CATMAT recommendations on malaria in special hosts

Special groups of travellers have different risks of acquiring malaria infection compared with the average traveller. If unable to defer travel to areas with high risk of malaria, pregnant and breastfeeding women and small children should receive tailored antimalarial chemoprophylaxis, since some of the drugs are contraindicated in these groups. Long-term travellers, expatriates and travellers visiting friends and relatives (VFRs) may perceive malaria risk differently and may adhere differently to chemoprophylaxis. They require additional information about self-diagnosis and treatment. The issue of counterfeit drugs is addressed specifically for long-term travellers.

Methods

The Malaria Subcommittee, a working group of CATMAT, developed the guidelines. The process undertaken to develop them has been described previously ^{Footnote 3}. It included a review of recent research and national and international epidemiological data, and the consideration of other factors, such as malaria epidemiology, and the anticipated values and preferences of travellers and health care providers. The evidence-based medicine recommendations for various malaria issues pertaining to special hosts were developed with associated rating scales for the strength and quality of the evidence.

Recommendations

The evidence-based CATMAT recommendations for malaria prevention and treatment in special hosts are summarized in Table 1. A discussion of some of the key recommendations follows.

Children

Malaria disproportionately affects children and can have nonspecific symptoms that mimic other common childhood illnesses, leading to delays in diagnosis. Severe or complicated malaria, such as cerebral malaria, severe anemia, shock or even death, may develop more quickly in children ^{Footnote 5}.

Young children should avoid travel to areas with significant malaria transmission, particularly of chloroquine-resistant malaria ^{Footnote 6}. When travel to malaria-endemic areas is unavoidable consider the following:

• All children should use effective personal protective measures (PPM: topical repellants, bed nets, behavioural choices) ^{Footnote 7} and appropriate malaria chemoprophylaxis ^{Footnote 1 Footnote 8}.
• For chloroquine-resistant areas, mefloquine, doxycycline (for those ≥ 8 years) and atovaquone-proguanil (≥ 5 kg) are most appropriate ^{Footnote 9 Footnote 10 Footnote 11 Footnote 12}.
• Primaquine may be suitable for children who are unable to take the first-line prophylactic agents, once adequate G6PD (glucose-6-phosphate dehydrogenase) levels have been confirmed ^{Footnote 13}.
• Prescribe antimalarial drugs for breastfeeding infants even if their mother is taking antimalarials ^{Footnote 6 Footnote 14}.
• Specific instructions related to dosing:
  • Prescribe sufficient tablets to allow a few doses to be vomited or spat out. Give clear instructions when to repeat doses that were not successfully ingested;
  • Have tablets pre-cut or crushed and inserted into capsules to increase the accuracy and ease of dosing;
  • Describe how to adjust the dose of medications to allow for an increase in children's weight.
• Explain that because there are few pediatric formulations, malaria tablets may be crushed and mixed with something sweet to disguise their unpleasant taste.

Pregnant and breastfeeding women

Pregnant women should defer travel to malaria-endemic areas and particularly to regions with drug-resistant falciparum malaria ^{Footnote 15}. Malaria increases the risk of maternal and neonatal death, miscarriage and stillbirth. Low birth-weight infants are more commonly born to women taking ineffective prophylaxis ^{Footnote 15}.

If travel is unavoidable,

• Pregnant and breastfeeding women should use PPM (topical repellents, insecticide-treated bed nets, and behavioural choices) ^{Footnote 16}.
• Prescribe chemoprophylaxis based on destination:
  • Chloroquine in chloroquine-sensitive areas;
  • Mefloquine where exposure to chloroquine-resistant falciparum malaria is unavoidable ^{Footnote 17 Footnote 18 Footnote 19};
  • Discuss the benefits and risks of atovaquone-proguanil after the first trimester in women who cannot avoid travel to mefloquine-resistant areas or who cannot take mefloquine ^{Footnote 20 Footnote 21};
  • Although safe in pregnancy, the combination of chloroquine and proguanil is inadequate as an antimalarial and cannot be recommended for chloroquine-resistant areas ^{Footnote 22};
  • Doxycycline is contraindicated during pregnancy.

