Case of the Month - July 2010

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Answers

Question 1. Plasmodium falciparum infection

The characteristic features of P. falciparum displayed on this blood film are:

1. Parasitized red blood cells that are not increased in size. In contrast, RBCs parasitized with P.vivax or P.ovale characteristically increase in size.
2. Young ring trophozoites with fine cytoplasm
3.  Accolé (appliqué) forms that abut the RBC surface
4.  Ring forms with 2 chromatin dots
5.  Multiple ring trophozoites in a single cell

Question 2. World Health Organisation (WHO) Staging.

The definition of severe falciparum malaria is taken from the WHO guidelines for treatment of malaria second edition1.

In a patient with P. falciparum asexual parasitaemia and no other obvious cause of symptoms, the presence of one or more of the following clinical or laboratory features classifies the patient as suffering from severe malaria:

Clinical features:

• impaired consciousness or unrousable coma
• prostration, i.e. generalized weakness so that the patient is unable to walk or sit up without assistance
• failure to feed
• multiple convulsions – more than two episodes in 24 h
• deep breathing, respiratory distress (acidotic breathing)
• circulatory collapse or shock, systolic blood pressure < 70 mm Hg in adults and < 50 mm Hg in children
• clinical jaundice plus evidence of other vital organ dysfunction
• haemoglobinuria
• abnormal spontaneous bleeding
• pulmonary oedema (radiological)

Laboratory findings:

• hypoglycaemia (blood glucose < 2.2 mmol/l or < 40 mg/dl)
• metabolic acidosis (plasma bicarbonate < 15 mmol/l)
• severe normocytic anaemia (Hb < 5 g/dl, packed cell volume < 15%)
• haemoglobinuria
• hyperparasitaemia (> 2%/100 000/μl in low intensity transmission areas or > 5%
  or 250 000/μl in areas of high stable malaria transmission intensity)
• hyperlactataemia (lactate > 5 mmol/l)
• renal impairment (serum creatinine > 265 μmol/l).

Question 3. Management

Proper assessment of severity indicators is crucial to determining the correct treatment of the patient, as uncomplicated falciparum malaria may be treated with oral therapy as an outpatient, whereas severe falciparum malaria requires intravenous combination therapy, usually with hospital admission.

This patient has severe falciparum malaria due to the following indicators:

a) Impaired consciousness
b) Clinical jaundice and evidence of vital organ involvement
c) Hyperparasitaemia

Severe malaria is a medical emergency. Management includes1,2:

• As the patient has a decreased level of consciousness, re-assess the patient’s airway and secure it as necessary.
• Ensure patient is not hypoglycaemic and correct if necessary with glucose-containing infusion. Monitor regularly
• An arterial blood gas and lactate level should be determined. If acidotic, this may be due to hypovolaemia which should be corrected, or sepsis
• This patient has developed a raised white blood cell count which is highly suggestive of superadded bacterial infection. At initial presentation, the patient had leucopaenia in keeping with malaria infection. In severe falciparum malaria, increased translocation of bacteria across the gut wall predisposes patients to secondary gram negative bacteraemia. Co-existing bacterial meningitis is well recognised and should be considered in this patient. The patient’s platelet count of 18 x 109/L (which may be as a result of the severe malaria and/or secondary infection) would contraindicate a lumber puncture, but blood cultures should be sent and high dose ceftriaxone 2g ivi bid should be started empirically in this patient.
• Patients who have been unwell for a prolonged period with fever and volume loss from the gut through vomiting and/or diarrhoea may be dehydrated on admission. Hypovolaemia should be corrected; however care must be taken as increased capillary permeability in severe falciparum malaria predisposes patients to pulmonary oedema. If possible, a central venous pressure line should be sited and the CVP maintained at 0-5cm. Fluid replacement will need to take into account the volume required to deliver antimalarial drugs.
• Should the patient’s renal function deteriorate or metabolic acidosis worsen, early haemofiltration is warranted and has been shown to reduce mortality.

Falciparum malaria is treated with antimalarial combination therapy (ACT). It is vital that the patient is weighed on entry to hospital or as close an approximation as possible is made of the patient’s weight, as drug dose is weight-dependent.

