Despite the burden of malaria falling worldwide, progress in outcomes has stalled with over 400,000 individuals dying annually. A majority of these deaths occur in young children under the age of five . Severe Malaria (SM) affects multiple organ systems, with frequent respiratory, cardiac, renal and neurological manifestations. Cardiovascular abnormalities in SM have long been appreciated  and take a multitude of forms [3, 4, 5, 6, 7]. Systemic inflammatory effects due to cytokine release, as well as extensive sequestration of the parasitized red blood cells causing microvascular obstruction in the coronary vessels, are likely contributors to the reported hemodynamic abnormalities [8, 9].
In the ‘Mortality after fluid bolus in African children with severe infection’ (FEAST) trial, significantly increased mortality was noted in children who received 20–40 ml/kg of either 5% albumin or normal saline boluses . Those with WHO defined shock at the time of randomization had a substantially increased absolute mortality risk (28%) with fluid bolus therapy. On later analysis, the excess mortality due to fluid bolus was reported to be caused by cardiogenic shock in all subgroups, including those with severe malaria . This conclusion was based on the presence of clinical signs of shock at the point of demise. No objective measurements of cardiovascular function were performed in the FEAST trial. It remains unclear if previous studies that measured cardiovascular parameters directly support the theory that cardiovascular failure is a major contributor to mortality in SM either before or after fluid bolus administration.
We therefore undertook this systematic review of previously published manuscripts describing cardiovascular parameters measured directly during SM infection in pediatric and adult patients. Our aim was to summarize the results in an attempt to improve the overall understanding of the effects of SM on the cardiovascular system.
This review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines .
A search was undertaken of Medline and Embase for studies published up until Sept 2019. Search terms included a combination of the following: ‘malaria,’ ‘cardiac,’ ‘cardiovascular,’ ‘hemodynamic,’ ‘echocardiography,’ ‘ultrasound,’ ‘heart’ and ‘myocardial.’ Relevant references cited in eligible studies were also sought.
Studies involving either pediatric or adult patients with severe malaria and documented echocardiography or other hemodynamic monitoring parameters published in English were considered. SM was defined as per World Health Organization (WHO) definition ; presence of plasmodium falciparum asexual parasitemia and no other confirmed cause for the patient’s symptoms or signs, accompanied by one or more clinical or laboratory features. Papers reviewing the pharmacodynamics of or cardiotoxicity from anti-malarial drugs or vaccines were excluded. Studies related to malaria in pregnancy or those involving patients with known cardiac disease were also not included. Studies whose primary focus was on myocardial infarction/heart failure in adults with SM were excluded given the high probability that the results were secondary to cardiovascular complications in the setting of coronary disease exacerbated by fever and anemia rather than a direct effect of malaria on the cardiovascular system. Those studies describing the effect of malaria on the cardiac rhythm or electrocardiogram were outside the scope of this review.
Data extraction was performed using a standardized form by one review author (GW). The following data was retrieved: author details, year and journal of publication, patient demographics, clinical cardiovascular and echocardiography findings, and results of any invasive cardiac output monitoring including Pulse Contour Cardiac Output (PiCCO) or Pulmonary Arterial catheters (PAC). The findings were then placed into broad categories, including pediatric or adult (some of which included a small number of children) studies and separated by parameters studied.
The methodological quality of the studies included was not assessed.
6058 citations were identified (Figure 1). After removal of duplicates, 2437 publications remained with 2371 of these excluded after abstract review. Full text review of 66 studies was undertaken, with exclusion of 42 for the following reasons: pregnancy related (2), no echocardiography or cardiac output parameters reported (24), only electrocardiogram (ECG) changes reported (2), underlying cardiac pathology (1), cardiac bypass or extracorporeal membrane oxygenation (ECMO) related (3), non-severe malaria (2), severe plasmodium vivax (4), vaccine related (2), not in English (2) and only pharmacodynamics reported (1). Twenty-three studies met inclusion criteria and are listed in Table 1.
