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Falciparum malaria: those born in endemic areas can’t assume immunity

By Reena Thakrar and Lucy Hedley

A 75-year-old, 65kg man diagnosed with Plasmodium falciparum malaria wastransferred to the intensive care unit (ICU) from an acute district general hospital. On transfer he had received one IV dose each of piperacillin with tazobactam, amikacin and quinine dihydrochloride.

Further details were as follows.

Presenting complaints

  • P falciparum malaria (see Panel 1)
  • Acute kidney injury (AKI)
  • Thrombocytopenia

Panel 1: Plasmodium falciparum malaria

Science Photo LibraryMalaria is an infection caused by the protozoan parasite, plasmodium, transmitted to humans by the bite of an infected female anopheles mosquito. It is the most common tropical disease in the UK, with 1,500–2,000 reported cases each year and around nine deaths each year due to all types of malaria,1,2 although there is thought to be some under-reporting despite malaria being a notifiable disease.

Cases of malaria arise mainly in those who have travelled to endemic areas. P falciparum accounts for around three-quarters of the reported cases in the UK and requires prompt treatment because untreated it is often fatal.

There are four other species of malaria parasite that can cause clinical disease in humans: P vivax, P ovale, P malariae and P knowlesi. These are known as the benign malarias because their clinical course is less severe, although there have been recent deaths in the UK due to P vivax, and P knowlesi may also progress rapidly.

Life cycle When an infected mosquito bites a human, sporozoites are injected through the skin and migrate to the liver where they reproduce to form schizonts, which eventually rupture to free merozoites into the circulation. These invade red blood cells, growing and reproducing inside them — at this stage they are often called trophozoites or ring forms — form schizonts and release more merozoites, which either generate further merozoites or gametocytes, which can be ingested by another biting mosquito.

Diagnosis
Malaria should be suspected in anyone with a fever or a history of fever and who has visited a malaria-endemic area, regardless of whether or not he or she has taken prophylaxis.

Patients with falciparum malaria generally present within a month of exposure but 10 per cent of cases present up to three months after travel,3 with almost all presenting within six months of exposure.

Patients infected with other species of plasmodium can present many months later and it is recommend, therefore, that malaria is considered as a differential diagnosis up to one year after a patient has returned from the area.

There are no specific symptoms of malaria. Many patients complain of fever, headache and general malaise but bear in mind that not all patients will experience these. Rapid diagnostic tests are now widely used to diagnose falciparum malaria, but should be used in conjunction with the examination of blood films because sensitivity and specificity are not as high.

A thick and thin blood film is the gold standard to confirm diagnosis. The results reported will include the species, parasite density (“parasitaemia”) and parasite stage (ie, trophozoites, preschizonts and gametocytes).

P falciparum is further classified according to severity. Severe or complicated disease is characterised when patients present with at least one of the following features:4,5

  • Impaired consciousness or seizures
  • Haemoglobin <8g/dl
  • Spontaneous bleeding (due to disseminated intravascular coagulation)
  • Haemoglobinuria (without glucose-6-phosphate dehydrogenase deficiency)
  • Renal impairment (creatinine >265mmol/L)
  • Acidosis (pH<7.3)
  • Acute respiratory distress syndrome or pulmonary oedema
  • Shock (due to algid malaria; BP<90/60mmHg)
  • Parasitaemia >2 per cent

History of presenting complaints

  • Felt unwell for a week
  • Cold and shivering
  • Aching joints and muscles
  • No headaches, photophobia or rashes
  • No diarrhoea or vomiting
  • No cough and no pain on urination (dysuria)

Travel history

  • Originally from Nigeria but living in the UK for a number of years
  • Travelled to Nigeria for five weeks; no malaria prophylaxis taken (he had assumed he was immune)
  • Well for two weeks after return

Previous medical and drug history

  • NKDA (no known drug allergies)
  • Hypertension (amlodipine 10mg od, bendroflumethiazide 2.5mg od, candesartan 16mg od)
  • Hypercholesterolaemia (atorvastatin 40mg on)
  • Glaucoma (timolol maleate 0.25 per cent one drop both eyes bd, latanoprost 50µg/ml one drop both eyes on)

Medication on transfer

  • Piperacillin with tazobactam 4.5g IV tds for community acquired pneumonia (CAP)
  • Amikacin 1.2g IV stat (15mg/kg) for severe CAP)
  • Quinine dihydrochloride 1.2g IV loading dose (20mg/kg) diluted in sodium chloride 0.9 per cent and given as a slow infusion over four hours — first-line therapy for P falciparum malaria (Panel 2, outlines treatment options)

Panel 2: first-line treatments

First-line treatment regimens for P falciparum malaria include the following:4,5

Severe or complicated disease In severe or complicated disease (ie, if the patient fulfils the criteria in Panel 1) IV quinine dihydrochloride (loading dose of 20mg/kg [up to 1,400mg] in 0.9 per cent sodium chloride over four hours, followed by 10mg/kg tds 7/7 diluted in 250ml in 0.9 per cent sodium chloride over four hours) is recommended.

