Risk factors associated with malaria deaths in travellers: A literature review

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MODEL

Travel Medicine and Infectious Disease (2014) xx, 1e12

Available online at www.sciencedirect.com

ScienceDirect journal homepage: www.elsevierhealth.com/journals/tmid

Risk factors associated with malaria deaths in travellers: A literature review Q5

¨thi*, Patricia Schlagenhauf Beda Lu University of Zu¨rich Centre for Travel Medicine, WHO Collaborating Centre for Travellers’ Health, Hirschengraben 84, CH-8001 Zu¨rich, Switzerland Received 15 January 2014; received in revised form 17 April 2014; accepted 23 April 2014

KEYWORDS

Q1

Malaria; Fatal; Traveller; Risk factors; Co-morbidities; Semi-immunity

Summary Malaria is the most frequently imported acute, life-treating, tropical disease in international travellers. We did a literature review in PubMed using pre-defined search terms to identify possible risk factors for malaria deaths in travellers. After screening, a total of 51 papers were selected for inclusion and were intensively scrutinised for details of “case fatality rates” and risk factors for fatal malaria associated with travel. The main risk factors were: non-use or inappropriate use of chemoprophylaxis, age, delay in seeking care, incorrect treatment, delay in diagnosis, infection with Plasmodium falciparum, non-immunity, travelling as a tourist and sex. The “case fatality rate” in most of the studies lay in the range 0.2%e3%. Possible reasons for this case fatality rate variation are: small case series, different populations included in the studies with different physiological and social determinants, including different species of malaria parasite and different traveller destinations in the case series. ª 2014 Elsevier Ltd. All rights reserved.

1. Introduction Malaria is a serious global infection; most recent estimates suggest a total of 219 million clinical cases per year and approximately 660 000 deaths [1]. A growing number of travellers from industrialized countries are visiting tropical regions of the world every year, resulting in about 50

* Corresponding author. E-mail addresses: [email protected], [email protected] (B. Lu ¨thi).

million arrivals in malaria-endemic areas annually [2]. Among these, 20%e70% report some level of associated illness and 3% report fever. Malaria is a common cause of fever and malaria is also the most frequently imported acute and life-threatening tropical disease in international travellers [3]. A major cause of severe illness is infection with Plasmodium falciparum malaria. But Plasmodium vivax and Plasmodium knowlesi can also be responsible for severe and sometimes lethal infection. The aim of this review is to search the literature for information on fatal malaria in travellers and to investigate the risk factors associated with malaria deaths.

http://dx.doi.org/10.1016/j.tmaid.2014.04.014 1477-8939/ª 2014 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Lu ¨thi B, Schlagenhauf P, Risk factors associated with malaria deaths in travellers: A literature review, Travel Medicine and Infectious Disease (2014), http://dx.doi.org/10.1016/j.tmaid.2014.04.014

61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62

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2

2. Methods We searched PubMed for papers published in English, German, Portuguese and Spanish. By using the search terms or combinations of the search terms “malaria”, “death” “travel”, we found 110 papers. Using the search terms “malaria”, “fatal” and “travel”, there were 145 results. 76 of these papers satisfied our criteria for further scrutiny. Ultimately 51 papers were used to provide in edepth information for this analysis. This cut off date for the literature search was May 26th, 2013. Further papers were found by screening the reference lists of these articles or as relevant articles suggested by Pubmed by screening the findings of the search terms. The abbreviation “CFR” which appears several times in this paper stands for “case fatality rate” and means the percentage of fatal cases among all of the cases during a specific period of time [4]. Depending on the included study, the CFR in this review can refer on all of the registered malaria cases or only to P. falciparum cases. In Table 1, we indicate for each study whether the CFR is for P. falciparum or for all malaria cases.