|Trial||Type of Study||Location||Patient Population||No of participants||Study used to assess cardiac function|
|Charoenpan (1990) ||Prospective Cohort||Thailand||Adult with SFM||13||Echo and PAC|
|Beards (1994) ||Case Report||South Africa||Adult with SFM undergoing exchange transfusion||1||PAC|
|Bruneel (1997) ||Retrospective study||France||Adult with SFM and shock||14||PAC|
|Lagudis (2000) ||Case Series||Brazil||Adult||2||PAC and ECHO|
|Saissy (2000) ||Prospective observational||Senegal||Adult with SFM||29 (control group=systemic vascular resistance of 800 dyne s–1 cm–5 or higher. Hyperkinetic group with a level lower than this)||PAC|
|Mohsen (2001) ||Case Report||UK||Adult with SFM||1||Echo, cardiac biomarkers|
|Janka (2010) ||Prospective observational||Mali||Pediatric with SM and those without. 1–5yrs with SM (excluded if CM though)||53 with SM||Echo, cardiac biomarkers|
|Yacoub (2010) ||Prospective observational as part of interventional trial||Kenya||Pediatric with severe malaria (>6m)–SM with metabolic acidosis, children without||30||Echo|
|Hanson (2011) ||Prospective observational||Bangladesh and India||Adult with SFM admitted to ICU||28 (same cohort of patients as in Hanson 2013 paper below)||CVP and PiCCO, (Transpulmonary thermodilution)|
|Herr (2011) ||Prospective Case control||Germany||Adult, complicated and uncomplicated FM||28||Non-invasive method based on the re-breathing technique|
|Mocumbi (2011) ||Prospective observational||Mozambique||Pediatric, 5–15yrs with FM||47, 10 with SM||Echo|
|Murphy (2011) ||Pilot observational||Uganda||Pediatric, SFM and non-severe||17 with SM||Echo|
|Nguyen (2011) ||Retrospective analysis of prospectively collected hemodynamic data from interventional trials||Vietnam||Adults with SFM||43 (managed with fluid loading or inotropes)||PAC|
|Sanklecha (2011) ||Case Series||India||Pediatric||3 (cardiac involvement in one only)||Echo|
|Nguah (2012) ||Prospective observational||Ghana||Pediatric||183||Echo|
|Hanson (2013) ||Interventional||Bangladesh and India||Adult||28||PiCCO (transpulmonary thermodilution)|
|Nayak (2013) ||Prospective observational||India||Adult and Pediatric (13–75yr), severe vivax and SFM||100 with SM, 28/100 with SFM. 9/28 had cardiac involvement||Echo|
|Sulaiman (2014) ||Case Report||Malaysia||Adult with SFM||1||Echo|
|Colomba (2017) ||Case Reports||Italy||Adults with SFM||2||Echo|
|Ray (2017) ||Prospective observational||India||Adult > 15 < 70yr with SFM||23/27 SFM. 7 had circulatory failure||Echo|
|Kotlyar (2018) ||Prospective observational–comparison of SM and SMA||Uganda||Pediatric with SFM (3m–12yr)||13 with SM||Echo and cardiac biomarkers (trop I and BNP)|
|Leopard (2018) ||Prospective observational–sepsis and SM||Bangladesh||> 12 years, SFM or sepsis||102, 13 with SFM||Lung ultrasound|
|Kingston (2019) ||Prospective observational||Bangladesh and India||Adult with SFM or sepsis||46 with SM||ECHO and Expired gas collection|
A total of seven studies included in the review evaluated pediatric patients only. All took place in Sub-Saharan Africa. The majority of cardiovascular parameters evaluated are available in Table 2.