The mechanism of action involves inhibition of parasite haem detoxification in the food vacuole, but is not well understood. Quinine acts principally on the mature trophozoite stage of parasite development and does not prevent sequestration or further development of circulating ring stages of P falciparum. It does not kill the mature gametocytes.

IV artesunate is an alternative to quinine and the recommended regimen is 2.4mg/kg given at 0 hours, 12 hours, 24 hours (dose based on actual body weight, no maximum dose documented) then once daily until parasite count falls below 20 per cent.
Both treatments are followed by oral artemether 20mg/lumefantrine 120mg (Riamet) four tablets bd 3/7. (Other oral regimens exist— see BNF section 5.4.1 “Treatment of malaria”.)

IV quinine is an unlicensed preparation. The patient will require additional monitoring, including an electrocardiogram before treatment is started and blood glucose levels every two hours during infusion and four-hourly after that. IV artesunate is more effective than quinine at treating severe malaria and reduces high parasite loads quicker.4 It should be used in preference to quinine for P falciparum malaria in adults but because quinine is more readily available it is often used first.5

Artesunate’s mechanism of action involves inhibiting an essential calcium adenosine triphosphatase, PfATPase.6 It is a potent and rapidly acting blood schizontocide and is active against all plasmodium species. It has a broad activity against asexual parasites, killing all stages from young rings to schizonts. In P falciparum malaria, it also kills the gametocytes, including the stage 4 gametocytes, which are otherwise sensitive only to primaquine. Note that parasite count may increase in the first 36 hours of treatment and this does not indicate treatment failure.4

Common side effects associated with IV administration of artesunate have included dizziness, light-headedness, nausea and taste alteration (metallic or bitter taste).2
A few clinical drug-drug interaction studies have been performed with artesunate. However from these no clinically significant interactions have been identified. In vitro drug-interaction studies have demonstrated minimal effects of artesunate on cytochrome P450 isoenzymes.2

Mild/uncomplicated disease For mild or uncomplicated disease oral artemether 20mg/lumefantrine 120mg (Riamet) four tablets bd 3/7. (Other regimens exist; see BNF section5.4.1 “Treatment of malaria”.6)

There are a number of special cases where the treatments described above may not be appropriate, for example, during pregnancy, and in children and adolescents.6 (Refer to BNF chapter 5 and UK malaria guidelines.)

 

Previous investigations

  • Thick and thin blood film via microscopy positive for preschizonts, trophozoites and gametocytes of P falciparum
  • Percentage of parasitised red blood cells (parasite count) — 26.5 per cent
  • Chest X-ray (to exclude CAP) normal
  • Bloods

Haemoglobin Normal 150g/L (130–180)
    Platelets 18x109/L (150–400)
Prothrombin time
(PT) 11.4s (10.0–12.0)
    Activated partial thromboplastin time (APTT) ratio 1.5 (0.7–1.3)
    Liver function tests (LFTs) All normal except bilirubin 39umol/L (2–22); albumin 22g/L (35–50)
Raised inflammatory markers (CRP 307mg/L [0–5]; white cell count 12.2x109/L [4–11])
Impaired renal function Urea 43mmol/L (2–7.8); creatinine 395?mol/L (66–112)
    Electrolytes Sodium 154mmol/L (135–145); but potassium normal 3.9mmol/L (3.5–5.1)
    Blood culture Positive for Gram-negative bacteria

  • Echocardiogram (ECG) showed atrial fibrillation with slow ventricular response
  • Observations included hypotensive (blood pressure 90/76mmHg [120/80–140/90]), tachypnoeic (respiratory rate 36bpm [12–14], fully responsive at Glasgow coma scale (GCS 15/15), normothermic (temperature 36.4C [36.1–37.2])
  • Arterial blood gas (ABG) on room air results indicated lactic acidosis (pH 7.24 [7.35–7.45] and lactate 5.9mmol/L [0.5–1]) and hypoxia (PaO2 4.9kPa [11–13]); PaCO2 6.1kPa [4.7–6]).

