Infection (2014) 42:239–250 DOI 10.1007/s15010-013-0563-3
GUIDELINE
New Italian guidelines for malaria prophylaxis in travellers to endemic areas G. Calleri • F. Castelli • I. El Hamad • F. Gobbi • A. Matteelli • G. Napoletano R. Romi • A. Rossanese
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Received: 5 September 2013 / Accepted: 14 November 2013 / Published online: 18 December 2013 Springer-Verlag Berlin Heidelberg 2013
Abstract Background and Methods As a consequence of the rapid evolution of malaria prophylaxis recommendations throughout the world, the Italian Society of Tropical Medicine (SIMET—Societa` Italiana di Medicina Tropicale) has set up a working group in charge of preparing a new national guideline. Other scientific societies interested in the topic were also involved in the project. Results and Conclusions The group stated that awareness about malaria risk and characteristics, as well as protection from mosquito bites, are recommended for all travellers visiting malaria-endemic countries. The risk and benefit of malaria chemoprophylaxis must be carefully balanced
G. Calleri (&) Travel Medicine Unit, Department of Infectious Diseases, Amedeo di Savoia Hospital, Turin, Italy e-mail: [email protected] F. Castelli A. Matteelli University Division of Infectious and Tropical Diseases, University of Brescia and Spedali Civili General Hospital, Brescia, Italy
before prescribing drugs: the disease-related risk must outweigh the possibility of drugs’ side effects. As a general rule, malaria pills are the first choice for travellers to highrisk areas, such as sub-Saharan Africa, Eastern India, Myanmar, Eastern Indonesia, Papua New Guinea and, with some limitations, South-East Asia, and the Amazon part of Venezuela, Guyana and French Guyana. However, several other factors, such as itinerary, season, duration of trip, availability of insect bite protection, pre-existing conditions and compliance, must be taken into account. In lowrisk areas, stand-by emergency treatment is the first option. In minimal-risk areas and in Plasmodium vivax areas, a prompt diagnosis only is advised (Central America, South America outside the Amazon basin, Middle East, China, Thailand, Nepal). Recommendations may be modified when particular groups of travellers are concerned, such as long-term residents, visiting friends and relatives, patients with pre-existing conditions, pregnant women and children. Keywords Malaria Prophylaxis Guidelines Travel medicine Insect bite prevention SIMET Background
I. El Hamad Department of Infectious Diseases, Spedali Civili General Hospital, Brescia, Italy F. Gobbi A. Rossanese Centre for Tropical Diseases, Sacro-Cuore Hospital, Negrar, Verona, Italy G. Napoletano Travel Diseases Prevention Unit, Department of Prevention, ULSS 20, Verona, Italy R. Romi Department of Infectious, Parasitic and Immune-Mediated Diseases, Istituto Superiore di Sanita`, Rome, Italy
In recent years, malaria prevention guidelines have seen a rapid evolution, moving from a basic risk approach (‘‘recommend prophylaxis whenever the risk is there’’) to a risk/benefit approach (balancing the risk of disease and drugs’ side effects). All national and international guidelines have moved in different degrees from a rigid recommendation of chemoprophylaxis to a greater use of other prevention systems (protection against vectors, early diagnosis, stand-by treatment), but this has led to a wider range of recommendations [1–5] and professionals in different countries seem to give different advice [6].
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Methods In early 2012, a specific working group on malaria prophylaxis was set up by the Italian Society of Tropical Medicine (SIMET—Societa` Italiana di Medicina Tropicale), in order to revise the national guideline for malaria prophylaxis, which had been last published in 2003 [7]. The group was composed of eight professionals in the field of tropical and travel medicine, representing different scientific societies interested in the topic of malaria prevention: SIMET itself, ‘‘Societa` Italiana di Malattie Infettive’’ (SIMIT), ‘‘Societa` Italiana di Medicina dei Viaggi’’ (SIMVIM), ‘‘Societa` Italiana di Medicina delle Migrazioni’’ (SIMM), ‘‘Societa` Italiana di Parassitologia’’ (SoIPa) and ‘‘Societa` Italiana di Igiene’’ (SItI). The discussion among the group developed mainly online, and several meetings were organised to discuss face-to-face the main issues. Firstly, the main controversial aspects of malaria prophylaxis, named ‘‘grey areas’’, were identified, and two rounds of discussion via online questionnaires were made within the group, according to the ‘‘Delphi method’’, a consensus development approach which has recently been experimented in this field [6, 8]. Secondly, the topic was split into different sections (Introduction, Vector protection, Chemoprophylaxis, Diagnosis and stand-by treatment, Recommendations in different areas, Special groups) and each member of the working group prepared a draft of one section. Subsequently, all drafts were examined and discussed in a meeting held in November 2012, so that a consensus was reached on all topics. A comprehensive draft was then prepared, further discussed online and finally approved on 28/1/2013. The final manuscript has been endorsed by the six scientific societies which participated in this project, and by the ‘‘Societa` Italiana di Medicina Generale’’ (SIMG). The main basis of the work was the best available evidence. Due to the scarcity of data in this field, existing guidelines as well as the opinion of experts have also been exploited. The starting point of the discussion was the double aspect of prevention practice: avoiding the disease-related risk and the possible harm of interventions. Thus, the choice of one prevention system must be based on a careful risk/benefit balance: on the one side, the efficacy and side effects of preventive measures, particularly drugs; on the other side, the probability and the severity of the disease. The guidelines are mainly addressed to travel medicine professionals, specialists in infectious diseases and in travel and migration medicine, general practitioners and nurses, who give information to travellers from Italy to malariaendemic countries. This document does not contain compelling directions but is, rather, aimed at providing a
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working track for recommending malaria prevention. However, the final decision in each individual case cannot be based on the culture, but on the experience and sensitivity of the individual operator.
‘‘ABCDE’’ of malaria protection The World Health Organization (WHO) states the so-called ‘‘ABCD of malaria’’ as a basis for protection against the disease [1]: A = awareness, B = bite prevention, C = chemoprophylaxis, D = diagnosis. A fifth point ‘‘E’’, for emergency stand-by treatment, may be added. ‘‘A’’ is the first step: everyone travelling in a malariaendemic area must be aware of the risk and be informed about the characteristics of the disease, in order to protect himself or herself by using the available tools and seek prompt medical advice in case of need. The quality of counselling is paramount in this perspective [9]. The main sources of information are reported in Table 1. The quantification of malaria risk is of primary importance, but is not always easy. Data about the risk in travellers should be preferred (cases of malaria/100,000 travellers), but are seldom available, mainly because of the lack of information about the total number of travellers, to be used as a denominator of incidence rates, or because many areas are visited by few travellers. In this case, various indexes of frequency in the resident population may be used, although they do not reflect Table 1 Information sources for travel medicine professionals Risk assessment: WHO International Travel and Health http://www.who.int/ith/ chapters/ith2012en_countrylist.pdf WHO, API http://www.who.int/malaria/publications/countryprofiles Malaria Atlas Project http://www.map.ox.ac.uk MARA Collaboration http://www.mara.org.za CDC Yellow Book http://wwwnc.cdc.gov/travel/yellowbook/ 2012/chapter-3-infectious-diseases-related-to-travel/yellowfever-and-malaria-information-by-country.htm WHO guidelines: http://www.who.int/ith/en/ National guidelines: Chiodini et al. [5] (http://www.hpa.org.uk/webc/HPAwebFile/ HPAweb_C/1203496943523) Deutsche Gesellschaft fu¨r Tropenmedizin und Internationale Gesundheit (DTG) [4] (http://www.dtg.org/uploads/media/ Malaria_2012_01.pdf) Haut Conseil de la Sante´ Publique [2] (http://www.sante.gouv.fr/ IMG/pdf/Recommandations_sanitaires_pour_les_voyageurs_ 2012.pdf) Centers for Disease Control and Prevention (CDC) [3] (http:// wwwnc.cdc.gov/travel/destinations/list.htm)
Asia Indian subcontinent Nepal (except Terai) South East Asia
Asia China (Hainan, Yunnan, Anhui, Henan, Hubei, Huizhou, Jiangsu) Asia Indian subcontinent Bangladesh (Chittagong area), India (Assam and Orissa, in particular, monsoon season) Asia Indian subcontinent Bangladesh (except Chittagong area), India (except Assam and Orissa), Nepal (Terai), Pakistan, Sri Lanka
Austral Africa Botswana (north), Namibia (north and Kavango and Kunene rivers), South Africa (Kruger and surroundings), Swaziland Austral Africa Botswana (except north), Namibia (except north and Kavango and Kunene rivers), South Africa (except Kruger and surroundings) Middle East and Central Asia Afghanistan, Saudi Arabia, Azerbaijan, Bhutan, Iran, Iraq, Kyrgyzstan, Yemen