Nursing women should continue to breastfeed if using chemoprophylaxis that is safe in infancy (chloroquine, mefloquine, atovaquone-proguanil in infants weighing ≥ 5 kg). Doxycycline absorption through breast milk is probably negligible, and breastfeeding is not an absolute contraindication to maternal use ^{Footnote 23}.

Migrants

Although in most cases disease will develop within three months of last exposure, malaria could be the reason for any fever that develops within 12 months of leaving a malaria-endemic region ^{Footnote 24}. The risk of malaria exists for migrants after their arrival in Canada:

• For at least 12 months after migrants arrive in Canada, test for malaria in cases of unexplained fever.
• Consider malaria screening in asymptomatic new migrants from highly endemic areas, and treat those with parasitemia (apart from the presence of gametocytes only) in blood smears.
• Ask migrants from malaria-endemic countries about future travel plans to provide anticipatory guidance about malaria ^{Footnote 25}.

Long-term travellers, expatriates and visiting friends and relatives

Recommendations for preventing malaria in long-term travellers (travel for longer than one month), expatriates or visiting friends and relatives are very similar to the standard recommendations for the short-term traveller ^{Footnote 26}: use prescribed malaria chemoprohylaxis and PPM consistently, including insecticide-treated bed nets and topical repellents containing 20%-30% DEET or 20% icaridin.

Some of the topics to cover when counselling expatriates and long-term travellers about malaria prevention include the following:

• Possible concern about safety with prolonged use of chemoprophylaxis medication.
• Use of PPM over the long term.
• Cost of medication over the long term.
• Use of locally procured and possibly counterfeit drugs.
• Conflicting counsel about chemoprophylaxis and self-treatment.
• Need for ongoing adherence to chemoprophylaxis.

Since overall nonadherence rates for chemoprophylaxis are as high as 61% ^{Footnote 27}, pre-travel advice should focus on these aspects:

• Malaria symptoms and risk, emphasizing the need for early diagnosis and treatment.
• Development of a plan for accessing competent medical care in case of illness.
• Standby emergency therapy (self-treatment).
• The affordability of chemoprophylaxis.
• The likelihood that local malaria drugs are counterfeit ^{Footnote 28}.
• The loss of partial immunity among visiting friends and relatives because of residence in a country without malaria ^{Footnote 25}.

The risk of malaria among visiting friends and relatives is almost the same as for local residents, but the risk of severe disease is higher because of loss of partial immunity after having lived in a non-endemic area ^{Footnote 25}.

VFRs tend to show certain characteristics:

• Be less likely to seek out or comply with preventive travel health advice ^{Footnote 29 Footnote 30 Footnote 31}, possibly because of:
  • Financial or time restrictions ^{Footnote 25};
  • Misconceptions about risk of disease and immunity; or
  • Reliance on advice from family members or local providers at their destination ^{Footnote 25 Footnote 27 Footnote 28 Footnote 32 Footnote 33}.
• Stay in rural locations (with higher rates of malaria transmission than urban centres) and for longer visits ^{Footnote 25}.
• Stay with local family members rather than in air-conditioned and well-screened hotels ^{Footnote 25}.
• Travel with their Canadian-born children ^{Footnote 25}.
• Make last-minute emergency travel plans ^{Footnote 25}.

Table 1: Evidence-based medicine recommendations for malaria prevention and treatment in special hosts

