Malaria

1. Republic of South Sudan
Ministry of Health
National Malaria Control Program
Case Management Training Trainers
29th
April -3rd
May 2024

2. Severe Malaria

3. Objectives
• Define severe malaria
• Discuss the host-parasite interaction that contributes to
the pathogenesis of severe malaria
• List the determinants of severe malaria and identify
groups at high risk
• Make a diagnosis of severe falciparum malaria
• Specify the emergency and supportive measures and
follow-up guidance for malaria patients with different
types of complications
• Describe the recommended antimalarial
chemotherapeutic regimen for severe malaria

4. Clinical features of uncomplicated disease
• history of fever
• febrile paroxysms
• chills
• rigors
• headaches and other body aches
• vomiting,
• joint pains,
• weakness,
• cough,
• nausea

5. Definitions Severe falciparum malaria
For epidemiological purposes
Severe falciparum malaria is defined as one or more of the following:
Impaired consciousness, Prostration Multiple convulsions, occurring
in the absence of an identified alternative cause and in the presence
of P. falciparum asexual parasitaemia
• Impaired consciousness: A Glasgow coma score < 11 in adults or a Blantyre
coma score < 3 in children
• Prostration: Generalized weakness so that the person is unable to sit, stand
or walk without assistance
• Multiple convulsions: More than two episodes within 24 h

6. Recognising Malaria
• One or more of the following
clinic features in the presence of
malaria parasitemia or positive
rapid diagnostic test
• Axillary temperature=>37,50
C
• And/or history of recent fever
and/or presence of anaemia
Clinical Features
• Impaired consciousness/coma
• Prostration/generalized weakness
• Multiple convulsions/more than 2
within 24 hrs
• Deep breathing/respiratory
distress
• Acute pulmonary oedema
• Circulatory collapse/shock systolic
BP<80mmHg
• Acute kidney injury
• Clinical jaundice and evidence of
other vital organ dysfunction
• Significant bleeding
Laboratory findings
• Hypoglycaemia
• Metabolic acidosis
• Severe normocytic
anaemia
• Haemoglobinuria
• Hyperparasitaemia
• Renal impairment
• Pulmonary oedema
• Plasma or serum
bilirubin>50micromoles
perLt(3mgs/deciliter with
a parasite count >100
000per microliter
Severe malaria one or more of the following clinical fitures or laboratory findings in
the presence of malaria parasitaemia or positive RDT test
Uncomplicated malaria

7. Risk factors for severe malaria and death in high
transmission
 Severe malaria is predominantly a disease of young
children (1 month to 5 years of age).
 pregnancy),
 delay in treatment
 severity of the illness at admission (coma, acute renal
failure, shock, pulmonary oedema, coagulation disorders).
 age greater than 65 years,
 nonimmune status, no antimalarial prophylaxis,
 coexisting medical conditions, eg HIV disease

8. Pathogenesis of Severe malaria
Involves cascading interaction between parasite and red cell membrane
products, cytokines and endothelial receptors,
Leading to inflammation, activation of platelets, hemostasis, a procoagulant
state, microcirculatory dysfunction and tissue hypoxia, resulting in various
organ dysfunctions
Pathophysiological factors observed
Parasite biomass;
‘malaria toxin(s)’ and inflammatory response;
Cytoadherence, rosetting and sequestration;
altered deformability and fragility of parasitized erythrocytes;
endothelial activation, dysfunction and injury; and altered thrombostasis

9. Pathophysiology of severe malaria

10. Broad Pathways of malaria pathogenesis

11. Microvascular obstruction of vital organs
• Plasmodium falciparum Erythrocytic membrane Protein1 (pfEMP1)
• Mediates attachment to vascular endothelium
• The red cells progressively adhere to the walls of venules and
capillaries (cytoadherence) in vital organs, producing sequestration
• Possible receptors
• Brain - intracellular adhesion molecule 1(ICAM1)
• Placenta – chondroitin sulphate A
• Other organs – CD36