For severe falciparum malaria, the SEAQUAMAT trial showed that ivi artesunate was associated with an absolute reduction in mortality of 34.7% over and above that achieved by ivi quinine3. Accordingly, where possible, ivi artesunate is the drug of first choice in severe falciparum malaria. However, artesunate is only currently available in South Africa under a section 21 access programme and therefore many healthcare facilities in the country do not yet have access. In this setting, the treatment of choice is ivi quinine. The following regimens should be employed:

• Artesunate 2.4mg/kg ivi (or im if unable to gain intravenous access) given at time 0 and then at 12 and 24 hours, followed by daily. Unlike quinine, artesunate does not need to be given as an intravenous infusion but can be administered as a slow iv push. A minimum of 24 hours iv therapy should be given. Thereafter, once able to take oral therapy, completion of therapy may be with Co-artem®, artesunate plus doxycycline or clindamycin, or quinine plus doxycycline or clindamycin.
• If artesunate is not available, the patient should be treated with quinine ivi. A loading dose of quinine salt 20mg/kg/ivi should be given at an infusion rate not exceeding 5mg/kg/hour. Thereafter, a dose of 10mg/kg 8hourly should be administered. Close monitoring of blood glucose is advised for patients on ivi quinine. Completion of therapy can be with either oral quinine plus doxycycline or clindamycin, or Co-artem®

Adjunctive therapy such as steroids, mannitol etc should not be employed and may be detrimental.

Question 4. Pathogenesis of severe malaria

The pathogenesis of severe falciparum malaria is multifactoral and remains incompletely understood. The central mechanism is sequestration or cytoadherence of parasitized RBCs in the capillary circulation of vital organs such as the brain, kidney, liver etc. Sequestration occurs due to a number of mechanisms4:

1. Parasitized RBCs express proteins of the plasmodium falciparum erythrocyte membrane protein-1 (PfEMP-1) family on the surface of infected RBCs in clusters termed ‘knobs’. Different forms of PfEMP-1 are encoded by over 60 different ‘var’ genes found in the P. falciparum genome5. PfEMP-1 proteins are able to bind to a variety of endothelial cell receptors such as ICAM-1, VCAM-1, E-selectin, and chondroitin sulfate-A (CSA), sequestering parasitized cells within the capillaries. Severe malaria has been correlated with expression of certain PfEMP-1 subsets that are encoded by a very small number of the total var gene repertoire6. Furthermore, interaction of PfEMP-1 with specific receptors is associated with particular manifestations of severe malaria. For example, PfEMP-1 binding to ICAM-1 in brain post-capillary venules enhanced by CD36 binding is associated with cerebral malaria. Binding to CD36 is also notable in kidney and liver7, and sequestration in the intervillous blood spaces of the placenta is mediated via binding to CSA, involved in severe malaria seen in primagravid women.
2. Rosetting, a process by which unparasitized RBCs bind to parasitized cells increases the ‘sludging’ or blockage effect that sequestration of parasitized cells causes8.
3. Unparasitized RBCs from patients with Falciparum malaria show increased membrane stiffness, cytoplasmic viscosity and cytoskeletal change that render them less deformable than normal, reducing their ability to pass through blockages.
   
4. Release of glycophosphatidyl inositols (GPI) increases TNF-a and nitric oxide expression, which upregulates expression of endothelial cell receptors for cytoadherence, inhbits gluconeogenesis thereby contributing to hypoglycaemia, and may be involved in impaired consciousness through the expression inducible nitric oxide synthetase.

References

1. World Health Organisation. Guidelines for the treatment of malaria. 2nd edition. 2010. Accessed at http://www.who.int/malaria/publications/atoz/9789241547925/en/ 29th June 2010

2. Guidelines for the Treatment of Malaria in South Africa 2010. Accessed at www.doh.gov.za  on 30th June 2010.

3. South East Asian Quinine Artesunate Malaria Trial (SEAQUAMAT) group. Artesunate versus quinine for the treatment of severe falciparum malaria: a randomised trial. Lancet 2005; 366: 717-25

4. World Health Organisation 2000. Severe falciparum malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene, 94, supplement 1.

5. Pasternak ND, Dzikowski R. PfEMP-1: An antigen that plays a key role in the Pathogenicity and immune evasion of the malaria parasite Plasmodium falciparum. Int J Biochem & Cell Biol. 2009; 41: 1463-66.

6. Montgomery J, Mphande FA, Berriman M, Pain A, Rogerson SJ, Taylor TE, Molyneux ME, Craig A. Differential var gene expression in the organs of patients dying of falciparum malaria. Mol. Microbiol. 2007; 65(4): 959-67

7. Baruch DI, Rogerson SJ, Cooke BM. Asexual blood stages of malarial antigens: cytoadherence. Chem Immunol 2002; 80: 144-62.

8. Kaul DK, Roth Jr EF, Nagel RL, Howard RJ, Handunnetti SM. Rossetting of Plasmodium falciparum-infected red blood cells with uninfected red blood cells enhances microvascular obstruction under flow conditions. Blood 1991; 3: 812-9.

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