Outpatient treatment of malaria in recently arrived African migrants

Australia was declared malaria-free in 1981,1 however, 600–900 cases of imported malaria are reported each year, mostly in returning travellers or people previously living in endemic areas. The region of northern Australia above 19°S is still a receptive zone for re-introduction of malaria because of the presence of Anopheles mosquitoes.1,2

In recent years, Australia has increased its intake of migrants under the Refugee and Special Humanitarian Program. The number of entry visas granted increased from 7113 in 2000–01 to 12 096 in 2004–05,3 and priority was given to people from Africa, the Middle East, and south-west Asia. In 2003–04, 71% of the offshore humanitarian visa grants were allocated to African refugees.4 The resultant changes in migration patterns to Australia are likely to be at least partly responsible for increasing numbers of notified cases of malaria, particularly those caused by Plasmodium falciparum.5

People infected with species of Plasmodium and who live in malaria-endemic regions often demonstrate few or no symptoms or signs of infection because they have acquired partial immunity. In these regions, people with all forms of non-severe malaria are routinely managed as outpatients, and recent reports from developed countries suggest that outpatient therapy for falciparum malaria may be appropriate in certain circumstances.6,7 In Australia, experts advocate that all patients diagnosed with P. falciparum infection receive initial treatment in hospital.8

Because of the significant number of recently arrived African migrants from malaria-endemic regions with asymptomatic or minimally symptomatic malaria being referred to Royal Perth Hospital (RPH), a management program was instituted whereby selected patients could receive antimalarial th1erapy as outpatients. Here, we report a retrospective observational study of adult African migrants referred from the Western Australian Migrant Health Unit (MHU) to RPH for the management of malaria. Our findings were presented, in part, in poster form at the 2005 Annual Scientific Meeting of the Australasian Society for Infectious Diseases.9

Patients with fever (≥ 37.5°C), hypotension, parasitaemia of 2% or greater at presentation, or other clinical and laboratory features of severe malaria according to World Health Organization criteria,10 or who were pregnant were offered admission; otherwise, patients received outpatient treatment. All antimalarial medications were administered as per product information, and possible side effects were carefully explained. Antimalarial medications were chosen according to national guidelines8 and at the discretion of the treating clinician. Those treated as outpatients had their first dose of antimalarial medication under supervision, were observed for 1 hour, and were offered admission only if therapy was not tolerated. Subsequent doses were given to the patients and the course was completed unsupervised at home. All patients were instructed to seek review if they became ill or could not tolerate subsequent doses after leaving RPH. Subsequent outpatient review was arranged for all patients. Patients were considered cured at subsequent review if they were asymptomatic and the thick and thin blood films were negative for malarial parasites at 4 weeks or more after completion of therapy. As this was a retrospective clinical audit, ethical approval was not necessary.

In the 31-month review period, 1609 African migrants aged 16 years and older were assessed at the MHU, of whom 57 were diagnosed with malaria. The most common country of origin was Sudan, and Uganda was the most common country of refuge before resettlement in Australia (Box 1).

Clinical and laboratory characteristics of the patients are shown in Box 2. Box 3 shows that most (52) were infected with P. falciparum. The species of malarial parasite could not be identified in one patient. No patients had severe malaria by WHO criteria. Eighteen patients with P. falciparum malaria were symptomatic; common symptoms included chills (in 16), headaches (10) and myalgias (2). Two patients were febrile; both had P. falciparum infection. The time after arrival in WA before treatment ranged from 7–67 days (median, 28 days). Sixteen patients had a haemoglobinopathy.

Fifty-three patients were treated entirely as outpatients. Although five patients satisfied criteria for hospital admission (two were febrile, three were pregnant), only one agreed to be admitted. The four patients who met admission criteria but refused admission were all successfully treated as outpatients. Three other patients who did not fulfil the criteria for admission were admitted because of significant constitutional symptoms. None of the patients (inpatients or outpatients) developed complications of malaria while on treatment.

Drugs used to treat malaria are outlined in Box 3. Atovaquone–proguanil was given to 52 patients and was well tolerated in 49. All patients tolerated their first dose of antimalarial medications. Two patients reported nausea and one reported dizziness while on atovaquone–proguanil, and one patient who received mefloquine reported nausea and dizziness during therapy; all of these patients completed their therapy.