Sub-Saharan Africa Zanzibar, Mafia, Djibouti
North Africa Egypt, Algeria, Cape Verde Sub-Saharan Africa Angola, Benin, Burkina Faso, Burundi, Cameroon, Chad, Comoros, Congo, Ivory Coast, Eritrea, Ethiopia, Gabon, Gambia, Ghana, Guinea, Guinea Bissau, Equatorial Guinea, Kenya, Liberia, Madagascar, Malawi, Mali, Mozambique, Mauritania, Niger, Nigeria, Central Africana Republic, Dem. Rep. Congo, Rwanda, Sao Tome´ and Principe, Senegal, Sierra Leone, Somalia, Sudan, South Sudan, Tanzania (except Zanzibar), Togo, Uganda, Zambia, Zimbabwe
Europe Greece
Region
Table 2 Prevention recommendations by geographic area
No risk above 2,000 m
India (in central India, risk is slightly higher than in the north and south of the country) Sri Lanka 96 % P. vivax Pakistan 70 % P. vivax
No malaria in other areas
Armenia, Azerbaijan, Kazakhstan, Syria, Turkey, Iran, Irak: 100 % P. vivax Afghanistan 90 % P. vivax
Seasonal malaria: chemoprophylaxis recommended only November through April
Yes
D
E?D
C
Yes
Yes
D
Yes
D
D
Yes
Yes
C
E?D
Yes
Yes
C
Yes
Eritrea: risk under 2,000 m, no malaria in Asmara Ethiopia: risk under 2,000 m, no malaria in Addis Ababa Mauritania: minimal risk only in the southern part Kenya: risk under 2,000 m, no malaria in Nairobi Senegal: lower risk during the dry season: January–May Zimbabwe: malaria in areas under 1,200 m, mostly November–June (minimal risk in Harare and Bulawayo) No risk in Djibouti town: greater risk in the rest of the country, May–October
D
D
First choice
Yes
Yes
AB
Sporadic cases reported: minimal risk
Sporadic case of autochthonous malaria reported (Plasmodium vivax 100 %)
Notes
C
E?D
E?D
C
Second choice
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123 Yes
D
E?D
Yes
Low risk in the Amazon part of all these countries Venezuela minimal risk on the coast Peru: P. vivax only Argentina: rare cases (P. vivax) in north-west Paraguay: rare cases in the eastern part, October–May
C
D
Yes
Yes
No risk on the coast
Mexico: only in the southern areas, near the Guatemalan border P. vivax [ 85 % in all areas
E?D
C
E?D
C Chloroquine
C
Second choice
The reported are not compelling directions but, rather, a working track for recommending malaria prevention: the first choice is the suggested one, and the ‘‘second choice’’ is an acceptable option at the end of the due discussion between the traveller and health care worker, particularly in the case of contraindication or refusal (or request) of drugs, or in case the risk of infection is significantly increased or reduced by particular factors. However, the final recommendation in the individual case cannot be based on the culture, but on the experience and sensitivity of the individual operator A awareness, B bite prevention, C chemoprophylaxis, D immediate diagnosis, E stand-by emergency treatment
South America Argentina, Bolivia (except Amazon area), Brazil (coastal area South of Fortaleza), Colombia (except Amazon area), Ecuador (except Amazon area), Paraguay, Peru (except Amazon area), Venezuela (western part)
South America Guyana, French Guyana, Suriname South America Bolivia (Amazon area), Brazil (except coastal area South of Fortaleza), Colombia (Amazon area), Ecuador (Amazon area), Peru (Amazon area), Venezuela (eastern part)
Central America Belize, Costa Rica, El Salvador, Jamaica, Guatemala, Honduras, Mexico, Nicaragua, Panama, Dominican Republic (except border with Haiti)
C
Yes Yes
D
Yes
Haiti and Dominican Republic: P. falciparum 100 %, no chloroquine resistance
E?D
Yes
Chloroquine-resistant P. vivax reported P. knowlesi reported (sporadic)
C
Yes
Chloroquine-resistant P. vivax reported P. knowlesi reported (sporadic)
First choice
Myanmar, Cambodia (except Phnom Penh, Angkor Wat, Tonle Sap), Indonesia (Lombok, Sumba, Sumbaya, Timor, Flores, Moluccas, Irian Jaya), Laos (southern part), Thailand (border with Myanmar and Cambodia) South East Asia Brunei, Cambodia (Phnom Penh, Siem Reap, Tonle Sap), Philippines, Laos (northern part), Malaysia, Vietnam, Indonesia (except Lombok, Sumba, Sumbaya, Timor, Flores, Moluccas, Irian Jaya) South East Asia Singapore, Thailand (except border with Myanmar and Cambodia) Oceania Papua New Guinea, Solomon, Vanuatu Central America Haiti, Dominican Republic (border with Haiti)
AB
Notes
Region
Table 2 continued
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exactly the risk in travellers [10]: annual parasite incidence (API) is the number of cases diagnosed in a specific area and period of time (data are reported on the WHO website [11], and referring to this data is recommended), parasite rate (PR) is the number of prevalent cases in an area at a point in time and the entomological inoculation rate (EIR) is the number of infecting bites in a defined period of time. The WHO classifies malarial areas as high transmission areas (API C 1) or low transmission areas (API \ 1) [12]. For the purpose of this guideline, we preferred to consider three areas, on the basis of data and authors’ opinions available in the literature [10, 13, 14], although one limit of this classification is obviously the frequent non-correspondence of the two parameters: • •
•
High risk: destinations with incidence [10 cases/ 100,000 travellers and/or API [10/1,000 residents Low risk: destinations with incidence from 1 to 10 cases/100,000 travellers and/or API 1–10/1,000 residents Minimal risk: destinations with incidence \1 case/ 100,000 travellers and/or API \1/1,000 residents
‘‘A’’ and ‘‘B’’ are recommended for all areas at risk, whereas ‘‘C’’, ‘‘D’’ and ‘‘E’’ are considered according to the degree of risk. Chemoprophylaxis is generally recommended as the first choice for high-risk areas. Only in some areas and in
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some cases (e.g. contraindication of drugs, traveller refusing pills or the risk is greatly reduced by particular circumstances) are early diagnosis and stand-by treatment possible second choices (Table 2; Fig. 1). Diagnosis and stand-by treatment are the first choices for low-risk areas, and chemoprophylaxis is prescribed as a second choice, if requested by the traveller, if severe underlying conditions exist, or if the risk is increased by additional factors (Table 2; Fig. 1). For minimal-risk areas, only seeking immediate diagnosis in case of fever is recommended. Plasmodium vivax Chemoprophylaxis is almost ineffective against P. vivax, since none of the currently used drugs kills liver hypnozoites, and, consequently, none prevent relapses. The frequency of relapse occurrence is greatly variable (0–100 % in different series) [15]. For this reason, we believe that only an accurate vector protection and an early diagnosis must be recommended in areas where P. vivax is the only or greatly predominant species. However, all other risk factors must be taken into account (API, underlying conditions, contraindications or refusal of vector protection), in order to adapt recommendations to the individual traveller.
Chemoprophylaxis recommended. Chemoprophylaxis recommended (with some limitations). Stand-by emergency treatment and/or early diagnosis recommended. (Modified from: Gething et al. A new world malaria map: Plasmodium falciparum endemicity in 2010. Malaria Journal 2011, 10:378 http://www.malariajournal.com/content/10/1/378).
Fig. 1 First-choice recommendations for malaria prophylaxis, according to geographic areas. Red chemoprophylaxis recommended. Yellow chemoprophylaxis recommended (with some limitations). Green stand-by emergency treatment and/or early diagnosis recommended
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Bite prevention
Malaria chemoprophylaxis
Insect bite prevention is based on behaviour (avoiding exposure between dusk and dawn, protective clothes etc.), chemical protection (repellents and insecticides), mechanical protection (window screens and bed nets) and combined chemical–mechanical protection (impregnated bed nets and clothes) [16]. Bite prevention is particularly recommended in case of P. vivax risk and no chemoprophylaxis. Suggestions for the choice of different tools on the basis of area and type of stay are reported in Table 3. Pursuant to the Italian ‘‘Istituto Superiore di Sanita`’’ recommendations, repellents should not be used in children under 2 years of age and may be used at a 10 % concentration in 2–12-year-old children. Over 12 years of age, N,N-diethyl-meta-toluamide (DEET) may be used at up to 30 % concentration (once daily), icaridin up to 35 % (once daily) and citriodiol up to 40 % (four times daily). During pregnancy, citriodiol may be used at up to 20 % concentration twice daily, whereas both DEET and icaridin should be avoided.
Malaria chemoprophylaxis is an effective evidence-based prevention tool [17]. Nonetheless, currently used medications have side effects, and must be used when their benefits outweigh the possible toxicity. Among drugs currently used in malaria chemoprophylaxis, the following ones are available in the Italian pharmacopeia. •
• • •
Atovaquone–proguanil 250/100 mg/day (1 day prior to entering the risk area, during stay and 7 days afterwards) Chloroquine, 300 mg/week (2 weeks prior to entering the risk area, during stay and 4 weeks afterwards) Doxycycline 100 mg/day (1 day prior to entering the risk area, during stay and 28 days afterwards) Mefloquine, 150 mg/week (2 weeks prior to entering the risk area, during stay and 4 weeks afterwards)
Atovaquone–proguanil in travellers under 40 kg body weight and doxycycline in all cases must be prescribed offlabel in this country.