12. Sequestration of parasitized red cells
Margination in larger calibre venules due to
cytoadherence in cerebral cortex HE stain at X400

13. Pathophysiology of malaria
• Cytokines
• Rupture of schizonts releases parasites into the blood streams
• Activates immune reaction with monocyte-macrophages
• Release of cytokines --------------fever

14. Severe anaemia
• most commonly in young children in areas of moderate and high
transmission
• Anaemia results from
• accelerated unparasitised red cell removal by the spleen
• both infected and uninfected erythrocytes become less deformable
• increased splenic clearance
• Ineffective erythropoiesis
• obligatory erythrocyte destruction at parasite schizogony
• Severe anaemia is often the end result of repeated infections which do
not allow sufficient time for the bone marrow to recover. In severe
malaria,

15. Acidosis
• Important cause of death from severe malaria
• Results from accumulation of organic acids
• lactic acid
• ketoacidosis in children
• acute renal failure in adults.
• Lactic acidosis is due to
• anaerobic glycolysis in tissues where sequestered parasites interfere with
microcirculatory flow
• lactate production by the malaria parasites,
• failure of hepatic and renal lactate clearance.

16. Hypoglycaemia
• Often associated with lactic acidosis and a poor prognosis.
• It is a particular problem in children and pregnant women.
• Hypoglycaemia is a result of:
• failure of hepatic gluconeogenesis
• increase in tissue consumption of glucose by
• febrile host (as a result of anaerobic glycolysis)
• malaria parasites
• Hyperinsulinaemic hypoglycaemia
• caused by quinine treatment
• common in pregnant women.
• Quinine is a powerful stimulant of pancreatic insulin secretion.
• Hyperinsulinaemic hypoglycaemia occurs after treatment and may be recurrent despite glucose
administration

17. Pulmonary oedema
• Acute respiratory distress syndrome (ARDS) is a feared complication in adults with severe
falciparum malaria,
• May also develop in acute vivax malaria.
• Pathogenesis is not fully understood
• Common features
• inflammatory mediated increased capillary permeability
• endothelial damage
• The role of parasite sequestration in the pulmonary microvasculature is unclear.
• Careful fluid management is essential.
• Without mechanical ventilation, the mortality of ARDS exceeds 80% in falciparum malaria,
• With mechanical ventilation, mortality exceeds 50% in most series
• Mortality in vivax malaria ARDS, is much lower

18. Acute Kidney Injury
• frequent feature of severe malaria.
• Oliguric renal failure is common in adults with severe falciparum malaria, but rare in children.
• It behaves clinically and pathologically as acute tubular necrosis.
• Hypertension and significant proteinuria never occur.
• The pathogenesis is still unclear,
• reduced microcirculatory flow
• inflammation
• Acute renal failure may occur with multiple vital organ dysfunction (carrying a high mortality) or may develop as
other disease manifestations resolve.
• In survivors, urine flow resumes in a median of 4 days, and serum creatinine levels return to normal in a mean of 17
days
• Early hemofiltration or dialysis considerably improve the prognosis, particularly in acute hypercatabolic renal failure
• Although a variety of glomerular abnormalities have been reported associated with malaria, the clinical features,
urine sediment (not ‘active’), and natural history of acute kidney injury do not suggest significant
glomerulonephritis.

19. Severe jaundice
• Associated with P. falciparum infections;
• More common among adults than among children,
• Causes of jaundice in malaria infections
• Haemolysis
• hepatocyte injury
• cholestasis.
• Jaundice is often accompanied by renal impairment.
• Liver blood flow is reduced in severe malaria
• hepatic gluconeogenesis is impaired
• Hepatic dysfunction contributes to
• Hypoglycaemia
• metabolic acidosis
• impaired drug metabolism.