3. Results

Q2

Our search results yielded 51 papers, which form the basis of Table 1. A total of 46 papers allowed for the calculation of a case fatality rate. Some 39 papers included information on the malaria species and in 11 papers the cases were exclusively P. falciparum. One paper concerned only inpatients and another detailed fatal cases only. Papers with data from residents where found for the following countries: US, UK, France, Germany, Italy, Switzerland, New Zealand, Australia, Indonesia/Singapore, South Africa and from comprehensive data from Europe. The CFR varies from 0.0 (in a report from Singapore with 200 patients) to a maximum of 7.1 (a French case series which includes only severe and P. falciparum cases with 42 patients), with the exception of the paper showing only fatal cases (CFR 100%). In six papers, there are data on different CFRs in different demographic groups. Two papers distinguish between tourists and “visiting friend and relatives” another two between “immune and non-immune” one between “Europeans and non-Europeans” and one between “immigrants and non-immigrants”. One of the papers mentioned above also distinguishes between “African and non-African born” individuals. 30 out of 49 papers have a CFR that lies between 0.3 and 1.5. In 43 papers the absolute numbers of patients and fatal cases were available and 35 papers included more than 1000 malaria cases (Table 2). All studies stratified by sex showed that more men than women died of malaria. In 45 papers 28 other risk factors were named or suggested; “age” (10 times), “careless or non-use of effective prophylaxis” appears (38 times), “delay in seeking care” (19 times), “delay in treatment” (22 times), “delay in diagnosis” (27 times), ”pregnancy” (11 times), “being a tourist vs. visiting friends and relatives” (twice), “not African born” (once), “no immunity” (4 times), ”origin in non endemic country” (once), “nonimmigrant”(once), “resident of a UK-region where malaria is less seen” (once), “presenting in wintertime” (once), “P.

B. Lu ¨thi, P. Schlagenhauf falciparum infections” (4 times called as a risk factor but higher CFR or only including P. falciparum patients, appeared in more papers), ”incorrect treatment by a physician“ (once), “start of treatment in foreign country“ (once), “in country infection“ (once), “infection acquired in Africa” (3 times), “reported year” (once), “European origin” (once), ”travel to east Africa” (once),”non-access to parenteral treatment“ (once), “no possibility for correct treatment“ (once), “Co infection with HIV, co infection with HIV during pregnancy” (twice), “sub Saharan infection“ (once), “bacterial co infection“ (once), “non-effective treatment“ (once), “non- informed physicians“ (once), “misdiagnosis“ (3 times), “travelling to high risk areas“ (once). Four studies with a caseload of over 10 000 cases were included in our review; an observational study from the UK on imported malaria in the last 20 years described 29 302 cases and 191 deaths, a French paper includes 21 888 malaria cases and 96 deaths, a paper from the US shows 20 000 cases and 185 deaths and a German paper describes 11 507 cases and 209 deaths In the afore-mentioned papers, the following risk factors were mentioned: age, careless use or non-use of chemoprophylaxis, tourist vs. VFR, not-African born versus African born, delay in seeking care, delay in treatment, presentation during winter time, P. falciparum Infection, European origin travel to east Africa, “no possibility for correct treatment”, P. falciparium infection.

4. Discussion Our review describes a number of risk factors that can contribute to fatal malaria. This paper is focused on imported malaria and the risk factors for malaria deaths in travellers differ from the risk factors in endemic populations. The CFR can be a complex measurement and this is a limitation of our review. There are no randomized control trials and the statistical power to investigate the CFR is rather low because in most countries and centres, there are only a few cases of fatal malaria. The case fatality rate varies between 0.0% and 7.1% in different datasets in nonendemic countries. It also has to be considered that the CFR is probably overestimated because it is more likely that fatal cases are reported compared to non-fatal cases although, in most countries, malaria is a notifiable disease. If we look for example at the malaria surveillance in the USA where the surveillance was performed in the same way each year. In the year 2001 there were 1383 reported cases of malaria and 11 fatal cases yielding a case fatality rate of 0.8%, in the year 2008 there where 1292 cases of imported malaria with 2 fatal cases which gives us a fatality rate of 0.15% which is more than 5 times lower then the one in 2001 [5,6]. This shows the variability of the CFR when there is such a small number of fatal cases. Some studies are performed only with P. falciparum, which is responsible for most fatal cases, other studies are performed with all types of malaria, which lowers the CFR. For example in the Italian paper from Calleri et al. they exclude all malaria species other than P. falciparum, which accounts for about half of the total cases included in the malaria statistics. By doing this they double the CFR from

Please cite this article in press as: Lu ¨thi B, Schlagenhauf P, Risk factors associated with malaria deaths in travellers: A literature review, Travel Medicine and Infectious Disease (2014), http://dx.doi.org/10.1016/j.tmaid.2014.04.014

63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 Studies and reports describing malaria deaths in travellers.