Table 3 Vector protection recommendations by area and type of travel (any repellent when no active ingredient is stated) Type of travel and activity-risk of bite exposure
Malaria risk Minimal
Low–medium
High
Behaviour
Behaviour
Behaviour
Repellents for night exposure (10–15 %); avoid daily use for [1-month stays
Repellents for night exposure (20 %) Accurate accommodation inspection (and spraying if needs be)
Repellents (DEET or icaridin 20–30 %) Daily insecticide room spraying
Tourism (1–3 weeks): partly in experienced area, but some stay in remote area
Behaviour
Behaviour
Behaviour
Repellents for night exposure (10 %)
Repellents (DEET or icaridin 20–30 %)
Repellents (DEET or icaridin 20–30 %)
Work: accommodation quality uncertain
Occasional insecticide room spraying
Daily insecticide room spraying
Daily insecticide room spraying
Behaviour
Behaviour
Behaviour
Repellents for night exposure (20 %)
Repellents for night exposure (DEET or icaridin 20–30 %)
Repellents (DEET or icaridin 30 %)
Insecticide room spraying
Insecticide room spraying
Daily insecticide room spraying
Bed net
Bed net
Impregnated bed nets
Behaviour
Behaviour
Behaviour
Repellents for night exposure (20 %). For long stays, avoid daily use
Repellents for night exposure (20–30 %). For long stays, avoid daily use
Repellents for night exposure ([30 %). For long stays, avoid daily use
Window screens when possible
Window screens when possible
Impregnated bed nets
Low risk Tourism (1–3 weeks): experienced area, safe accommodation Work: (regardless of duration) both rural and urban area, safe accommodation Uncertain
Bed net
High risk Tourism (1–3 weeks): adventure travel, possible unsafe accommodation, night exposure
Work: both short and long stays. Temporary residents, missionaries, volunteers, health care workers, troops
Impregnated uniforms (troops) In the evaluation of malaria risk, not only the geographic area but also the type of area (urban/rural), altitude and season must be taken into account
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Only atovaquone–proguanil has a causal effect (activity on exo-erythrocytic stages of plasmodia), and none of the drugs is effective on hypnozoites. Consequently, malaria chemoprophylaxis cannot prevent P. vivax relapses [18], and, therefore, is not currently recommended for exclusive P. vivax areas. Drug choice The first criterion for drug choice is resistance to antimalarials in the destination area. Chloroquine is still effective on Plasmodium falciparum only in limited areas, and is the drug of choice only in Haiti and Dominican Republic. The association chloroquine–proguanil can no longer be recommended in areas of chloroquine resistance. Furthermore, proguanil is not available in Italy. In some areas of South-East Asia (Thailand-Myanmar and Thailand-Cambodian border), mefloquine resistance is widespread; consequently, this drug must not be used in these settings. In all other areas, atovaquone–proguanil, doxycycline and mefloquine can be used. These three regimens demonstrate similarly effectiveness (92–95 % protection). The presence of contraindications or previous experiences of the traveller with chemoprophylaxis and its side effects can guide the choice. In non-experienced travellers, atovaquone–proguanil may be the first choice, since it has proved to be significantly more tolerable in a recent meta-analysis; doxycycline has fewer neuropsychiatric side effects than mefloquine [19]. Finally, the regimen choice may be based on its convenience or cost [6, 20].
Diagnosis In case of onset of fever while staying in malaria-endemic areas (with the exception of the first 7 days, because of the incubation period of the disease), medical assistance must be sought within 24 h. A thin or thick blood film is the test of choice and is widely available in endemic countries. Malaria must be suspected also if fever occurs in the first 3 months after the travel [21]. The results of the test must be provided within 2 h and must include, if positive, the diagnosis of species and the parasitised cells count. Rapid diagnostic tests for Plasmodium antigen detection are widely available (dipsticks or cassette format), but are not currently recommended for self-diagnosis by inexperienced travellers. Immediate medical advice must also be sought in case of fever during chemoprophylaxis. If malaria is diagnosed, a proper treatment with a different drug must be given, but chemoprophylaxis must not be withdrawn.
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Stand-by emergency treatment Carrying drugs for stand-by emergency treatment can be recommended to those who travel in low-risks area and do not take chemoprophylaxis. In case of onset of fever, presenting at least 7 days after entering the malarial area and if medical advice is not available, one course of treatment can be taken as a temporary alternative to diagnosis. However, seeking medical advice as soon as possible is always recommended. A course of stand-by treatment may be assumed in case of fever also by travellers to remote areas taking chemoprophylaxis. Thereafter, chemoprophylaxis must not be withdrawn and medical advice must be sought. Two drug regimens for malaria stand-by treatment are currently available in Italy: dihydroartemisinin/piperaquine (once daily for 3 days; daily dose for children 5–6 kg: 80/10 mg, 7–12 kg: 160/20 mg, 13–24 kg: 1 tablet 320/40 mg, 25–36 kg: 2 tablets; 36–74 kg: 3 tablets, 75–100 kg: 4 tablets) and atovaquone–proguanil (once daily for 3 days; children 5–8 kg: 2 paediatric tablets, 9–10 kg: 3 paediatric tablets, 11–20 kg: 1 adult tablet, 21–30 kg: 2 adult tablets, 31–40 kg: 3 adult tablets, C41 kg: 4 adult tablets).
Recommendations for malaria prevention according to geographic areas Endemic areas for malaria have been classified into macrozones, and preventive measures recommended for every zone have been reported (Table 2). The same recommendation has been schematically plotted in the map (Fig. 1), which also reports the levels of malaria endemicity, according to the P. falciparum parasite rate (PfPR) [22]. Reported recommendations constitute a general guideline, but malaria risk may vary within an individual country or area, and for some destinations, more detailed information about the itinerary are necessary. Access to databases or local information may be helpful for individual prescribing decisions.
Special groups Pregnancy and breastfeeding During pregnancy and the post-partum period, the risk of developing severe and complicated malaria is higher [23], with increased risk of abortion or stillbirth, mostly in nonimmune women [1]. For this reason, avoiding travel in endemic areas is recommended to all pregnant women or whenever pregnancy is suspected, particularly in chloroquine-resistant P. falciparum areas.
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If travel cannot be postponed, using insect repellents in appropriate doses is recommended [24]. Chemoprophylaxis is recommended in high-risk areas, according to pregnancy period and Plasmodium sensitivity.
•
•
Newborns, children, and adolescents
•
•
•
Chloroquine. This drug is safe for the mother and for the foetus, and is recommended in chloroquine-sensitive P. falciparum areas. Mefloquine. This drug is recommended in pregnancy (second and third trimesters) for chloroquine-resistant P. falciparum areas. Limited data suggest that it is also safe in the first trimester [25, 26], but a careful evaluation of risk and benefit is mandatory in this case: as a general rule, the use of mefloquine may be recommended in case of very high malaria risk. Atovaquone–proguanil. Due to the lack of data about its safety in pregnancy, this drug is not recommended in pregnant women. It may be considered in case of very high malaria risk, and mefloquine intolerance or contraindication [1, 25, 27, 28]. Doxycycline. This drug is contraindicated in pregnancy [1, 25, 27].
Stand-by treatment In case of suspected malaria in pregnancy, immediate medical advice must be sought. If this is not possible within 24 h from the onset of symptoms, an antimalarial drug must be taken as stand-by emergency treatment. Quinine is the drug of choice, and mefloquine may be used in the second and third trimesters. Atovaquone–proguanil has been used safely, but data are very limited [25]. The combination dihydroartemisinin–piperaquine is contraindicated so far. Chemoprophylaxis prior to conception Waiting some time before attempting to conceive is advised after completing malaria chemoprophylaxis with mefloquine (3 months), doxycycline (1 week) or atovaquone–proguanil (3 weeks) [1]. Breastfeeding Antimalarial medications are retrieved in milk in very low concentrations, so they are not considered harmful to the child. On the other hand, they are not sufficient to provide the child with antimalarial protection: he/she must take his/ her own chemoprophylaxis if indicated. • •
Chloroquine and mefloquine are safe during breastfeeding Doxycycline is contraindicated, but many experts consider adverse events to be very unlikely [1, 3]
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Atovaquone–proguanil may be used only if the child has a body weight over 5 kg [27], since no data are currently available regarding smaller children
Travelling in malaria-endemic countries, particularly if chloroquine-resistant P. falciparum is present, is not recommended to newborns and children, since they are more prone to severe and complicated malaria [7]. In case of unavoidable travel, adequate insect bite protection is mandatory (DEET and icaridin 10 % in children over 2 years of age). • • •
•
Chloroquine drug is recommended for children of any age, with a dosage of 5 mg/kg/week Mefloquine is recommended above 5 kg body weight, at a dose of 5 mg/kg/week Atovaquone–proguanil is recommended for children C11 kg. Dosage: 11–20 kg, 1 paediatric tablet; 21–30 kg: 2 paediatric tablets; 31–40 kg: 3 paediatric tablets. Prescription in these cases is off-label in this country Doxycycline is recommended in children C8 years old. Dosage 1.5 mg/kg/day
Short-term travel There is no minimum period for recommending prophylaxis, and general advice also applies to short stays. However, in the case of particularly low risk (e.g. urban area, dry season, protected environment etc.), a careful balance of the risks and benefits of using drugs must be made. Short and repeated travel Travellers who enter malaria-endemic areas frequently for short stays (e.g. air crew or business persons) must carefully protect themselves against mosquito bites, and may use prophylaxis only in case of very high risk. Carrying medications for stand-by emergency treatment and promptly seeking medical advice in case of unexplained fever after returning home is suggested. Long-term travellers People staying in malaria-endemic countries for more than 6 months are defined as, for the purpose of this document, long-term travellers [5, 27]. In this group, the significant drop in adherence to chemoprophylaxis after the first few months [29] and possibly limited indications for some
New Italian guidelines for malaria prophylaxis
drugs are the main problems. However, the risk of malaria is proportional to the duration of stay, whereas the risk of new side effects decreases over time. The prescribing decision must be based on multiple factors, including seasonal risk, availability of health care facilities and health conditions of the traveller. Careful insect bite protection is always recommended. As a general rule, chemoprophylaxis is recommended for up to 6 months of stay. For longer stays, it can be recommended for the initial period or during periods of maximum transmission (i.e. wet seasons). Chloroquine may be used for a long time, but an ophthalmic consultation must be sought every 6 months after 6 years of use. Mefloquine has not shown additional side effects up to 3 years. Atovaquone–proguanil has been tested for 3 months in residents in endemic areas, and for a median of 28 days in travellers; limited data suggest that it may be used for up to 1 year. Doxycycline may be used safely for up to 2 years [5]. Visiting friends and relatives (VFRs) Immigrants and previous immigrants from malaria-endemic countries to Europe, including their children born in non-endemic areas, constitute the main risk group for imported malaria in Italy [30]. Their proportion among malaria cases is increasing over time, as is the severity of the disease, along with their loss of immunity [31]. Both accessibility of travel clinics and VFRs’ awareness about malaria severity and risk in adults and children must be improved [32]. Measures of protection against vectors must be explained, and benefits of chemoprophylaxis must be highlighted. Sometimes, the cost of chemoprophylaxis may be an issue in such travellers, and could entail an incomplete adherence to recommendations. In this case, choosing the cheapest regimen may be considered.