|Trial||Mean Age (months)||Mean Hb (dg/L)||Preload D0||Cardiac Function||Structural||Pulmonary Artery Pressures mmHg||Cardiac Biomarkers|
|LVEF D0||CI (l/min/m2) DO|
|Janka (2010) ||30.1||4.2||–||64%||–||–||31
TRV = 2.5m/s (controls 2m/s)
|CK-MB 4.31 ng/mL and Troponin T 10 pg/mL|
|Yacoub (2010) ||46(median)||7.5 (median)||IVC collapsibility index 43.8
|63.1%||4.6 Ultrasound Cardiac Output Monitor (USCOM) stroke volume index improved after fluid bolus in 80% of acidotic patients from an average of 36.7 mL/m2 (95% CI, 30.9–42.5) to 41.5 mL/m2 (95% CI, 37.19–45.8; p = .007)||–||–||–|
|Mocumbi (2011) ||84||9.3||–||“Preserved systolic and diastolic function”||‘Left ventricular dimensions indexed for body surface were abnormal in two children with severe anemia’(4.4%)||–||–||cTNT undetectable|
|Murphy (2011) ||36||7||–||“Good” LV function||–||No pericardial effusions seen||2 patients demonstrated a low-velocity, tricuspid, regurgitant jet (1.5 m/sec and 2.4 m/sec. 3 trace TR. Nil had RV enlargement||–|
|Sanklecha (2011) ||Case report of 3 patients with Myocarditis 24,120, 144 of age||7.2||–||–||Patient two only: Myocardial dysfunction with serial ejection fractions of 45%, 35% and 25%||–||–||–|
|Nguah (2012) ||36 (median)||7.4||LV-EDDI (mm/m2) 53.15||66%||5.8||–||–||–|
|Kotlyar (2018) ||19.2 (median)||5.12||58%||6.4 (T0 all), SM 5.28 T0, SMA 6.89 T0||–||–||Trop I 0.08 (ng/mL)
BNP 69.1 (pg/mL)
Multiple studies in pediatric patients demonstrated indices indicative of decreased preload in infected patients:
Markers of cardiac function were variable in different studies, using heterogenous timepoints, markers and indices of function:
While no study directly measured SVR or other parameters of afterload, mean arterial pressure may have been lower in more ill children or those earlier in the time course:
Pediatric patient pulmonary arterial pressures were higher than control patients:
No studies mentioned the presence of pericardial effusions or other structural abnormalities.
Troponin subtypes varied from normal to elevated in some studies, while BNP and NT-proBNP levels were higher in the two pediatric studies that followed it:
Sixteen studies included in the review evaluated a majority of adult patients. Studies took place worldwide. Table 3 reports studies describing echocardiography findings in patients with myocarditis, pericarditis, myocardial ischemia and cardiac dysfunction thought to be primarily related to SM. Table 4 represents selected clinical and measured cardiovascular findings in adult studies reporting invasive measurements of cardiac output.
|Trial||Proposed SM induced cardiac diagnosis||Age (years)||Hemoglobin g/dL||Dimensions||EF %||Structural||Pulmonary artery pressures mmHg||Cardiac Biomarkers|
|Mohsen (2001) ||Myocarditis||30||11.2||–||D0 admission echo normal. Cardiac Output was supra-normal at 11l/min. Echo on d10 demonstrated severe global left ventricular dysfunction with no regional wall abnormalities (EF 38%)||Normal RAP and PWP (12–18mmHg)||Normal creatinine phosphokinase|
|Nayak (2013) ||–||13–75years||–||(LVEDD) of 4.04 (LVESD) of 2.55||56% with cardiac involvement (59% without cardiac involvement)||9 patients had mitral regurgitation, mild tricuspid regurgitation, mild aortic regurgitation and mild pulmonary regurgitation; these findings were present at the time of admission, on the day of discharge as well as on Day 21 of follow up. None of these patients had any valvular thickening. No patient had any evidence of pericardial effusion and regional or global hypokinesia||Both Troponin-I and CPK-MB were increased in 14% cases and were found normal in 3 out of 17 patients who presented with cardiovascular involvement|
|Sulaiman (2014) ||Myocardial Ischemia||51||10.7||–||Hyperdynamic contractility with preserved LV systolic function||Normal (and normal coronary angiography)|
|Colomba (2017) ||Pericarditis||19 and 52||8.2/8.6||–||Pt 1. Revealed an anterior non-compressive pericardial effusion (6 mm behind the right atrium, 9 mm in lateral) and a congenital intra-atrial and intra-ventricular communication with left-to-right shunt