Author

Year

Name of the paper

Checkley et al.

2012

Risk factors for mortality from imported falciparum malaria in the United Kingdom over 20 years: an observational study

Case-fatality rate all %

0.7

Kain et al.

2001

100

Krause et al.

2006

Malaria deaths in visitors to Canada and in Canadian travellers: a case series Chemoprophylaxis and malaria death rates

Legros et al.

2007

Newman et al.

2004

Mu ¨hlberger et al.

2003

Foca ` et al.

2012

Breslin et al.

2013

Santos et al.

2012

Shingadia et al. Badiaga et al.

2011 2005

Corne et al.

2004

Scho ¨neberg et al.

2003

Risk factors for imported fatal Plasmodium falciparum malaria, France, 1996e2003 Malaria-related deaths among U.S. travelers, 1963e2001 Age as a risk factor for severe manifestations and fatal outcome of falciparum malaria in European patients: observations from TropNetEurop and SIMPID surveillance data Clin Infect Dis Malaria and HIV in adults: when the parasite runs into the virus Malarial cases presenting to a European urban emergency department Severe imported malaria in an intensive care unit: a review of 59 cases UK treatment of malaria Severe imported malaria: Clinical presentation at the time of hospital admission and outcome in 42 cases diagnosed from 1996 to 2002 Severe imported malaria in adults: a retrospective study of 32 cases admitted to intensive care units Malaria surveillance in Germany 2000/2001–results and experience with a new reporting system

Scho ¨neberg et al.

2003

Bryam et al.

1998

Data from the Paper above; incidence and deaths in Germany from malaria 1990e2001 Report of the Australian malaria register for 1992

Total 0.73 Tourists 3.0 VFR 0.32 African born 0.4 Other countries 2.4 Total 1.2 Europeans 1.7 Non-European 0.2

191/29302

Study performed on P. falciparum cases only

All33/4600 P. fal. 33/2871

Study performed on P. falciparum cases only

7/7

Fatal cases only

3

116/3935

0.36

0.44

0.9

1.3

All96/27085 P.fal 96/21888 All 185/20000

1.4

17/1270

Study performed on P. falciparum and non-immune cases only Study performed on P. falciparum cases only P. falciparum CFR only for the years 1985-2001 P. falciparum and European cases only

e

e

e

1/56

e

3.1

9/284

P. falciparum cases only

e 7.1

2/42

e P. falciparum and severe cases only

16

5/32

e 1.5

e

Total 0.85 Nonimmune13.0 Immune 0.0 1.89

16/1876

P. falciparum and severe cases only e

209/11057

e

0.4

5/1470

e

3

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Q6

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Deaths caused by malaria in Switzerland 1988e2002

Comments

MODEL

2006

Deaths/cases

+

Christen et al.

Case-fatality rate P. falciaprum %

Risk factors associated with malaria deaths in travellers

Please cite this article in press as: Lu ¨thi B, Schlagenhauf P, Risk factors associated with malaria deaths in travellers: A literature review, Travel Medicine and Infectious Disease (2014), http://dx.doi.org/10.1016/j.tmaid.2014.04.014

Table 1

63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 4

2003

Bradley et al.

1994

Bradley et al.

1993

Bradley et al.

1991

Buck et al.

1994

Wiselka et al.

1990

Mazaudier et al.

1990

Lobel et al. Mu ¨hlberger et al.

1985 2003

Oh et al.

1999

McNeeley et al.

1998

Stoppacher et al.

2003

Romi et al.

2010

Cullen et al. Mali et al. Mali et al. Mali et al. Mali et al. Mali et al. Thwing et al. Skarbinski et al. Eliades et al. Shah et al.