Treatment and monitoring

On transfer the patient was diagnosed with severe complex malaria and admitted directly to ICU (Panel 1 details assessing malaria severity). He was switched to IV artesunate 2.4mg/kg because of his high parasitaemia as well as his deterioration despite optimum loading with quinine dihydrochloride. The ICU doctor initially prescribed artesunate 185mg (based on an over-estimated weight). This was corrected to 155mg before administration (once a confirmed weight had been documented in the ICU electronic prescription) but caused a delay in treatment.

Fluid replacement was also prescribed because the patient had lactic acidosis and was hypovolaemic, oliguric, hypernatraemic and hypotensive. However, because patients with malaria are susceptible to pulmonary oedema induced by over-hydration it was particularly important to have a tight fluid balance.

Approximately 0.37 per cent of patients with falciparum malaria can develop shock secondary to complicating bacteraemia or septicaemia, also known as “algid malaria”.4 The patient’s blood cultures were positive for Gram-negative bacteria and if hypovolaemia did not resolve after initial attempts at fluid balance correction and signs of shock occurred, it would have been appropriate to prescribe a broad-spectrum antibiotic.

A summary of his acute initial management was as follows:

  • Artesunate IV 155mg at 0, 12 and 24 hours then 24-hourly
  • Sodium lactate compound IV 100ml/h for 12 hours

No pharmacokinetic data are available for patients with impaired renal function (our patient had acute kidney injury). However, based on the known mechanisms of metabolism and elimination of artesunate through the liver, combined with clinical data from patients with severe malaria and accompanying renal compromise of various degrees, no dose modifications are considered necessary in any degree of renal impairment.3

After four doses of IV artesunate (48 hours) the parasite count had reduced to 0.025 per cent; creatinine and platelets improved (creatinine 113µmol/L; platelets 161x109/L). The hypernatraemia had resolved after hydration and the patient was stepped down to the infectious diseases ward before discharge.

At this stage, it was also appropriate to stop the artesunate and switch to oral artemether 20mg/lumefantrine 120mg (Riamet) four tablets bd for 3/7 (see Panel 2) due to the lower parasite count and the fact that the patient could reliably swallow.

On the day of discharge (eight days after admission) a repeat malaria count showed a further drop in parasitaemia to 0.001 per cent.

The patient’s medication on discharge was:

  • Timolol maleate 0.25 per cent one drop both eyes bd
  • Latanoprost 50µg/ml one drop both eyes
  • Atorvastatin 40mg on

The antihypertensives were not restarted because the patient was normotensive and a follow-up appointment was arranged to review and investigate the atrial fibrillation.

Relapse of malaria is well recognised with P vivax and P ovale infections, being caused by persistent liver forms (hypnozoites), and may occur months or sometimes several years, after exposure. Relapses are not prevented by current chemoprophylactic regimens, with the exception of primaquine.

Recurrence of P falciparum malaria is less likely but is thought to occur by two different mechanisms: reinfection or recrudescence. Recrudescence can be due to incomplete or inadequate treatment as a result of drug resistance or improper choice of medication, an antigenic variation,7 and or multiple infection by different strains. There is no drug prophylaxis for relapse.

Role of the pharmacist

Artesunate is unlicensed in the UK and is sourced from China. There have been manufacturing problems in the past where manufacturers have not achieved good manufacturing practice and are not legally obliged to. It was important to ensure that sufficient supply was available on the ward, bearing in mind quality assurance and quality control requirements (ie, it is important to ensure that the medicine has been passed by the hospital’s QC department).

It was also important that the medical teams were aware that an unlicensed medicine was being used so, for example, they can inform the patient of the risks. If the patient had been transferred back to the base hospital, it would have been important to ensure a continuing supply was sent with the patient. Our hospital is one of two specialist disease centres that can initiate supply of artesunate to other hospitals, under certain criteria,4 until further supplies can be sourced from a recognised pharmaceutical importer.

Education

The nurses were unfamiliar with the administration of artesunate. The directions for administration were transcribed by the pharmacist onto the patients’ electronic drug chart to avoid confusion and delay because one of the key features of effective malaria treatment is ensuring that patients receive the appropriate medicine quickly.