Travellers with underlying conditions
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• •
• •
Chloroquine has no documented interactions with warfarin Mefloquine probably has no interaction, but starting prophylaxis 2–3 weeks in advance and checking the INR is recommended Doxycycline may reduce the effect of anticoagulants [33] Atovaquone–proguanil: proguanil increases the anticoagulant effect of warfarin, but no adverse effects have been reported [3, 5, 28]
Glucose-6-phosphate dehydrogenase (G6PD) deficiency G6PD deficiency entails the risk of haemolysis when assuming particular drugs. Chloroquine has a theoretical risk of haemolysis, but this does not seem to be a problem at prophylactic dosage [5]. No risk of haemolysis has been identified with mefloquine, atovaquone–proguanil and doxycycline. Immune deficiency These patients are more prone to severe malaria: vector protection and chemoprophylaxis, as well as immediate diagnosis, are particularly important. HIV/AIDS Malaria can cause an increase in viral load in HIV patients, and possibly a progression of the disease. Antimalarial drugs may have interactions with antiretrovirals, and reduce or increase their activity: single interactions must be checked before recommending chemoprophylaxis [34]. HIV-infected pregnant women may have a higher parasitaemia, anaemia and placental colonisation by plasmodia, such that they may deliver low-weight children. Malaria also increases the HIV transmission rate to the child [5, 35].
Epilepsy Immune-suppressed patients Chloroquine and mefloquine are contraindicated in epileptic patients. Doxycycline may reduce the concentration of phenytoin, carbamazepine and barbiturates: their blood level must be checked after starting chemoprophylaxis [5]. Anticoagulant therapy Travellers must check their international normalised ratio (INR) before leaving their home country, as well as during long stays and after stopping chemoprophylaxis.
Patients under treatment with steroids, alkylating agents, cancer chemotherapy, TNF inhibitors, and transplanted patients assuming ciclosporin, tacrolimus, sirolimus, mycophenolate mofetil and mitoxantrone, particularly need correct information on malaria prevention for the possible increased severity of this disease and worsening of the underlying condition. Possible drug interactions must also be previously checked (e.g. chloroquine and ciclosporin).
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Splenectomised
Obesity
The risk of severe malaria is increased in asplenic and splenectomised patients, and they should avoid malariaendemic countries. If travel is unavoidable, a careful vector protection, a correct chemoprophylaxis and a particularly rapid diagnosis of fever episodes are mandatory.
No specific data are available in overweight patients [38]. An increased dosage of mefloquine (1.5 tablets/week if over 90 kg and 2 tablets over 120 kg) has been suggested [4]. No information is available for other drugs.
Liver disease The severity of liver disease must be evaluated prior to travelling; in case of liver failure, all antimalarial drugs are contraindicated and travelling should be avoided. •
• •
Severe liver disease: all antimalarial drugs are contraindicated, except for atovaquone–proguanil; no data about using precautions or adapting the regimen of this drug are available [5] Moderate liver disease: atovaquone–proguanil and mefloquine are suitable Mild liver disease: chloroquine, atovaquone–proguanil or mefloquine may be used. Caution is necessary when using doxycycline
Renal failure • •
•
Chloroquine: partially excreted via the kidneys: in case of severe liver failure, the dosage must be reduced Atovaquone–proguanil: proguanil is totally excreted via the kidneys, and is contraindicated in patients with creatinine clearance \30 ml/min and in patients undergoing haemodialysis [5, 33] Mefloquine and doxycycline are metabolised by the liver, and can be used by patients with severe renal failure. Dosage must not be adapted in case of haemodialysis [5, 33]
Severe heart disease Mefloquine is not recommended in case of heart conduction disorders. Concurrent cardio-active drugs, particularly beta-blockers, must be administered with caution [36].
Medications not available in Italy In some guidelines as well as in the literature, antimalarial drugs which are not available in Italy may be suggested. Although not recommended in this country, they are mentioned here for their importance. Purchasing these drugs in many countries in Africa or Asia entails a significant risk of using poor-quality or fake drugs [39]. Primaquine Primaquine is the only antimalarial drug that is effective on liver forms including hypnozoites of P. vivax and Plasmodium ovale. It may be used either as primary prophylaxis for a short period in areas of prevalent P. vivax, being effective on P. falciparum too, or as terminal prophylaxis for 14 days, after any regimen of chemoprophylaxis, after leaving an area with P. vivax risk (in order to destroy liver hypnozoites). The daily dose is 30 mg in adults [18]. It may cause severe haemolysis in G6PD-deficient individuals, so this should be tested prior to its consumption. It is contraindicated in pregnancy and breastfeeding, since it can be dangerous in G6PD-deficient foetuses and newborns. Proguanil It has been recommended in association with chloroquine in several guidelines in chloroquine-resistant P. falciparum areas. Proguanil is registered but not currently marketed in Italy. The association chloroquine–proguanil is less effective and less tolerated than other antimalarials [19], but is safe in pregnancy, so it could be an option in mefloquineintolerant women in drug resistance areas. The dosage for chloroquine is 300 mg/week and for proguanil, it is 200 mg/day.
Chronic malaria or hyper-reactive malarial splenomegaly
Artemether/lumefantrine
This particular malaria picture is mainly found in long-term expatriates, and is characterised by massive splenomegaly, increased IgM in serum and antimalarial antibodies. Being a risk factor for blackwater fever, continuous long-term chemoprophylaxis (mefloquine or, preferably, doxycycline) is mandatory in those who have had such a diagnosis [37].
It is a first-line treatment for non-complicated malaria pursuant to WHO guidelines [40], and is recommended for stand-by emergency treatment too. It is effective and well tolerated at a dose of four 20/120 mg tablets, twice daily for 3 days. There is a limited risk of QT prolongation during electrocardiography.
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New Italian guidelines for malaria prophylaxis Conflict of interest GC has received grants for speaking by SigmaTau; FC has acted as PI for a Sigma-Tau-sponsored trial; IEH, FG, AM, GN, RR, and AR declare no conflict of interest.