Recommendation		EBM rating Table 1 - Footnote *
Children
1.	Young children should avoid travel to areas with significant malaria transmission, particularly of chloroquine-resistant malaria Footnote 6.	C III
2.	All children who travel to malaria-endemic areas should use PPM Footnote 7.	A I
3.	In chloroquine-resistant areas, mefloquine, doxycycline (≥ 8 years) and atovaquone-proguanil (≥ 5 kg) are the drugs of choice for chemoprophylaxis Footnote 9 Footnote 10 Footnote 11 Footnote 12.	A I
4.	Primaquine chemoprophylaxis may be suitable for children who cannot take any of the first-line prophylactic agents, after confirmation of G6PD status Footnote 13.	B II
Pregnant women
5.	Pregnant women should avoid travel to areas with significant malaria transmission Footnote 15.	C III
6.	Pregnant women who travel to malaria-endemic areas should use PPM, including appropriate topical repellents and insecticide-treated bed nets Footnote 16.	A I
7.	In chloroquine-sensitive areas, pregnant women should use chloroquine as chemoprophylaxis.	A I
8.	Where exposure to chloroquine-resistant falciparum malaria is unavoidable, pregnant women should use mefloquine from conception through the first trimester (A II) and during the second and third trimesters (A I) Footnote 17 Footnote 18 Footnote 19.	A II, A I
9.	There are no currently approved antimalarials for pregnant women travelling to mefloquine-resistant regions. Atovaquone-proguanil after the first trimester may be considered after careful discussion of the benefits and risks Footnote 20 Footnote 21.	B II
10.	Although safe in pregnancy, the combination of chloroquine and proguanil is inadequate as an antimalarial and cannot be recommended for chloroquine-resistant areas Footnote 22.	E I
Breastfeeding women
11.	Infants should receive their own appropriate chemoprophylaxis even if breastfed Footnote 23.	A III
12.	Women breastfeeding a child < 5 kg should avoid atovaquone-proguanil Footnote 23.	C II
13.	Limited data suggest that doxycycline absorption through breast milk is negligible and that breastfeeding is not an absolute contraindication to maternal use Footnote 23.	C III
Migrants
14.	For at least 12 months after migrants arrive in Canada, test for malaria in cases of unexplained fever.	C III
15.	Consider malaria screening in asymptomatic new arrivals from highly endemic areas, and treat those who have parasitemia (apart from the presence of gametocytes only) in blood smears.	C III
16.	Ask migrants from malaria-endemic countries about future travel plans. Doing so may provide the opportunity for anticipatory guidance about malaria Footnote 25.	C III
Long-term travellers or expatriates
17.	Guidelines for preventing malaria in long-term travellers or expatriates should not deviate considerably from the recommendations for short-term travellers Footnote 26.	B III
18.	Training long-term travellers in the use of rapid diagnostic tests is reasonable Footnote 26 Footnote 34.	C III
19.	For long-term travellers who are more likely to buy drugs in countries without quality controls, provide education about counterfeit antimalarial medications Footnote 35 Footnote 37.	C II
20.	Consider primaquine for terminal prophylaxis for military personnel, long-term travellers or expatriates returned from regions with P. vivax transmission Footnote 26 Footnote 38 Footnote 39.	A I
Visiting friends and family (VFRs)
21.	Inform Canadian VFRs travelling to malaria-endemic countries about the risk of malaria, including the loss of partial immunity from living in Canada and the increased risk of severe disease in children and pregnant women Footnote 25.	C III
22.	Counsel Canadian VFRs travelling to malaria-endemic countries about PPM (repellents, bed nets, behavioural choices) and chemoprophylaxis Footnote 25.	C III
23.	Discuss the affordability of chemoprophylaxis  with Canadian VFRs travelling to malaria-endemic countries, taking cost into account in deciding about choices Footnote 25.	C III
Travellers with co-morbidities
24.	Individuals who are immunosuppressed or have co-morbidities should consult with a travel medicine or infectious disease expert Footnote 40.	B III
25.	Potential drug interactions and overlapping toxicities warrant careful review before antimalarial drugs are prescribed for people with chronic medical conditions, including HIV infection Footnote 41.	A I
26.	HIV-infected individuals who are pregnant or have advanced immune suppression should be encouraged to choose non-malaria endemic locations or defer travel until after pregnancy or restoration of immune function.	B III
27.	Provide standby antimalarial therapy for travellers with asplenia who may experience delays in accessing appropriate care for febrile illness.	A II
28.	A pre-travel trial with INR (international normalized ratio) testing should be done if mefloquine, doxycycline or proguanil (including atovaquone-proguanil) are to be used by people taking warfarin Footnote 42 Footnote 43 Footnote 44 Footnote 45.	A II
29.	Avoid chloroquine and mefloquine in the presence of a chronic seizure disorder.	E II
30.	Avoid chloroquine and mefloquine for travellers with myasthenia gravis.	E III
31.	Carefully review mental health history before prescribing mefloquine to ensure that psychotic, depressive or anxiety disorders are absent Footnote 46.	A I
32.	Chloroquine may exacerbate psoriasis. Mefloquine, doxycycline and atovaquone-proguanil are preferable to chloroquine in patients with underlying psoriasis.	B III
33.	Primaquine should not be used as chemoprophylaxis in the presence of G6PD deficiency.	E II
34.	Atovaquone-proguanil may be the preferred choice for malaria prophylaxis in the presence of porphyria.	B III
Footnote * *EBM = Evidence-based medicine. The EBM ratings are as follows: Strength of recommendation: A = Good evidence to support a recommendation for use B = Moderate evidence to support a recommendation for use C = Poor evidence to support a recommendation for or against use D = Moderate evidence to support a recommendation against use E = Good evidence to support a recommendation against use Quality of evidence: I = Evidence from at least one properly randomized, controlled trial II = Evidence from at least one well-designed clinical trial without randomization; from cohort or case-controlled analytic studies, preferably from more than one centre; from multiple time series; or from dramatic results in uncontrolled experiments III = Evidence from opinions of respected authorities on the basis of clinical experience, descriptive studies or reports of expert committees.