Each 60mg artesunate vial needs to be reconstituted with the diluent provided and then further diluted to 5ml with either sodium chloride 0.9 per cent or glucose 5 per cent and injected as a bolus slowly over five minutes.3,5 There is no specific post-administration monitoring required apart from observing for a severe allergic reaction (estimated risk one in 3,000), which can involve rash, hypotension, pruritus, oedema and dyspnoea.3

The on-call ICU doctor initially prescribed an incorrect dose of artesunate, which caused a delay in administration. With malaria treatment it is essential to ensure the appropriate drug, dose and duration in order to optimise clinical outcome. If the electronic drug chart had been endorsed with a guideline template set up to populate the weight automatically from the electronic notes, (which is documented on admission to ICU), this would have calculated the dose, removing the possibility of using an estimated weight and the potential incorrect dosing.

In future, a template would be beneficial to ensure correct dosing intervals, particularly at the beginning of the regimen. This template would not prevent further checks, however, because all prescriptions for artesunate are screened by pharmacy before supply.

Finally, there is a role in patient education. Being infected with falciparum malaria does not provide any acquired immunity for either the long term or short term. It was, therefore, important to make sure the patient understood the need to take prophylactic measures — both pharmaceutical and non-pharmaceutical — when travelling to Nigeria (or other endemic countries) in the future. The need to check travel vaccination requirements was also mentioned.

Key points

  • Immunity from malaria rapidly wanes once a patient migrates to the UK — appropriate prophylaxis is important.
  • Intravenous artesunate is more effective than quinine at treating severe malaria. It should be used in preference to quinine for P falciparum malaria in adults, although quinine is more readily available.

 

Case comment: Paul Wade, consultant pharmacist, infectious diseases

As well as highlighting a therapy that many pharmacists working in secondary care may be unaware of, this case also highlights a couple of important points about malaria that are relevant to all pharmacists.

The first point is around the potential for malaria in returning travellers. Any patient presenting with a fever should be asked about their travel history and malaria should be considered as a potential diagnosis in every ill patient returning from the tropics in the previous year. Pharmacists are well placed to be able to refer affected patients to their GP for review.

Immunity The second point is around the assumption of immunity in many UK-resident travellers who may be visiting their country of origin. Malaria in the UK is predominantly a disease of the non-UK born population and there is data to suggest that this group is less likely to take malaria prophylaxis. There is, perhaps, an incorrect assumption that there is some protection against malaria by being brought up in a country where malaria is endemic, and that the risks of acquisition on return are low, but immunity from malaria rapidly wanes once a patient migrates to the UK.

Pharmacists who provide malaria prophylaxis or help with other aspects of travel are well placed to guide patients on appropriate malaria prophylaxis for themselves and their family members, and advise of the need for GP review if anyone becomes unwell on return.

New guidance for malaria prevention in travellers from the UK has recently been published by Public Health England.1 This provides a useful template for risk assessment of travellers for malaria prevention. It also highlights that consideration of other travel-related health issues is needed when discussing malaria prevention.

Reference

  1. Chiodini PL, Field VK, Hill DR et al. Guidelines for malaria prevention in travellers from the United Kingdom.

Further reading

A CPD article on malaria prophylaxis is available.

About the authors

Reena Thakrar, MPharm,  is a rotational clinical pharmacist and Lucy Hedley PGDipGPP, MRPharmS, is a senior clinical pharmacist, both at University College London Hospitals NHS Foundation Trust.

References

  1. WHO Factsheet on malaria. Available at www.who.int/mediacentre/factsheets/fs094/en/index.html (accessed on 21 August 2013).
  2. Malaria imported into the United Kingdom in 2011: implications for those advising travellers. Health Protection Agency (2012) Health Protection Report Volume 6, Number 17 Available at www.hpa.org.uk/hpr/archives
    /2012/hpr1712.pdf
    (accessed on 1 August 2013).
  3. Summary of product characteristics, Artesunate 60 mg for injection, Guilin Pharmaceutical Co., Ltd, 09/2011.
  4. Lalloo DG, Shingadia D, Pasvol G et al (on behalf of the HPA Advisory Committee on Malaria Prevention in UK Travellers). UK malaria treatment guidelines. Journal of Infection 2007;54:111–21.
  5. World Health Organization, Guidelines for the treatment of malaria, 2nd Edition, 2010.
  6. British National Formulary 65th Edition, pages 421 to 430 (2013), London. BMJ Group and Royal Pharmaceutical Society of Great Britain.
  7. Miller LH, Good MF, Milon G. Malaria pathogenesis. Science 1994;264:1878–83.

Citation: The Pharmaceutical Journal DOI: 10.1211/PJ.2013.11129119

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