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249 19. Jacquerioz FA, Croft AM. Drugs for preventing malaria in travellers. Cochrane Database Syst Rev. 2009;(4):CD006491. 20. Genton B, D’Acremont V. Malaria prevention in travelers. Infect Dis Clin North Am. 2012;26:637–54. doi:10.1016/j.idc.2012.05. 003. 21. Askling HH, Bruneel F, Burchard G, Castelli F, Chiodini PL, Grobusch MP, Lopez-Ve´lez R, Paul M, Petersen E, Popescu C, Ramharter M, Schlagenhauf P; European Society for Clinical Microbiology and Infectious Diseases Study Group on Clinical Parasitology. Management of imported malaria in Europe. Malar J. 2012;11:328. doi:10.1186/1475-2875-11-328. 22. Gething PW, Patil AP, Smith DL, Guerra CA, Elyazar IR, Johnston GL, Tatem AJ, Hay SI. A new world malaria map: Plasmodium falciparum endemicity in 2010. Malar J. 2011;10:378. 23. Ramharter M, Grobusch MP, Kiessling G, Adegnika AA, Mo¨ller U, Agnandji ST, Kramer M, Schwarz N, Kun JF, Oyakhirome S, Issifou S, Borrmann S, Lell B, Mordmu¨ller B, Kremsner PG. Clinical and parasitological characteristics of puerperal malaria. J Infect Dis. 2005;191:1005–9. 24. McGready R, Ashley EA, Nosten F. Malaria and the pregnant traveller. Travel Med Infect Dis. 2004;2:127–42. 25. Royal College of Obstetricians and Gynaecologists. The prevention of malaria in pregnancy. Green-top guideline no. 54A. 2010. http://www.rcog.org.uk/files/rcog-corp/GTG54aPrevention MalariaPregnancy0410.pdf. 26. Schlagenhauf P, Blumentals WA, Suter P, Regep L, Vital-Durand G, Schaerer MT, Boutros MS, Rhein HG, Adamcova M. Pregnancy and fetal outcomes after exposure to mefloquine in the preand periconception period and during pregnancy. Clin Infect Dis. 2012;54:e124–31. 27. Schlagenhauf P, Petersen E. Malaria chemoprophylaxis: strategies for risk groups. Clin Microbiol Rev. 2008;21:466–72. 28. Matteelli A, Carvalho AC, Bigoni S. Visiting relatives and friends (VFR), pregnant, and other vulnerable travelers. Infect Dis Clin North Am. 2012;26:625–35. 29. Steffen R, Heusser R, Ma¨chler R, Bruppacher R, Naef U, Chen D, Hofmann AM, Somaini B. Malaria chemoprophylaxis among European tourists in tropical Africa: use, adverse reactions, and efficacy. Bull World Health Organ. 1990;68:313–22. 30. Romi R, Boccolini D, D’Amato S, Cenci C, Peragallo M, D’Ancona F, Pompa MG, Majori G. Incidence of malaria and risk factors in Italian travelers to malaria endemic countries. Travel Med Infect Dis. 2010;8:144–54. doi:10.1016/j.tmaid.2010.02. 001. 31. Mascarello M, Gobbi F, Angheben A, Concia E, Marocco S, Anselmi M, Monteiro G, Rossanese A, Bisoffi Z. Imported malaria in immigrants to Italy: a changing pattern observed in north eastern Italy. J Travel Med. 2009;16:317–21. 32. Scolari C, Tedoldi S, Casalini C, Scarcella C, Matteelli A, Casari S, El Hamad I, Castelli F. Knowledge, attitudes, and practices on malaria preventive measures of migrants attending a public health clinic in northern Italy. J Travel Med. 2002;9:160–2. 33. Joint Formulary Committee. British National Formulary. London: British Medical Association and Royal Pharmaceutical Society of Great Britain; 2006. 34. Castelli F, Patroni A. The human immunodeficiency virusinfected traveler. Clin Infect Dis. 2000;31:1403–8. 35. World Health Organization (WHO). Standards for maternal and neonatal care. Geneva: WHO; 2004. 36. Abecasis J, Dores H, Arroja I, Santos JM, Silva A. Travelers on beta-blockers: is malaria chemoprophylaxis dangerous? Rev Port Cardiol. 2009;28:1153–9. 37. Steketee RW, Nahlen BL, Parise ME, Menendez C. The burden of malaria in pregnancy in malaria-endemic areas. Am J Trop Med Hyg. 2001;64:28–35.
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GUIDELINE
New Italian guidelines for malaria prophylaxis in travellers to endemic areas G. Calleri • F. Castelli • I. El Hamad • F. Gobbi • A. Matteelli • G. Napoletano R. Romi • A. Rossanese
•
Received: 5 September 2013 / Accepted: 14 November 2013 / Published online: 18 December 2013 Springer-Verlag Berlin Heidelberg 2013
Abstract Background and Methods As a consequence of the rapid evolution of malaria prophylaxis recommendations throughout the world, the Italian Society of Tropical Medicine (SIMET—Societa` Italiana di Medicina Tropicale) has set up a working group in charge of preparing a new national guideline. Other scientific societies interested in the topic were also involved in the project. Results and Conclusions The group stated that awareness about malaria risk and characteristics, as well as protection from mosquito bites, are recommended for all travellers visiting malaria-endemic countries. The risk and benefit of malaria chemoprophylaxis must be carefully balanced
G. Calleri (&) Travel Medicine Unit, Department of Infectious Diseases, Amedeo di Savoia Hospital, Turin, Italy e-mail: [email protected] F. Castelli A. Matteelli University Division of Infectious and Tropical Diseases, University of Brescia and Spedali Civili General Hospital, Brescia, Italy
before prescribing drugs: the disease-related risk must outweigh the possibility of drugs’ side effects. As a general rule, malaria pills are the first choice for travellers to highrisk areas, such as sub-Saharan Africa, Eastern India, Myanmar, Eastern Indonesia, Papua New Guinea and, with some limitations, South-East Asia, and the Amazon part of Venezuela, Guyana and French Guyana. However, several other factors, such as itinerary, season, duration of trip, availability of insect bite protection, pre-existing conditions and compliance, must be taken into account. In lowrisk areas, stand-by emergency treatment is the first option. In minimal-risk areas and in Plasmodium vivax areas, a prompt diagnosis only is advised (Central America, South America outside the Amazon basin, Middle East, China, Thailand, Nepal). Recommendations may be modified when particular groups of travellers are concerned, such as long-term residents, visiting friends and relatives, patients with pre-existing conditions, pregnant women and children. Keywords Malaria Prophylaxis Guidelines Travel medicine Insect bite prevention SIMET Background
I. El Hamad Department of Infectious Diseases, Spedali Civili General Hospital, Brescia, Italy F. Gobbi A. Rossanese Centre for Tropical Diseases, Sacro-Cuore Hospital, Negrar, Verona, Italy G. Napoletano Travel Diseases Prevention Unit, Department of Prevention, ULSS 20, Verona, Italy R. Romi Department of Infectious, Parasitic and Immune-Mediated Diseases, Istituto Superiore di Sanita`, Rome, Italy
In recent years, malaria prevention guidelines have seen a rapid evolution, moving from a basic risk approach (‘‘recommend prophylaxis whenever the risk is there’’) to a risk/benefit approach (balancing the risk of disease and drugs’ side effects). All national and international guidelines have moved in different degrees from a rigid recommendation of chemoprophylaxis to a greater use of other prevention systems (protection against vectors, early diagnosis, stand-by treatment), but this has led to a wider range of recommendations [1–5] and professionals in different countries seem to give different advice [6].
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Methods In early 2012, a specific working group on malaria prophylaxis was set up by the Italian Society of Tropical Medicine (SIMET—Societa` Italiana di Medicina Tropicale), in order to revise the national guideline for malaria prophylaxis, which had been last published in 2003 [7]. The group was composed of eight professionals in the field of tropical and travel medicine, representing different scientific societies interested in the topic of malaria prevention: SIMET itself, ‘‘Societa` Italiana di Malattie Infettive’’ (SIMIT), ‘‘Societa` Italiana di Medicina dei Viaggi’’ (SIMVIM), ‘‘Societa` Italiana di Medicina delle Migrazioni’’ (SIMM), ‘‘Societa` Italiana di Parassitologia’’ (SoIPa) and ‘‘Societa` Italiana di Igiene’’ (SItI). The discussion among the group developed mainly online, and several meetings were organised to discuss face-to-face the main issues. Firstly, the main controversial aspects of malaria prophylaxis, named ‘‘grey areas’’, were identified, and two rounds of discussion via online questionnaires were made within the group, according to the ‘‘Delphi method’’, a consensus development approach which has recently been experimented in this field [6, 8]. Secondly, the topic was split into different sections (Introduction, Vector protection, Chemoprophylaxis, Diagnosis and stand-by treatment, Recommendations in different areas, Special groups) and each member of the working group prepared a draft of one section. Subsequently, all drafts were examined and discussed in a meeting held in November 2012, so that a consensus was reached on all topics. A comprehensive draft was then prepared, further discussed online and finally approved on 28/1/2013. The final manuscript has been endorsed by the six scientific societies which participated in this project, and by the ‘‘Societa` Italiana di Medicina Generale’’ (SIMG). The main basis of the work was the best available evidence. Due to the scarcity of data in this field, existing guidelines as well as the opinion of experts have also been exploited. The starting point of the discussion was the double aspect of prevention practice: avoiding the disease-related risk and the possible harm of interventions. Thus, the choice of one prevention system must be based on a careful risk/benefit balance: on the one side, the efficacy and side effects of preventive measures, particularly drugs; on the other side, the probability and the severity of the disease. The guidelines are mainly addressed to travel medicine professionals, specialists in infectious diseases and in travel and migration medicine, general practitioners and nurses, who give information to travellers from Italy to malariaendemic countries. This document does not contain compelling directions but is, rather, aimed at providing a
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working track for recommending malaria prevention. However, the final decision in each individual case cannot be based on the culture, but on the experience and sensitivity of the individual operator.