Long-term safety of chemoprophylaxis and PPM

Long-term use of chemoprophylaxis recommended for short-stay travellers does not result in additional risk of severe adverse events although data on the effectiveness and tolerance of recommended regimens are limited. Table 2 summarizes the safety of chemoprophylaxis with long-term use.

Table 2: Safety of chemoprophylaxis with long-term use

Chemoprophylactic drug	Effects of long-term use
Chloroquine	Requires an ophthalmologic examination at least every 2 years Footnote 30. However, chloroquine is seldom indicated because of extensive drug resistance.
Mefloquine	Well tolerated Footnote 47 Footnote 48 Footnote 49 Footnote 50. Mefloquine tolerance improves over time, possibly because any adverse events become apparent relatively early Footnote 47. Consequently, there does not appear to be increased risk with long-term use Footnote 28.
Atovaquone-proguanil	Although data on prolonged use of atovaquone-proguanil are limited, the individual components have been used for extended periods Footnote 30.
Doxycycline	Although data are limited, the drug and the related minocycline have been used for extended periods for other indications Footnote 31.

Currently, no long-lasting, insecticide-treated nets are registered for use in Canada. Insecticide-treated bed nets can be obtained from some Canadian travel health clinics and other domestic and international suppliers ^{Footnote 8}:

• The insecticide in most bed nets starts to lose its effect after six months ^{Footnote 8}.
• Liquid permethrin used to treat bed nets is not available in Canada.
• Travellers should renew the insecticide treatment of their bed nets at the start of rainy seasons.

Counterfeit drugs

Many expatriates and long-term travellers may have the opportunity to buy their antimalarial chemoprophylaxis and antimalarial drugs over the counter at local pharmacies where they are staying and cannot evaluate the authenticity of these drugs. Encourage all travellers and expatriates to buy a supply of medication in countries with strict quality control measures ^{Footnote 35 Footnote 36 Footnote 37}.

If travellers are buying outside of Canada bear in mind the following:

• Coartem® (artemether-lumefantrine) is not yet licensed for distribution in Canada but is recommended by the World Health Organization as first-line treatment for P. falciparum malaria. Travellers should buy it in Europe, the USA or other countries where counterfeiting is unlikely ^{Footnote 39}.
• Atovaquone-proguanil prophylaxis may be too expensive for most long-term use. Long-term travellers and expatriates may choose to purchase enough for one or two self-treatment courses ^{Footnote 51}.

Rapid diagnostic tests

Rapid diagnostic tests are essential diagnostic tools when malaria microscopy results are not available within two hours ^{Footnote 26}. Rapid diagnostic tests are simple to use, require no equipment or specialized laboratory skills and can be valuable adjuncts in diagnosing malaria ^{Footnote 52}. However, many travellers are unable to complete the procedures or interpret the results correctly ^{Footnote 26 Footnote 53 Footnote 54}. Without adequate training of laboratory staff, the usefulness of rapid diagnostic tests may be no better among expatriates ^{Footnote 34 Footnote 55}. Nevertheless, key members of a reasonably stable expatriate community could be trained in their use and in administration of appropriate self-treatment ^{Footnote 26 Footnote 34}.