Pt 2. Left ventricular concentric hypertrophy with preserved global systolic function, absence of any segmental wall-motion abnormalities of the left ventricle; right sections were of normal size with preserved right ventricular function. It also showed pericardial effusion
|Ray (2017) ||–||–||–||<55% in 3, left ventricular diastolic dysfunction in 1||mild pericardial effusion (1)||mild TR with mild PAH (1)||–|
|Leopard (2018) ||–||33||LVFS % 41
IVC collapsibility % 18
Uncomplicated 31% LVFS
26% IVCC (all medians)
|Trial||Invasive Monitoring||Preload: CVP||Cardiac Index (L/min/m2)||SVR (dyne/s/cm–5m2)||PAOP mmHg||Cardiac Biomarkers|
|Charoenpan (1990) ||PAC||–||4.66||832 reported as low as (normal values 900–1100 in paper) low PVR||–||–|
|Beards (1994) ||PAC||12 (prior to exchange)||4.42||586||–||–|
|Bruneel (1997) ||PAC–7 patients only||–||–||Peripheral vasodilatation with elevated cardiac output||–||–|
|Lagudis (2000) ||PAC – hyperdynamic pattern and normal LV stroke work index||Normal echo||1st patient 6
2nd patient 4.3
|SVRI 1st patient 1049
2nd patient 1078
|1st patient 17
2nd patient 15
|Saissy (2000) ||PAC||3.9 control group
6.1 hyperkinetic group
|1098 control group
536 hyperkinetic group
|6 control group
9 hyperkinetic group
|Hanson (2011) ||CVP and PiCCO||5.2 (median)||3.08 (median)||SVRI 2155 (median)||–||–|
|Herr (2011) ||Non-invasive method based on the re-breathing technique||-||2.9 9SM cases (healthy controls 3.4) (median)||SVRI 29.2 l/min (median)||–||Pro-BNP 139.3 pg/ml
Myoglobin 43.6 μg/l
Trop T and CK-MB similar to controls
H-FABP 1.9ng/ml (1.7 in uncomplicated)
|Nguyen (2011) ||PAC||2 fluid load, 4.5 no fluid load||4 (with and without fluid load)||1633/without fluid 1589||6 fluid load/10 no fluid loading||–|
|Hanson (2013) ||PiCCO||4.5 (median)||3.08 (median)||2155 (median)||–||–|
|Kingston (2019) ||ECHO and Expired gas collection||–||4.1 (median)||–||–||–|
Adult studies of preload found varying markers:
A majority of adult studies found some degree of cardiac dysfunction or low end of normal, although some studies found higher cardiac function:
Studies had conflicting results with regards to measures of afterload in adult patients:
Pericardial effusion was a rare finding in adult studies: No patient had any evidence of pericardial effusion or regional hypokinesia .
Cardiac biomarkers also varied between studies:
Improved understanding of the cardiovascular effects of SM is an imperative step in the identification of appropriate adjunctive therapies that may reduce the morbidity and mortality of this global health menace. The results of this systematic review highlight the heterogeneity of reported effects of severe malaria on the cardiovascular system. Numerous reasons may account for the variability in the reported results including the relatively small number of patients evaluated as well as differences in approaches and parameters measured.
Suggestion of a reduced preload state was present in two pediatric studies and one adult study. This would fit the common clinical presentation and suspicion of hypovolemia, especially in children who are commonly unwell for a few days prior to admission with vomiting, fever and a reduced intake. Through the use of tracer dilution methods and bioelectrical impedance, Planche et al. demonstrated that mild dehydration was often present in children with SM (mean (SD) depletion of TBW of 37(±33) ml/kg) . Maitland et al. recruited patients with evidence of compensated shock (tachycardia, prolonged capillary refill and low central venous pressure (CVP) < 5cmH2O) and reported an improvement in haemodynamics and acidosis with administration of fluid bolus, concurrently with an increase in CVP . However, other studies do not demonstrate significant preload loss and with the minimal literature available, it is difficult to make definitive conclusions, except that it may be present in some SM cases.