20. Thrombocytopenia
• Common feature of malaria, particularly P Vivax
• Not a marker of severity
• Exact mechanism of leading to thrombocytopenia in malaria not clear
• Possible causes
• Immune mechanisms
• Formation of immune complexes
• Destruction by the spleen
• Non immune mechanisms
• DIC, though quite rare
• mechanical

21. Indicators of severe falciparum malaria and poor prognosis
Manifestation Features
1. Impaired
consciousness
[ Cerebral malaria]
Unarousable coma not attributable to any other cause, with a Glasgow
Coma Scale score <11 in adults (non localising, incomprehensible) or a
Blantyre Coma Scale of <3 in children
2. Metabolic Acidosis A base deficit of >8 meq/l or, if unavailable, a plasma bicarbonate of <15
mM or venous plasma lactate >5mM. Severe acidosis manifests clinically as
respiratory distress–rapid, deep and laboured breathing
3. Hypoglycemia Whole blood glucose concentration of less than 2.2 mmol/l (less than 40
mg/dl).
4. Severe anemia A haemoglobin concentration <5 g/dl or a haematocrit of <15% in children
<12 years of age (<7 g/dl and <20%, respectively, in adults) together with a
parasite count >10 000/µl
5. Renal
impairment (acute
kidney injury)
Serum creatinine >265 µmol/l (> 3.0 mg/dl) or blood urea >20mM

22. Indicators of severe falciparum malaria and poor prognosis
Manifestation Features
6. Jaundice Plasma or serum bilirubin >50 µM (3 mg/dl) together with a parasite count
>100 000/µl
7. Pulmonary edema Radiologically confirmed, or oxygen saturation <92% on room air with a
respiratory rate >30/min, often with chest indrawing and crepitations on
auscultation
8. Significant bleeding Including recurrent or prolonged bleeding from nose gums or venepuncture
sites; haematemesis or melaena
9. Shock Compensated shock is defined as capillary refill ≥3 s or temperature gradient
on leg (mid to proximal limb), but no hypotension. Decompensated shock is
defined as systolic blood pressure <70 mm Hg in children or <80 mm Hg in
adults with evidence of impaired perfusion (cool peripheries or prolonged
capillary refill)
10. Hyperparasitemia P. falciparum parasitaemia >10%

23. Immediate clinical management of severe manifestations
and complications of falciparum malaria
Manifestation/complication Immediate management (in addition to antimalarial
treatment)
Coma (cerebral malaria) Maintain airway, place patient on his or her side, exclude other treatable
causes of coma (e.g. hypoglycaemia, bacterial meningitis); avoid harmful
ancillary treatment such as corticosteroids, heparin and adrenaline;
intubate if necessary
Hyperpyrexia Administer tepid sponging, fanning, cooling blanket and antipyretic drugs
Convulsions Maintain airways; treat promptly with intravenous or rectal diazepam or
intramuscular paraldehyde
Hypoglycaemia (blood glucose
concentration of<2.2 mmol/l; <40
mg/100ml)
Check blood glucose, correct hypoglycaemia and maintain with glucose-
containing infusion
Severe anaemia (haemoglobin <5
g/100ml or packed cell volume
<15%)
Transfuse with screened fresh whole blood

24. Immediate clinical management of severe manifestations and
complications of falciparum malaria
Manifestation/
complication
Immediate management (in addition to antimalarial treatment)
Acute pulmonary oedema Over-enthusiastic rehydration should be avoided so as to prevent pulmonary oedema. Prop
patient up at an angle of 45o
, give oxygen, give a diuretic, stop intravenous fluids, intubate
and add positive end-expiratory pressure/continuous positive airway pressure in life-
threatening hypoxaemia
Acute renal failure Exclude pre-renal causes, check fluid balance and urinary sodium; if in established renal
failure add haemofiltration or haemodialysis, or if unavailable, peritoneal dialysis. The
benefits of diuretics/dopamine in acute renal failure are not proven
Spontaneous bleeding and
coagulopathy
Transfuse with screened fresh whole blood (cryoprecipitate, fresh frozen plasma and platelets
if available); give vitamin K injection
Metabolic acidosis Exclude or treat hypoglycaemia, hypovolaemia and septicaemia. If severe add haemofiltration
or haemodialysis
Shock Suspect septicaemia, take blood for cultures; give parenteral antimicrobials, correct
haemodynamic disturbances
Hyperparasitaemia Treat with artemisinins, intravenously or orally (See below)