‘‘ABCDE’’ of malaria protection The World Health Organization (WHO) states the so-called ‘‘ABCD of malaria’’ as a basis for protection against the disease [1]: A = awareness, B = bite prevention, C = chemoprophylaxis, D = diagnosis. A fifth point ‘‘E’’, for emergency stand-by treatment, may be added. ‘‘A’’ is the first step: everyone travelling in a malariaendemic area must be aware of the risk and be informed about the characteristics of the disease, in order to protect himself or herself by using the available tools and seek prompt medical advice in case of need. The quality of counselling is paramount in this perspective [9]. The main sources of information are reported in Table 1. The quantification of malaria risk is of primary importance, but is not always easy. Data about the risk in travellers should be preferred (cases of malaria/100,000 travellers), but are seldom available, mainly because of the lack of information about the total number of travellers, to be used as a denominator of incidence rates, or because many areas are visited by few travellers. In this case, various indexes of frequency in the resident population may be used, although they do not reflect Table 1 Information sources for travel medicine professionals Risk assessment: WHO International Travel and Health http://www.who.int/ith/ chapters/ith2012en_countrylist.pdf WHO, API http://www.who.int/malaria/publications/countryprofiles Malaria Atlas Project http://www.map.ox.ac.uk MARA Collaboration http://www.mara.org.za CDC Yellow Book http://wwwnc.cdc.gov/travel/yellowbook/ 2012/chapter-3-infectious-diseases-related-to-travel/yellowfever-and-malaria-information-by-country.htm WHO guidelines: http://www.who.int/ith/en/ National guidelines: Chiodini et al. [5] (http://www.hpa.org.uk/webc/HPAwebFile/ HPAweb_C/1203496943523) Deutsche Gesellschaft fu¨r Tropenmedizin und Internationale Gesundheit (DTG) [4] (http://www.dtg.org/uploads/media/ Malaria_2012_01.pdf) Haut Conseil de la Sante´ Publique [2] (http://www.sante.gouv.fr/ IMG/pdf/Recommandations_sanitaires_pour_les_voyageurs_ 2012.pdf) Centers for Disease Control and Prevention (CDC) [3] (http:// wwwnc.cdc.gov/travel/destinations/list.htm)
Asia Indian subcontinent Nepal (except Terai) South East Asia
Asia China (Hainan, Yunnan, Anhui, Henan, Hubei, Huizhou, Jiangsu) Asia Indian subcontinent Bangladesh (Chittagong area), India (Assam and Orissa, in particular, monsoon season) Asia Indian subcontinent Bangladesh (except Chittagong area), India (except Assam and Orissa), Nepal (Terai), Pakistan, Sri Lanka
Austral Africa Botswana (north), Namibia (north and Kavango and Kunene rivers), South Africa (Kruger and surroundings), Swaziland Austral Africa Botswana (except north), Namibia (except north and Kavango and Kunene rivers), South Africa (except Kruger and surroundings) Middle East and Central Asia Afghanistan, Saudi Arabia, Azerbaijan, Bhutan, Iran, Iraq, Kyrgyzstan, Yemen
Sub-Saharan Africa Zanzibar, Mafia, Djibouti
North Africa Egypt, Algeria, Cape Verde Sub-Saharan Africa Angola, Benin, Burkina Faso, Burundi, Cameroon, Chad, Comoros, Congo, Ivory Coast, Eritrea, Ethiopia, Gabon, Gambia, Ghana, Guinea, Guinea Bissau, Equatorial Guinea, Kenya, Liberia, Madagascar, Malawi, Mali, Mozambique, Mauritania, Niger, Nigeria, Central Africana Republic, Dem. Rep. Congo, Rwanda, Sao Tome´ and Principe, Senegal, Sierra Leone, Somalia, Sudan, South Sudan, Tanzania (except Zanzibar), Togo, Uganda, Zambia, Zimbabwe
Europe Greece
Region
Table 2 Prevention recommendations by geographic area
No risk above 2,000 m
India (in central India, risk is slightly higher than in the north and south of the country) Sri Lanka 96 % P. vivax Pakistan 70 % P. vivax
No malaria in other areas
Armenia, Azerbaijan, Kazakhstan, Syria, Turkey, Iran, Irak: 100 % P. vivax Afghanistan 90 % P. vivax
Seasonal malaria: chemoprophylaxis recommended only November through April
Yes
D
E?D
C
Yes
Yes
D
Yes
D
D
Yes
Yes
C
E?D
Yes
Yes
C
Yes
Eritrea: risk under 2,000 m, no malaria in Asmara Ethiopia: risk under 2,000 m, no malaria in Addis Ababa Mauritania: minimal risk only in the southern part Kenya: risk under 2,000 m, no malaria in Nairobi Senegal: lower risk during the dry season: January–May Zimbabwe: malaria in areas under 1,200 m, mostly November–June (minimal risk in Harare and Bulawayo) No risk in Djibouti town: greater risk in the rest of the country, May–October
D
D
First choice
Yes
Yes
AB
Sporadic cases reported: minimal risk
Sporadic case of autochthonous malaria reported (Plasmodium vivax 100 %)
Notes
C
E?D
E?D
C
Second choice
New Italian guidelines for malaria prophylaxis 241
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D
E?D
Yes
Low risk in the Amazon part of all these countries Venezuela minimal risk on the coast Peru: P. vivax only Argentina: rare cases (P. vivax) in north-west Paraguay: rare cases in the eastern part, October–May
C
D
Yes
Yes
No risk on the coast
Mexico: only in the southern areas, near the Guatemalan border P. vivax [ 85 % in all areas
E?D
C
E?D
C Chloroquine
C
Second choice
The reported are not compelling directions but, rather, a working track for recommending malaria prevention: the first choice is the suggested one, and the ‘‘second choice’’ is an acceptable option at the end of the due discussion between the traveller and health care worker, particularly in the case of contraindication or refusal (or request) of drugs, or in case the risk of infection is significantly increased or reduced by particular factors. However, the final recommendation in the individual case cannot be based on the culture, but on the experience and sensitivity of the individual operator A awareness, B bite prevention, C chemoprophylaxis, D immediate diagnosis, E stand-by emergency treatment
South America Argentina, Bolivia (except Amazon area), Brazil (coastal area South of Fortaleza), Colombia (except Amazon area), Ecuador (except Amazon area), Paraguay, Peru (except Amazon area), Venezuela (western part)
South America Guyana, French Guyana, Suriname South America Bolivia (Amazon area), Brazil (except coastal area South of Fortaleza), Colombia (Amazon area), Ecuador (Amazon area), Peru (Amazon area), Venezuela (eastern part)
Central America Belize, Costa Rica, El Salvador, Jamaica, Guatemala, Honduras, Mexico, Nicaragua, Panama, Dominican Republic (except border with Haiti)
C
Yes Yes
D
Yes
Haiti and Dominican Republic: P. falciparum 100 %, no chloroquine resistance
E?D
Yes
Chloroquine-resistant P. vivax reported P. knowlesi reported (sporadic)
C
Yes
Chloroquine-resistant P. vivax reported P. knowlesi reported (sporadic)
First choice
Myanmar, Cambodia (except Phnom Penh, Angkor Wat, Tonle Sap), Indonesia (Lombok, Sumba, Sumbaya, Timor, Flores, Moluccas, Irian Jaya), Laos (southern part), Thailand (border with Myanmar and Cambodia) South East Asia Brunei, Cambodia (Phnom Penh, Siem Reap, Tonle Sap), Philippines, Laos (northern part), Malaysia, Vietnam, Indonesia (except Lombok, Sumba, Sumbaya, Timor, Flores, Moluccas, Irian Jaya) South East Asia Singapore, Thailand (except border with Myanmar and Cambodia) Oceania Papua New Guinea, Solomon, Vanuatu Central America Haiti, Dominican Republic (border with Haiti)
AB
Notes
Region
Table 2 continued
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exactly the risk in travellers [10]: annual parasite incidence (API) is the number of cases diagnosed in a specific area and period of time (data are reported on the WHO website [11], and referring to this data is recommended), parasite rate (PR) is the number of prevalent cases in an area at a point in time and the entomological inoculation rate (EIR) is the number of infecting bites in a defined period of time. The WHO classifies malarial areas as high transmission areas (API C 1) or low transmission areas (API \ 1) [12]. For the purpose of this guideline, we preferred to consider three areas, on the basis of data and authors’ opinions available in the literature [10, 13, 14], although one limit of this classification is obviously the frequent non-correspondence of the two parameters: • •
•
High risk: destinations with incidence [10 cases/ 100,000 travellers and/or API [10/1,000 residents Low risk: destinations with incidence from 1 to 10 cases/100,000 travellers and/or API 1–10/1,000 residents Minimal risk: destinations with incidence \1 case/ 100,000 travellers and/or API \1/1,000 residents
‘‘A’’ and ‘‘B’’ are recommended for all areas at risk, whereas ‘‘C’’, ‘‘D’’ and ‘‘E’’ are considered according to the degree of risk. Chemoprophylaxis is generally recommended as the first choice for high-risk areas. Only in some areas and in
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some cases (e.g. contraindication of drugs, traveller refusing pills or the risk is greatly reduced by particular circumstances) are early diagnosis and stand-by treatment possible second choices (Table 2; Fig. 1). Diagnosis and stand-by treatment are the first choices for low-risk areas, and chemoprophylaxis is prescribed as a second choice, if requested by the traveller, if severe underlying conditions exist, or if the risk is increased by additional factors (Table 2; Fig. 1). For minimal-risk areas, only seeking immediate diagnosis in case of fever is recommended. Plasmodium vivax Chemoprophylaxis is almost ineffective against P. vivax, since none of the currently used drugs kills liver hypnozoites, and, consequently, none prevent relapses. The frequency of relapse occurrence is greatly variable (0–100 % in different series) [15]. For this reason, we believe that only an accurate vector protection and an early diagnosis must be recommended in areas where P. vivax is the only or greatly predominant species. However, all other risk factors must be taken into account (API, underlying conditions, contraindications or refusal of vector protection), in order to adapt recommendations to the individual traveller.
Chemoprophylaxis recommended. Chemoprophylaxis recommended (with some limitations). Stand-by emergency treatment and/or early diagnosis recommended. (Modified from: Gething et al. A new world malaria map: Plasmodium falciparum endemicity in 2010. Malaria Journal 2011, 10:378 http://www.malariajournal.com/content/10/1/378).