Standby emergency self-treatment

Self-treatment is a temporary, life-saving measure for 24 hours while medical attention is sought. Travellers to high-risk regions should never rely exclusively on self-treatment ^{Footnote 40 Footnote 56 Footnote 57 Footnote 58}. Self-treatment regimens by region are summarized in Table 3.

Reasons for self-treatment include travelling/staying in these areas:

• Sub-Saharan Africa, where 90% of global malaria morbidity and mortality occurs.
• Remote regions where access to health care is a problem.
• Regions where malaria risk is small and self-treatment is preferable to long-term prophylaxis ^{Footnote 26 Footnote 28 Footnote 56 Footnote 59}.

Standby malaria treatment with atovaquone-proguanil or quinine and doxycycline is recommended for travellers who are more than a day away from malaria diagnostic help.

Table 3: Self-treatment regimens

Region	Self-treatment regimens
Chloroquine-sensitive regions	Self-treat with chloroquine and then resume or start chloroquine prophylaxis Footnote 54 Footnote 56 Footnote 60.
Chloroquine-resistant and/or chloroquine- and mefloquine-resistant P. falciparum regions	Self-treat with a drug different from that used for prophylaxis: Atovaquone-proguanil (Malarone®) or oral quinine and doxycycline or artemether-lumefantrine (Coartem®), purchased from a country with high standards of quality control to minimize the likelihood of being sold counterfeit products Footnote 36 Footnote 37 Footnote 54 Footnote 60.

Some antimalarials are contraindicated for the treatment of malaria (self-treatment or otherwise):

• mefloquine ^{Footnote 61 Footnote 62}
• pyrimethamine-sulfadoxine (Fansidar) ^{Footnote 63}
• mefloquine-Fansidar ^{Footnote 62}
• halofantrine ^{Footnote 39}
• chloroquine-Fansidar ^{Footnote 59}.

Terminal prophylaxis

P. vivax and P. ovale parasites can persist in the liver and cause relapses for as long as five years after the person has left a malaria-endemic area. Primaquine anti-relapse therapy (PART) decreases the risk of relapses by acting against the liver stages of P. vivax and P. ovale. PART is usually administered during or after the last two weeks of chemoprophylaxis to those who have been in malaria-endemic regions (most malarial areas of the world except Haiti and the Dominican Republic) ^{Footnote 26 Footnote 38 Footnote 39 Footnote 64}. Primaquine is contraindicated for use as PART in people with G6PD deficiencies, in pregnancy and in nursing mothers if the infant is G6PD deficient.

Travellers with co-morbidities

Interactions between malaria and other underlying medical conditions may result in increased susceptibility to and severity of malaria or complications of the underlying conditions. Some underlying health conditions may be exacerbated by or preclude using one or more antimalarial medications.

Routinely undertake a drug interaction check to avoid any potential adverse drug interactions unless the traveller's medications are known to be safely used with the proposed antimalarial agent.

Immunocompromised hosts

Immunocompromised travellers should carefully adhere to both PPM and chemoprophylaxis.

HIV/AIDS

There is a significant and complex interaction between human immunodeficiency virus (HIV) and P. falciparum. Assess for drug interactions, and consider the risk of overlapping adverse effect profiles ^{Footnote 65}. CATMAT recommends consulting with a travel/tropical medicine/infectious disease expert and the traveller's HIV specialist ^{Footnote 40}.

Asplenia

Asplenia increases the risk, magnitude and duration of parasitemia, even among partially immune individuals in malaria-endemic countries ^{Footnote 41}, and enhances the risk of severe and fatal malaria in travellers with this condition ^{Footnote 66}. Recommend standby self-treatment in addition to prophylactic measures if the traveller is heading to remote regions and/or access to care is limited. Since fever may be due to malaria or bacterial infection, provide antibacterial standby treatment ^{Footnote 67}.

Other conditions

A list of other conditions and their effects on the choice of malaria chemoprophylaxis are summarized in Table 4.