25. Management of severe malaria
•Death from severe malaria often occurs within hours of admission to a
hospital
•Main objective of the treatment of severe malaria is to prevent the
patient from dying.
•Secondary objectives are prevention of disabilities and prevention of
recrudescent infection.
•It is essential that therapeutic concentrations of a highly effective
antimalarial drug be achieved as soon as possible.
Management of severe malaria comprises mainly
i. Clinical assessment of the patient,
ii. Specific antimalarial treatment,
iii. Additional treatment
iv. Supportive care.

26. Management of severe malaria
• Manage complications
• Treat malaria

27. Treatment of severe falciparum malaria
In principle, severe falciparum malaria is treated in the same way in
elimination as in control programmes, except that the single dose of
primaquine should be added once the patient can take oral treatment.
Parenteral artesunate (IV/IM) is preferred choice OR
Parenteral quinine
PLUS single dose primaquine

28. Differential diagnosis
•Differential diagnosis is broad.
•Coma and fever may be due to meningoencephalitis or malaria.
•Cerebral malaria is not associated with signs of meningeal irritation (neck
stiffness, photophobia or Kernig’s sign), but the patient may be opisthotonic.
•Bacterial meningitis is almost invariably fatal, a diagnostic lumbar puncture
should be performed to exclude this condition.
•There is also considerable clinical overlap between septicaemia, pneumonia and
severe malaria, and these conditions may coexist. When possible, blood should
always be taken on admission for bacterial culture.
•In malaria-endemic areas, particularly where parasitaemia is common in young
age groups, it is difficult to rule out septicaemia immediately in a shocked or
severely ill obtunded child. empirical parenteral broad-spectrum antibiotics
should be started immediately, together with antimalarial treatment.

29. Evaluation of the Patient
• Malaria is a very simple disease to diagnose and treat; yet it claims more lives than
any other infectious disease in the world. It is therefore very essential that every
case of malaria be assessed thoroughly.
Clinical examination:
• General: Functional status, prostration, breathlessness, level of consciousness,
hydration, toxicity, puffiness of face and lids, etc.
• Vital signs: Pulse rate, blood pressure (hypotension), temperature (hyperpyrexia),
respiratory rate (tachypnoea, acidotic breathing).
• Other signs: Pallor, Jaundice, Cyanosis, Edema, etc.
• Abdomen: Liver, spleen, bowel sounds – Tender hepato/ splenomegaly is more
common in acute malaria.
• Respiratory system: Basal crackles, wheezes; sometimes, associated pneumonia
and its bronchial breath sounds.
• C.N.S.: Level of sensorium, convulsions, neck stiffness, ocular fundii, any focal
deficits.

30. Evaluation of the Patient
Full blood count,
Blood cross-matching,
Platelet count,
Full biochemistry
clotting studies,
blood culture
Lumbar Puncture Exclude bacterial meningitis in unconscious pat: .
Plasma bicarbonate or venous lactate concentration.
Arterial or capillary blood pH and gases should be measured in
patients who are unconscious, hyperventilating or in shock.
Fluid balance is critical to avoid over- or under-hydration. Individual
requirements vary widely and depend on fluid losses before
admission.