Cardiac systolic function in both pediatric and adult studies was demonstrated to be ‘normal’ or ‘supra-normal’ in a number of studies. However, the finding that there are ‘normal’ cardiac functional parameters does not mean that there is an adequate cardiac output in the face of severe anemia and cytokine induced capillary leak. In two pediatric studies there appeared to be an increase in cardiac index, as expected in those with severe anemia, predominately produced by a rise in stroke volume. A significant proportion of the remaining studies performed echocardiography after the initial resuscitation period. It is therefore difficult to determine what overall effect fluid loading had on cardiac function and if it was normal or reduced prior to the intervention in these studies.
Presumably due to sequestration in the myocardial vessels with secondary ischemic changes, myocarditis with diminished cardiac function is not uncommonly reported in adults with SM [19, 39, 40]. Similar findings have not clearly been reported in pediatric patients except one included case report . Cardiac biomarkers are largely normal or at the most, modestly elevated, with return to normal following resolution of the acute infection in the presented studies. Myocardial oxygen demand is high during acute SM due to tachycardia, and thus elevations in these values may occur secondary to myocardial stress rather than any significant myocardial injury.
The effect of SM on afterload is unclear as the results evaluating this in the available literature are mixed. In a limited number of pediatric patients, blood pressure tended to increase from admission to follow up in SM patients, perhaps indicating initial reduced afterload. Other adult trials also suggest low to normal SVR. This is in comparison to evidence for increased systemic vascular resistance in two different adult studies. The interaction of the plasmodium infected erythrocytes with the endothelium has been extensively studied. Intuitively, pro-inflammatory cytokine release known to occur in SM should result in reduced systemic vascular resistance [13, 14, 28, 41]. Alternatively, extensive microvascular and widespread obstruction from parasitized and sequestered red blood cells may result in increased SVR . At an individual level, variations in the overall severity and impact of each of these pathophysiological processes may occur in patients with SM. If this is the case, this may explain the differing results of available studies. It is important to note that anti-malarials such as intravenous quinine, are commonly considered cardiodepressants, and their use may be at least partially responsible for some of the cardiovascular effects reported in the literature before artesunate became standard of care.
Approximately 10–15% of children and 10% of adults with severe malaria present with shock [41, 42, 43, 44, 45], and those that do have a very high mortality . These patients have traditionally been managed with fluid resuscitation and vasoactive medications to support failing haemodynamics. Additionally, adults have a propensity towards ill-defined and frequently fatal pulmonary edema during the management of SM [29, 30, 47, 48]. Such pulmonary edema associated with a mortality rate of 80% in resource limited settings . One would expect these apparently preload deficient and hypoperfused patients, with mostly normal cardiac function and variable afterload, to respond well to fluid therapy. Indeed, the cardiac function of these shocked patients may not be considered normal in the face of SM and they could actually have myocarditis. It is clear, however, that fluid loading increases mortality in children despite improving perfusion at one hour [10, 11] and recent re-analysis of the data discovered that the detrimental effect on mortality risk persisted for up to 4 days post randomization . Fluid loading also increases the risk of pulmonary edema in adults and is associated with worse outcomes . The overall results of the available studies presented here, that directly measure myocardial function, do not support clear mechanisms by which a poor response to fluid resuscitation would occur.
Future research needs to be done in larger numbers of patients meeting strict and uniform inclusion criteria with the same instruments of measurements and parameters recorded. In order to conclusively understand the effect of SM on the cardiovascular system, cardiac function needs to be closely and quantitatively tracked over the disease duration.
Available studies of children and adults with SM report variable changes in preload, myocardial contractility, and systemic vascular resistance. It remains unclear if there is legitimate heterogeneity in these measurements across a cohort of patients with SM or if findings are limited by patient numbers and disparate approaches to and timing of measurements. Larger, more detailed studies are required to explore and understand the cardiovascular abnormalities in this multi-systemic high burden disease, including if there is a subset of SMA patients with under-recognized cardiac dysfunction despite normal indices.
This research received no specific grant from any funding agency in the public, commercial or not for profit sectors.
NO was responsible for study conception. GW undertook the systematic review, extracted data and completed the first draft of the manuscript. GW, ND, YC and NO were involved in drafting and editing the final manuscript.
The authors have no competing interests to declare.
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