Follow-up blood films were performed between 1 to 20 weeks after treatment (median, 4 weeks) in 50 patients. Forty-one of these patients had blood films performed at 2 weeks or more, and 27 had films performed at 4 weeks or more after completion of treatment. All follow-up films were negative for malarial parasites.

The concept of ambulatory treatment of P. falciparum malaria is not new. Outpatient treatment of uncomplicated P. falciparum malaria is accepted practice in malaria-endemic areas,6,11,12 and in returned travellers in Switzerland.7,13 As a result of a combination of factors, including pre-existing immunity, coexisting protective haemoglobinopathy, initial low parasitaemia and/or partial treatment by refugee resettlement agencies before entering Australia, recently arrived African migrants are probably less likely to develop complications of malaria than non-immune returned travellers, and are therefore potentially suitable for outpatient therapy. Outpatient antimalarial therapy is also less resource-demanding and is significantly less disruptive to migrant families.

Atovaquone–proguanil was selected at our institution as the preferred therapy for uncomplicated malaria in this cohort because of its short treatment course, favourable side-effect profile and the previous favourable response to this therapy in non-immune patients. Furthermore, the once-daily dosing (with food) is easily understood by non-English-speaking people, which may minimise the likelihood of incorrect dosing in an unsupervised setting. Atovaquone and proguanil act synergistically against blood-stage malarial parasites, interfering with plasmodial respiration, and the combination is effective in the treatment of P. falciparum infection.14 It is also efficacious against non-falciparum malaria.15

There are reports of clinical failures of atovaquone–proguanil in the treatment of P. falciparum infections in travellers returning from Africa.16,17 However, atovaquone–proguanil resistance in Africa is not a widespread concern at present,17 and we did not see any treatment failures in our cohort, although follow-up was incomplete.

Efficacious alternative agents include mefloquine and artemether–lumefantrine; artemether–lumefantrine has the additional benefit of activity against early-stage gametocytes, thereby potentially preventing malaria transmission. Acquisition costs for one course of atovaquone–proguanil, mefloquine, and artemether–lumefantrine at our institution are $56, $21 and $80, respectively. Outpatient-based treatment of recently arrived African migrants with uncomplicated malaria with any antimalarial is thus likely to be cost-effective relative to the expense of “bed-costs” of a hospital admission ($450 per day in 2005 at RPH).

We believe that screening and treatment for malaria in people migrating to Australia from malaria-endemic regions is an essential part of the initial health assessment, and should be performed as soon as possible after arrival. Individuals with untreated P. falciparum malaria, including those with minimally symptomatic or asymptomatic infection, can: (i) progress to developing severe malaria, even after prompt initiation of appropriate treatment; (ii) potentially reintroduce malaria into Australia if they settle or travel to a malaria-receptive zone; (iii) have persistent symptomatic anaemia; and/or (iv) present months or even years later with symptomatic disease.18

Our study has several limitations. It was a retrospective uncontrolled study, and therefore subject to bias. As attendance at the MHU for screening is voluntary, the real prevalence of malaria in African migrants cannot be known. However, given that most refugee and humanitarian entrants arriving in WA do attend for screening (Dr Jennifer Martin, Resident Medical Officer, MHU, personal communication), the reported prevalence of 3.5% in this cohort is likely to be close to the true prevalence.

Our study did not include children, a group that bears a significant burden of P. falciparum infection in Africa. Over half of all P. falciparum cases diagnosed at the MHU between 2003 and 2004 occurred in children aged 15 years or less (Dr Jennifer Martin, Resident Medical Officer, MHU, personal communication). Children with malaria are also more likely to vomit oral therapy. Ambulatory treatment of malaria in this group warrants further study. In addition, we would stress that the implications of our data cannot be extrapolated to the treatment of malaria in returned travellers, in whom there is unlikely to be any pre-existing protective immunity.

Follow-up was incomplete, with seven of our patients not returning for outpatient review. For those who did attend at least once for review, only 27 were seen at 4 weeks or more after treatment. It has been shown in prior malaria treatment studies in endemic areas that treatment success is best predicted with assessments at 4 weeks or more after treatment is completed.19,20 Although unlikely, treatment failures cannot be completely excluded in those patients assessed after shorter follow-up times.

Our study suggests that outpatient treatment of asymptomatic or minimally symptomatic malaria (including P. falciparum infection) in recently arrived adult African migrants is a potentially efficacious and safe strategy in carefully selected patients. A large, prospective, randomised clinical trial would be required to validate our findings.