31. Investigations
• Hemoglobin: Anemia is common in malaria. Rapid reduction in level of
hemoglobin is seen in falciparum malaria and less than 7 g/ dl should be a
warning.
• FBC :Total leukocyte count: It can vary from low to high, and neutrophilic
leukocytosis is common in severe malaria with or without associated
bacterial infection. Leukopenia is seen in severe malaria with septicemia,
and chronic hypersplenism.
• Platelet count: Thrombocytopenia is common in P. falciparum and P.
vivax malaria, but it does not correlate with the severity of the infection.
• Parasite count: This is a simple yet very important and useful method of
assessing the severity of infection in falciparum malaria. It should be done
routinely in all cases of falciparum malaria.

32. Laboratory Features
• Hypoglycaemia (blood glucose < 2.2mmol/litre or < 40mg/dl);
• Metabolic acidosis (plasma bicarbonate < 15mmol/litre);
• Severe normocytic anaemia (Hb < 5g/dl, packed cell volume <
15%);
• Haemoglobinuria;
• Hyperparasitaemia ;
• Hyperlactataemia (lactate > 5mmol/litre);
• Acute kidney injury (serum creatinine 265mmol/litre or
greater).

33. Indications for hospitalization of malarial cases
1.Persistence of fever even after 48 hours of initial treatment.
2.Continuously worsening headache.
3.Persistent vomiting.
4.Any complications of P. falciparum malaria– altered sensorium,
convulsions, anemia, jaundice, hyperpyrexia, bleeding and
clotting disorders, breathlessness, high coloured urine etc.
5.Patients who are at higher risk for development of complications
of P. falciparum malaria-extremes of age, pregnancy etc.
6.Patients who appear sick and prostrated
7.Significant dehydration

34. Prognostic indicators in severe falciparum malaria
Clinical indicators
• age < 3 years
• deep coma
• witnessed or reported convulsions
• absent corneal reflexes
• decerebrate or decorticate rigidity or opisthotonus
• clinical signs of organ dysfunction (e.g. renal injury, pulmonary oedema) •
respiratory distress (acidosis) • shock
• papilloedema

35. Prognostic indicators in severe falciparum malaria
Laboratory indicators
• hyperparasitaemia (> 250 000/µl or > 5%)
• peripheral schizontaemia
• peripheral blood polymorphonuclear leukocytosis (> 12 000/µl)
• mature pigmented parasites (> 20% of parasites)
• peripheral blood polymorphonuclear leukocytes with visible malaria
pigment (> 5%)
• erythrocyte volume fraction (< 15%)
• haemoglobin concentration (< 2.2mmol/l (< 40mg/dl)

36. Prognostic indicators in severe falciparum malaria
• blood urea > 60mg/dl • serum creatinine > 265 µmol/l (>
3.0mg/dl)
• high CSF lactate (> 6mmol/l) and low CSF glucose
• raised venous lactate (> 5mmol/l)
• greater than threefold elevation in serum transaminases
• increased plasma 5’-nucleotidase
• raised muscle enzymes
• low antithrombin III levels
• very high plasma concentrations of tumour necrosis factor

37. Key points
• Severe malaria is a medical emergency requiring teamwork
Nursing,
Medical staff
Laboratory staff to be alert at all times.
• Prompt action is especially important for high-risk groups such as young
children and pregnant women.
• Artesunate IV or IM should be used in preference to quinine IV or IM for
the treatment of severe malaria.
• The management of the patient is as important as chemotherapy and
here the nurse has a crucial role to play.
Regular monitoring of the core temperature, respiration (rate and depth), blood
pressure, level of consciousness of consciousness and other vital signs is essential.

38. Key points
• Key observations will make it possible to identify the late onset of
important complications such as
hypoglycaemia,
metabolic acidosis,
pulmonary oedema and shock.
Urine output should be recorded.
• Laboratory measurements should include regular checks on PCV, Hb,
glucose, urea or creatinine (also electrolytes and arterial blood gases
when possible).
• A proportion of children who survive cerebral malaria have neurological
sequelae which persist into the convalescent period.
• It is important to retest PCV and Hb one month after discharge, especially
if the patient was anaemic.

40. Thank you