on thecontribution of Pv to severe disease. As the term “benigntertian malaria” implies, Pv malaria is usually an uncompli-cated disease that runs a benign course and is rarely fatal, butsporadically, all complications associatedwith Pf malaria havealso been reported in Pv malaria [4]. Earlier studies fromThailand and Vanuatu (an island nation located in the SouthPacific Ocean) in last decade suggested a protective effect ofPv and suggested that Pv co-infection with Pf may attenuateseverity of Pf malaria [10, 11]. However, recent studies fromPapua New Guinea, Indonesia and India have reported allcomplications of severe malaria with Pv infections andmixed infections are reported to have more severe diseases[4, 9, 12]. In the present study, cerebral symptoms, shockand severe anemia were more commonly seen in Pf group.More importantly, there was no significant difference observedin occurrence of other clinical syndromes and some syndromes(hepatitis, ARF, ARDS and bleeding manifestations) wereobserved even more frequently in Pv group.

Complications in severe malaria are either sequestrationrelated, such as cerebral malaria, renal dysfunction, hepaticdysfunction and ARDS, or non-sequestration related, suchas anemia and thrombocytopenia. Sequestration relatedcomplications are usually seen in Pf infection only, whilenon-sequestration–related complications can be seen in Pvinfection as well [13].

Anstey et al. recently suggested that Pv patients are morelikely to suffer from respiratory distress syndrome comparedwith Pf, as they have more severe alveolar-capillary dysfunc-tion. Sequestration of Pv infected erythrocytes in pulmonarymicrovasculature and greater inflammatory response to a givenparasite burden in Pv is probably responsible for this alveolar-capillary dysfunction. Small airway obstruction, gas exchangealteration, increased phagocytic activity and accumulation of

Table 1 Characteristics of patients

Characteristics Pv (n=131) Pf (n=79)

Sex distribution

Male 98 (74.8) 58 (73.4)

Female 33 (25.2) 21 (26.7)

Age range 1 mo–18 y 2.5 mo–9 y

Median age 3 y 3 y

<5 y 98 (74.8) 44 (55.7)*

>5 y 34 (25.9) 35 (44.3)*

Duration of illness

Median 7 d 5 d

Range 1–30 d 1–30 d

Duration of hospitalization

Median 5 d 5 d

Range 1–21 d 1–40 d

Complications

Severe anemia 45 (34.4) 39 (49.4)**

Cerebral 22 (16.8) 22 (27.8)**

Hepatitis 23 (17.6) 13 (16.5)

Bleeding/DIC 12 (9.2) 05 (6.3)

ARF 08 (6.1) 03 (3.8)

Septicemia 04 (3) 04 (5)

CHF 02 (1.5) 02 (2.5)

Shock 02 (1.5) 05 (6.3)**

ARDS 03 (2.3) 01 (1.3)

Hypoglycemia 01 (0.7) 02 (2.5)

Mortality 4 (3) 6 (7.6)

Hemoglobin

<5 g% 45 (34.4) 40 (50.6)**

5–11 g% 76 (58) 34 (43)**

>11 g% 10 (7.6) 05 (6.3)

Platelet count (/mm3)

<100,000 109 (83.2) 55 (69.6)**

<20,000 17 (13) 09 (11.4)

Figures in parenthesis are percentages. *p value<0.005, **p value<0.05

Pv plasmodium vivax, Pf Plasmodium falciparum, DIC disseminatedintravascular coagulation, ARF acute renal failure, CHF congestiveheart failure, ARDS acute respiratory distress syndrome

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pulmonary monocytes are the other suggested mechanisms forrespiratory complications [14]. Severe Pv malaria is thus anemerging recognized entity, and the longstanding belief thatPv is a non sequestering parasite might need to be revisited.

Severe anemia was significantly more frequently observedin Pf group and more frequently required packed red celltransfusions, while, bleeding symptoms and thrombocytope-nia were more frequently observed in Pv patients in thepresent series. Severe anemia, DIC and thrombocytopenia areconsidered to be non-sequestration-related complications withmultifactorial etiology, e.g., hemolysis, reduced cell deformityof erythrocytes, decreased platelet survival and increasedsplenic uptake. Patients with Pv infection are less likely topresent with severe anemia, as they have lower parasitedensities than Pf patients, and therefore, the likelihood ofhaving profound anemia is less, even if other immunologicalfactors may contribute to red cell destruction [15]. Profoundthrombocytopenia is a well-recognized complication of Pfmalaria but has been less well described in Pv malaria. Arecent study from Venezuela, reported thrombocytopenia in58.9% cases with Pv malaria, with 25.6% requiring platelettransfusions [16]. Another series on adult patients with Pvmonoinfection reported thrombocytopenia in 12.5% cases[13]. Much higher percentage (83.2%) of children hadthrombocytopenia in present series; however, severe throm-bocytopenia was seen in only 13% and 12.2% of theserequired platelet transfusions. These findings suggest benignnature of thrombocytopenia in Pv, mostly recovering withantimalarials without platelet transfusions.

The mechanism of thrombocytopenia in malaria is notclearly known. Fajardo and Tallent demonstrated Pv withinplatelets by electron microscopy and suggested a direct lyticeffect of the parasite on the platelets [17]. Both non-immunological destruction as well as immune mechanismsinvolving specific platelet-associated IgG antibodies thatbind directly to the malarial antigen in the platelets has beenreported. These antibodies play a role in the lysis of plateletsand the development of subsequent thrombocytopenia [18,19].Oxidative stress damage of thrombocytes has also beenimplicated in the etiopathogenesis based on the finding oflow levels of platelet superoxide-dismutase and glutathione-peroxidase activity and high platelet lipid peroxidation levelsin malaria patients, when compared to those of healthysubjects [20]. Higher mortality rates were seen in Pf group.However, 4 patients died with severe Pv infections, whichunderlines the importance of emerging severe Pv malaria.

This is probably the largest pediatric series from Indiacomparing the morbidity profile of Pf and Pv infection.Possible limitation of this study is that parasite species wereidentified by microscopy and rapid antigen test. Thesemethods are known to miss minority of co-infections. Thus,mixed infections might have been underestimated. A moresensitive detection method, polymerase chain reaction (PCR)

has been used in one of the earlier studies [7]. While thislimitation may be valid, it is believed that, in general, theinfections that make the patient sick are those of highdensity, and that these are the ones that are identified bymicroscopy and rapid antigen tests, and those with very lowdensities are unlikely to contribute much to the acute phase,and even less to severe manifestations. Furthermore PCR hasbeen used as a research tool only, and not feasible to be usedin clinical settings.

Conclusions

Severe and fatal vivax malaria challenges the authors’perception of Pv as a benign disease. Severe vivax malaria isan emerging recognized entity and all the complications seenwith falciparum malaria, are now reported with vivax as well.Thrombocytopenia, respiratory complications, renal dysfunc-tions and hepatitis are more commonly reported with vivax inpresent series. Further clinical studies and molecular researchis required to understand emergence of severe manifestationsin vivax mono-infection.

Conflict of Interest None.

Role of Funding Source None.

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