Fig. 1 First-choice recommendations for malaria prophylaxis, according to geographic areas. Red chemoprophylaxis recommended. Yellow chemoprophylaxis recommended (with some limitations). Green stand-by emergency treatment and/or early diagnosis recommended
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Bite prevention
Malaria chemoprophylaxis
Insect bite prevention is based on behaviour (avoiding exposure between dusk and dawn, protective clothes etc.), chemical protection (repellents and insecticides), mechanical protection (window screens and bed nets) and combined chemical–mechanical protection (impregnated bed nets and clothes) [16]. Bite prevention is particularly recommended in case of P. vivax risk and no chemoprophylaxis. Suggestions for the choice of different tools on the basis of area and type of stay are reported in Table 3. Pursuant to the Italian ‘‘Istituto Superiore di Sanita`’’ recommendations, repellents should not be used in children under 2 years of age and may be used at a 10 % concentration in 2–12-year-old children. Over 12 years of age, N,N-diethyl-meta-toluamide (DEET) may be used at up to 30 % concentration (once daily), icaridin up to 35 % (once daily) and citriodiol up to 40 % (four times daily). During pregnancy, citriodiol may be used at up to 20 % concentration twice daily, whereas both DEET and icaridin should be avoided.
Malaria chemoprophylaxis is an effective evidence-based prevention tool [17]. Nonetheless, currently used medications have side effects, and must be used when their benefits outweigh the possible toxicity. Among drugs currently used in malaria chemoprophylaxis, the following ones are available in the Italian pharmacopeia. •
• • •
Atovaquone–proguanil 250/100 mg/day (1 day prior to entering the risk area, during stay and 7 days afterwards) Chloroquine, 300 mg/week (2 weeks prior to entering the risk area, during stay and 4 weeks afterwards) Doxycycline 100 mg/day (1 day prior to entering the risk area, during stay and 28 days afterwards) Mefloquine, 150 mg/week (2 weeks prior to entering the risk area, during stay and 4 weeks afterwards)
Atovaquone–proguanil in travellers under 40 kg body weight and doxycycline in all cases must be prescribed offlabel in this country.
Table 3 Vector protection recommendations by area and type of travel (any repellent when no active ingredient is stated) Type of travel and activity-risk of bite exposure
Malaria risk Minimal
Low–medium
High
Behaviour
Behaviour
Behaviour
Repellents for night exposure (10–15 %); avoid daily use for [1-month stays
Repellents for night exposure (20 %) Accurate accommodation inspection (and spraying if needs be)
Repellents (DEET or icaridin 20–30 %) Daily insecticide room spraying
Tourism (1–3 weeks): partly in experienced area, but some stay in remote area
Behaviour
Behaviour
Behaviour
Repellents for night exposure (10 %)
Repellents (DEET or icaridin 20–30 %)
Repellents (DEET or icaridin 20–30 %)
Work: accommodation quality uncertain
Occasional insecticide room spraying
Daily insecticide room spraying
Daily insecticide room spraying
Behaviour
Behaviour
Behaviour
Repellents for night exposure (20 %)
Repellents for night exposure (DEET or icaridin 20–30 %)
Repellents (DEET or icaridin 30 %)
Insecticide room spraying
Insecticide room spraying
Daily insecticide room spraying
Bed net
Bed net
Impregnated bed nets
Behaviour
Behaviour
Behaviour
Repellents for night exposure (20 %). For long stays, avoid daily use
Repellents for night exposure (20–30 %). For long stays, avoid daily use
Repellents for night exposure ([30 %). For long stays, avoid daily use
Window screens when possible
Window screens when possible
Impregnated bed nets
Low risk Tourism (1–3 weeks): experienced area, safe accommodation Work: (regardless of duration) both rural and urban area, safe accommodation Uncertain
Bed net
High risk Tourism (1–3 weeks): adventure travel, possible unsafe accommodation, night exposure
Work: both short and long stays. Temporary residents, missionaries, volunteers, health care workers, troops
Impregnated uniforms (troops) In the evaluation of malaria risk, not only the geographic area but also the type of area (urban/rural), altitude and season must be taken into account
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Only atovaquone–proguanil has a causal effect (activity on exo-erythrocytic stages of plasmodia), and none of the drugs is effective on hypnozoites. Consequently, malaria chemoprophylaxis cannot prevent P. vivax relapses [18], and, therefore, is not currently recommended for exclusive P. vivax areas. Drug choice The first criterion for drug choice is resistance to antimalarials in the destination area. Chloroquine is still effective on Plasmodium falciparum only in limited areas, and is the drug of choice only in Haiti and Dominican Republic. The association chloroquine–proguanil can no longer be recommended in areas of chloroquine resistance. Furthermore, proguanil is not available in Italy. In some areas of South-East Asia (Thailand-Myanmar and Thailand-Cambodian border), mefloquine resistance is widespread; consequently, this drug must not be used in these settings. In all other areas, atovaquone–proguanil, doxycycline and mefloquine can be used. These three regimens demonstrate similarly effectiveness (92–95 % protection). The presence of contraindications or previous experiences of the traveller with chemoprophylaxis and its side effects can guide the choice. In non-experienced travellers, atovaquone–proguanil may be the first choice, since it has proved to be significantly more tolerable in a recent meta-analysis; doxycycline has fewer neuropsychiatric side effects than mefloquine [19]. Finally, the regimen choice may be based on its convenience or cost [6, 20].
Diagnosis In case of onset of fever while staying in malaria-endemic areas (with the exception of the first 7 days, because of the incubation period of the disease), medical assistance must be sought within 24 h. A thin or thick blood film is the test of choice and is widely available in endemic countries. Malaria must be suspected also if fever occurs in the first 3 months after the travel [21]. The results of the test must be provided within 2 h and must include, if positive, the diagnosis of species and the parasitised cells count. Rapid diagnostic tests for Plasmodium antigen detection are widely available (dipsticks or cassette format), but are not currently recommended for self-diagnosis by inexperienced travellers. Immediate medical advice must also be sought in case of fever during chemoprophylaxis. If malaria is diagnosed, a proper treatment with a different drug must be given, but chemoprophylaxis must not be withdrawn.
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Stand-by emergency treatment Carrying drugs for stand-by emergency treatment can be recommended to those who travel in low-risks area and do not take chemoprophylaxis. In case of onset of fever, presenting at least 7 days after entering the malarial area and if medical advice is not available, one course of treatment can be taken as a temporary alternative to diagnosis. However, seeking medical advice as soon as possible is always recommended. A course of stand-by treatment may be assumed in case of fever also by travellers to remote areas taking chemoprophylaxis. Thereafter, chemoprophylaxis must not be withdrawn and medical advice must be sought. Two drug regimens for malaria stand-by treatment are currently available in Italy: dihydroartemisinin/piperaquine (once daily for 3 days; daily dose for children 5–6 kg: 80/10 mg, 7–12 kg: 160/20 mg, 13–24 kg: 1 tablet 320/40 mg, 25–36 kg: 2 tablets; 36–74 kg: 3 tablets, 75–100 kg: 4 tablets) and atovaquone–proguanil (once daily for 3 days; children 5–8 kg: 2 paediatric tablets, 9–10 kg: 3 paediatric tablets, 11–20 kg: 1 adult tablet, 21–30 kg: 2 adult tablets, 31–40 kg: 3 adult tablets, C41 kg: 4 adult tablets).
Recommendations for malaria prevention according to geographic areas Endemic areas for malaria have been classified into macrozones, and preventive measures recommended for every zone have been reported (Table 2). The same recommendation has been schematically plotted in the map (Fig. 1), which also reports the levels of malaria endemicity, according to the P. falciparum parasite rate (PfPR) [22]. Reported recommendations constitute a general guideline, but malaria risk may vary within an individual country or area, and for some destinations, more detailed information about the itinerary are necessary. Access to databases or local information may be helpful for individual prescribing decisions.
Special groups Pregnancy and breastfeeding During pregnancy and the post-partum period, the risk of developing severe and complicated malaria is higher [23], with increased risk of abortion or stillbirth, mostly in nonimmune women [1]. For this reason, avoiding travel in endemic areas is recommended to all pregnant women or whenever pregnancy is suspected, particularly in chloroquine-resistant P. falciparum areas.
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If travel cannot be postponed, using insect repellents in appropriate doses is recommended [24]. Chemoprophylaxis is recommended in high-risk areas, according to pregnancy period and Plasmodium sensitivity.
•
•
Newborns, children, and adolescents
•
•
•
Chloroquine. This drug is safe for the mother and for the foetus, and is recommended in chloroquine-sensitive P. falciparum areas. Mefloquine. This drug is recommended in pregnancy (second and third trimesters) for chloroquine-resistant P. falciparum areas. Limited data suggest that it is also safe in the first trimester [25, 26], but a careful evaluation of risk and benefit is mandatory in this case: as a general rule, the use of mefloquine may be recommended in case of very high malaria risk. Atovaquone–proguanil. Due to the lack of data about its safety in pregnancy, this drug is not recommended in pregnant women. It may be considered in case of very high malaria risk, and mefloquine intolerance or contraindication [1, 25, 27, 28]. Doxycycline. This drug is contraindicated in pregnancy [1, 25, 27].