Table 4: Other conditions that affect choice of malaria chemoprophylaxis

Condition	Impact on choice of malaria chemoprophylaxis
Abnormal coagulation	Mefloquine, doxycycline and proguanil may potentiate warfarin Footnote 42 Footnote 43 Footnote 44 Footnote 45 Footnote 68. Conduct a medication trial several weeks in advance of travel and International Normalized Ratio (INR) serial testing to allow adjustment of the anticoagulant dose both before and after travel.
Seizure disorders	Chloroquine and mefloquine may exacerbate seizures, so prescribe alternative agents. There is no evidence that febrile seizures in children are a contraindication for these drugs. Concurrent use of anticonvulsant drugs that induce hepatic microsomal enzymes (e.g. barbiturates, phenytoin, carbamazepine) may decrease serum levels and the half-life of doxycycline, and may require dosage adjustment Footnote 45.
Myasthenia gravis	Malaria infections may exacerbate myasthenia gravis. Optimal prevention through adherence to chemoprophylaxis and PPMs should be reinforced. Avoid chloroquine, mefloquine and doxycycline as they have been associated with worsening of myasthenic symptoms. Doxycycline may be considered in stable patients, particularly for those with only ophthalmologic symptoms, though CATMAT recommends a pre-travel therapy trial. A pre-travel trial of atovaquone-proguanil therapy is recommended, since proguanil monotherapy has been reported to worsen myasthenic symptoms Footnote 69. Primaquine has not been associated with myasthenic symptoms and may be an option for P. falciparum prophylaxis (after ruling out G6PD deficiency) in myasthenic travellers who are unable to tolerate doxycycline and atovaquone-proguanil.
Psychiatric disorders	Assess for history of depression, generalized anxiety disorder or psychosis before prescribing mefloquine Footnote 46 Footnote 70. Dose-related neuropsychiatric adverse effects are well recognized with mefloquine and to a lesser extent with chloroquine Footnote 71 Footnote 72.
Hepatic or renal dysfunction	Moderate to severe hepatic or renal dysfunction may alter antimalarial medication levels Table 4 - Footnote *. If necessary, consult with a travel/tropical medicine expert. Severe renal insufficiency (creatinine clearance < 30 mL/min) is a contraindication to atovaquone-proguanil use.
Psoriasis	Avoid chloroquine as it may trigger acute flares of psoriasis Footnote 73 Footnote 74.
Glucose-6-phosphate dehydrogenase (G6PD) deficiency	Primaquine is associated with a potentially life-threatening risk of hemolysis. Although G-6PD deficiency is raised as a concern by the manufacturers of chloroquine, experts do not consider this a contraindication, since significant hemolysis is unlikely at prophylactic doses.
Porphyria	Apart from atovaquone-proguanil Footnote 75, all the first-line malaria chemoprophylactic agents may be porphyrinogenic. Use with caution.
Footnote * *See Canadian Recommendations for the Prevention and Treatment of Malaria Among International Travellers, Table 5.4.3: Antimalarial drug considerations for people with renal or hepatic disease.

Conclusion

Special groups of travellers require additional information for prevention and management of malaria. In addition, they should recognize the importance of adherence to recommendations for chemoprophylaxis and PPM. Treatment varies according to the species of Plasmodium, the severity of disease and the region where the malaria was acquired, as well as potential interactions between chronic medications and recommended antimalarial therapy.

Acknowledgements

CATMAT acknowledges and appreciates the contribution of Joanna Odrowaz and Elspeth Payne to the development of the summaries and Manisha Kulkarni for her contribution to the statement.

CATMAT Members: Boggild A, Brophy J, Bui YG, Crockett M, Ghesquiere W, Greenaway C, Henteleff A, Libman M, Teitelbaum P and McCarthy A (Chair).

Liaison members: Hui C (Canadian Paediatric Society) and Gershman M (US Centers for Disease Control and Prevention).

Ex-officio members: Marion D (Canadian Forces Health Services Centre, Department of National Defence), McDonald P (Division of Anti-Infective Drugs, Health Canada), Schofield S (Directorate of Force Health Protection, Department of National Defence) and Tepper M (Directorate of Force Health Protection, Department of National Defence).

Member Emeritus: Jeanes CWL.

Conflict of interest

There are no conflicts of interest to declare.

Funding

This work was supported by the Public Health Agency of Canada.