Stand-by treatment In case of suspected malaria in pregnancy, immediate medical advice must be sought. If this is not possible within 24 h from the onset of symptoms, an antimalarial drug must be taken as stand-by emergency treatment. Quinine is the drug of choice, and mefloquine may be used in the second and third trimesters. Atovaquone–proguanil has been used safely, but data are very limited [25]. The combination dihydroartemisinin–piperaquine is contraindicated so far. Chemoprophylaxis prior to conception Waiting some time before attempting to conceive is advised after completing malaria chemoprophylaxis with mefloquine (3 months), doxycycline (1 week) or atovaquone–proguanil (3 weeks) [1]. Breastfeeding Antimalarial medications are retrieved in milk in very low concentrations, so they are not considered harmful to the child. On the other hand, they are not sufficient to provide the child with antimalarial protection: he/she must take his/ her own chemoprophylaxis if indicated. • •
Chloroquine and mefloquine are safe during breastfeeding Doxycycline is contraindicated, but many experts consider adverse events to be very unlikely [1, 3]
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Atovaquone–proguanil may be used only if the child has a body weight over 5 kg [27], since no data are currently available regarding smaller children
Travelling in malaria-endemic countries, particularly if chloroquine-resistant P. falciparum is present, is not recommended to newborns and children, since they are more prone to severe and complicated malaria [7]. In case of unavoidable travel, adequate insect bite protection is mandatory (DEET and icaridin 10 % in children over 2 years of age). • • •
•
Chloroquine drug is recommended for children of any age, with a dosage of 5 mg/kg/week Mefloquine is recommended above 5 kg body weight, at a dose of 5 mg/kg/week Atovaquone–proguanil is recommended for children C11 kg. Dosage: 11–20 kg, 1 paediatric tablet; 21–30 kg: 2 paediatric tablets; 31–40 kg: 3 paediatric tablets. Prescription in these cases is off-label in this country Doxycycline is recommended in children C8 years old. Dosage 1.5 mg/kg/day
Short-term travel There is no minimum period for recommending prophylaxis, and general advice also applies to short stays. However, in the case of particularly low risk (e.g. urban area, dry season, protected environment etc.), a careful balance of the risks and benefits of using drugs must be made. Short and repeated travel Travellers who enter malaria-endemic areas frequently for short stays (e.g. air crew or business persons) must carefully protect themselves against mosquito bites, and may use prophylaxis only in case of very high risk. Carrying medications for stand-by emergency treatment and promptly seeking medical advice in case of unexplained fever after returning home is suggested. Long-term travellers People staying in malaria-endemic countries for more than 6 months are defined as, for the purpose of this document, long-term travellers [5, 27]. In this group, the significant drop in adherence to chemoprophylaxis after the first few months [29] and possibly limited indications for some
New Italian guidelines for malaria prophylaxis
drugs are the main problems. However, the risk of malaria is proportional to the duration of stay, whereas the risk of new side effects decreases over time. The prescribing decision must be based on multiple factors, including seasonal risk, availability of health care facilities and health conditions of the traveller. Careful insect bite protection is always recommended. As a general rule, chemoprophylaxis is recommended for up to 6 months of stay. For longer stays, it can be recommended for the initial period or during periods of maximum transmission (i.e. wet seasons). Chloroquine may be used for a long time, but an ophthalmic consultation must be sought every 6 months after 6 years of use. Mefloquine has not shown additional side effects up to 3 years. Atovaquone–proguanil has been tested for 3 months in residents in endemic areas, and for a median of 28 days in travellers; limited data suggest that it may be used for up to 1 year. Doxycycline may be used safely for up to 2 years [5]. Visiting friends and relatives (VFRs) Immigrants and previous immigrants from malaria-endemic countries to Europe, including their children born in non-endemic areas, constitute the main risk group for imported malaria in Italy [30]. Their proportion among malaria cases is increasing over time, as is the severity of the disease, along with their loss of immunity [31]. Both accessibility of travel clinics and VFRs’ awareness about malaria severity and risk in adults and children must be improved [32]. Measures of protection against vectors must be explained, and benefits of chemoprophylaxis must be highlighted. Sometimes, the cost of chemoprophylaxis may be an issue in such travellers, and could entail an incomplete adherence to recommendations. In this case, choosing the cheapest regimen may be considered.
Travellers with underlying conditions
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• •
• •
Chloroquine has no documented interactions with warfarin Mefloquine probably has no interaction, but starting prophylaxis 2–3 weeks in advance and checking the INR is recommended Doxycycline may reduce the effect of anticoagulants [33] Atovaquone–proguanil: proguanil increases the anticoagulant effect of warfarin, but no adverse effects have been reported [3, 5, 28]
Glucose-6-phosphate dehydrogenase (G6PD) deficiency G6PD deficiency entails the risk of haemolysis when assuming particular drugs. Chloroquine has a theoretical risk of haemolysis, but this does not seem to be a problem at prophylactic dosage [5]. No risk of haemolysis has been identified with mefloquine, atovaquone–proguanil and doxycycline. Immune deficiency These patients are more prone to severe malaria: vector protection and chemoprophylaxis, as well as immediate diagnosis, are particularly important. HIV/AIDS Malaria can cause an increase in viral load in HIV patients, and possibly a progression of the disease. Antimalarial drugs may have interactions with antiretrovirals, and reduce or increase their activity: single interactions must be checked before recommending chemoprophylaxis [34]. HIV-infected pregnant women may have a higher parasitaemia, anaemia and placental colonisation by plasmodia, such that they may deliver low-weight children. Malaria also increases the HIV transmission rate to the child [5, 35].
Epilepsy Immune-suppressed patients Chloroquine and mefloquine are contraindicated in epileptic patients. Doxycycline may reduce the concentration of phenytoin, carbamazepine and barbiturates: their blood level must be checked after starting chemoprophylaxis [5]. Anticoagulant therapy Travellers must check their international normalised ratio (INR) before leaving their home country, as well as during long stays and after stopping chemoprophylaxis.
Patients under treatment with steroids, alkylating agents, cancer chemotherapy, TNF inhibitors, and transplanted patients assuming ciclosporin, tacrolimus, sirolimus, mycophenolate mofetil and mitoxantrone, particularly need correct information on malaria prevention for the possible increased severity of this disease and worsening of the underlying condition. Possible drug interactions must also be previously checked (e.g. chloroquine and ciclosporin).
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Splenectomised
Obesity
The risk of severe malaria is increased in asplenic and splenectomised patients, and they should avoid malariaendemic countries. If travel is unavoidable, a careful vector protection, a correct chemoprophylaxis and a particularly rapid diagnosis of fever episodes are mandatory.
No specific data are available in overweight patients [38]. An increased dosage of mefloquine (1.5 tablets/week if over 90 kg and 2 tablets over 120 kg) has been suggested [4]. No information is available for other drugs.
Liver disease The severity of liver disease must be evaluated prior to travelling; in case of liver failure, all antimalarial drugs are contraindicated and travelling should be avoided. •
• •
Severe liver disease: all antimalarial drugs are contraindicated, except for atovaquone–proguanil; no data about using precautions or adapting the regimen of this drug are available [5] Moderate liver disease: atovaquone–proguanil and mefloquine are suitable Mild liver disease: chloroquine, atovaquone–proguanil or mefloquine may be used. Caution is necessary when using doxycycline
Renal failure • •
•
Chloroquine: partially excreted via the kidneys: in case of severe liver failure, the dosage must be reduced Atovaquone–proguanil: proguanil is totally excreted via the kidneys, and is contraindicated in patients with creatinine clearance \30 ml/min and in patients undergoing haemodialysis [5, 33] Mefloquine and doxycycline are metabolised by the liver, and can be used by patients with severe renal failure. Dosage must not be adapted in case of haemodialysis [5, 33]
Severe heart disease Mefloquine is not recommended in case of heart conduction disorders. Concurrent cardio-active drugs, particularly beta-blockers, must be administered with caution [36].
Medications not available in Italy In some guidelines as well as in the literature, antimalarial drugs which are not available in Italy may be suggested. Although not recommended in this country, they are mentioned here for their importance. Purchasing these drugs in many countries in Africa or Asia entails a significant risk of using poor-quality or fake drugs [39]. Primaquine Primaquine is the only antimalarial drug that is effective on liver forms including hypnozoites of P. vivax and Plasmodium ovale. It may be used either as primary prophylaxis for a short period in areas of prevalent P. vivax, being effective on P. falciparum too, or as terminal prophylaxis for 14 days, after any regimen of chemoprophylaxis, after leaving an area with P. vivax risk (in order to destroy liver hypnozoites). The daily dose is 30 mg in adults [18]. It may cause severe haemolysis in G6PD-deficient individuals, so this should be tested prior to its consumption. It is contraindicated in pregnancy and breastfeeding, since it can be dangerous in G6PD-deficient foetuses and newborns. Proguanil It has been recommended in association with chloroquine in several guidelines in chloroquine-resistant P. falciparum areas. Proguanil is registered but not currently marketed in Italy. The association chloroquine–proguanil is less effective and less tolerated than other antimalarials [19], but is safe in pregnancy, so it could be an option in mefloquineintolerant women in drug resistance areas. The dosage for chloroquine is 300 mg/week and for proguanil, it is 200 mg/day.
Chronic malaria or hyper-reactive malarial splenomegaly
Artemether/lumefantrine
This particular malaria picture is mainly found in long-term expatriates, and is characterised by massive splenomegaly, increased IgM in serum and antimalarial antibodies. Being a risk factor for blackwater fever, continuous long-term chemoprophylaxis (mefloquine or, preferably, doxycycline) is mandatory in those who have had such a diagnosis [37].
It is a first-line treatment for non-complicated malaria pursuant to WHO guidelines [40], and is recommended for stand-by emergency treatment too. It is effective and well tolerated at a dose of four 20/120 mg tablets, twice daily for 3 days. There is a limited risk of QT prolongation during electrocardiography.
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New Italian guidelines for malaria prophylaxis Conflict of interest GC has received grants for speaking by SigmaTau; FC has acted as PI for a Sigma-Tau-sponsored trial; IEH, FG, AM, GN, RR, and AR declare no conflict of interest.
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