2013 2012 2011 2010 2009 2008 2007 2006 2005 2004

and 1993 The clinical spectrum of severe imported falciparum malaria in the intensive care unit: report of 188 cases in adults Malaria imported in the United Kingdom in 1992 and 1993 Malaria imported in the United Kingdom in 1991 Malaria imported in the United Kingdom in 1989 and 1990 Prognostic factors in malaria tropica-results of a 1963e1988 evaluation study in Germany Malaria In Leicester 1983e1988: A review of 114 cases Imported malaria in Bordeaux in 1989. Epidemiologic, clinical and therapeutic study of 71 cases Fatal malaria in US Civilians Imported falciparum malaria in Europe: sentinel surveillance data from the European network on surveillance of imported infectious diseases Imported malaria in a Singapore hospital: clinical presentation and outcome. Malaria surveillance in New York City: 1991e1996 Malaria deaths in the United States: case report and review of deaths, 1979e1998 Incidence of malaria and risk factors in Italian travelers to malaria endemic countries Malaria surveillance–United States, 2011 Malaria surveillance–United States, 2010 Malaria surveillance–United States, 2009 Malaria surveillance–United States, 2008 Malaria surveillance–United States, 2007 Malaria surveillance–United States, 2006 Malaria surveillance–United States, 2005 Malaria surveillance–United States, 2004 Malaria surveillance–United States, 2003 Malaria surveillance–United States, 2002

Case-fatality rate all %

Case-fatality rate P. falciaprum %

Deaths/cases

Comments

Total 11.0 Nonimmune 22.0 Immune 0.0

10/188

0.39

14/3551

P. falciparum and intensive care unit cases only e

0.51

12/2332

e

0.19

8/4083

e

2.1

173/8049

e

0.87

1/114

e

1.4

1/71

e

e 5/1659

e P. falciparum cases only

0

0/200

e

0.4

4/988

e

118 Deaths

e

0.5

26/5219

e

0.26 0.53 0.27 0.15 0.07 0.38 0.46 0.3 0.54 0.6

5/1925 6/1691 4/1484 2/1298 1/1505 6/1564 7/1528 4/1324 7/1278 8/1337

4.2 Total 0.3 Tourists 0.6 Visiting friends and relatives 0.0

e e e e e e e e

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Bruneel et al.

Name of the paper

B. Lu ¨thi, P. Schlagenhauf

Year

MODEL

Author

+

Please cite this article in press as: Lu ¨thi B, Schlagenhauf P, Risk factors associated with malaria deaths in travellers: A literature review, Travel Medicine and Infectious Disease (2014), http://dx.doi.org/10.1016/j.tmaid.2014.04.014

Table 1 (continued )

63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124

+

MODEL

e

e

Inpatients cases only

P. falciparum cases only

3/867

2/56

11/507

e 3/336

Total2.2 Non-immigrants 2.37 Immigrants1.57 1.67

3.3 3.3

0.34

1.5 2003 2002 2001 1999 1997 1997 1998

1996

1994

2007

1998 2005

Kriechbaum et al.

Moore et al.

Spinazzola et al.

Apitzsch et al. Cohen et al.

Malaria surveillance–United States, 2001 Malaria surveillance–United States, 1999 Malaria surveillance–United States, 1998 Malaria surveillance–United States, 1995 Malaria surveillance–United States, 1994 Malaria surveillance–United States, 1993 Severe and complicated falciparum malaria in Italian travelers The epidemiology of imported malaria in New Zealand 1980e92 Imported malaria in the 1990s. A report of 59 cases from Houston, Tex. Imported malaria at Italy’s National Institute for Infectious Diseases Lazzaro Spallanzani, 1984e2003 Imported malaria in Germany in 1996 Increased prevalence of severe malaria in HIV-infected adults in South Africa

0.8 0.32 0.32 0.51 0.4 0.63

0.9

e e e e e e P. falciparum cases only 11/1383 5/1540 4/1227 6/1167 4/1014 8/1275 3/193

Risk factors associated with malaria deaths in travellers

Filler et al. Newman et al. Holtz et al. Williams et al. Kachur et al. Barat et al. Calleri et al.

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62

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5 0.75% to 1.5% [7]. In Table 1, studies concerned only with P. falciparum tend to have a higher CFR. The risk factors nevertheless seem to be comparable between the two different study designs. A further possible weakness of our review is the fact that we may be including some cases more than once in overlapping publications. The review by Newman et al. is a comprehensive summary of US surveillance data from 1963 to 2001. The Lobel 1985 paper is a subset of those same patients from 1966e1984. The surveillance summaries: Barat 97, Kachur 97, Williams 99, Holtz 01, Newman 02 and Filler 03 would also have been included in the Newman review article [6,8e14].

4.1. Different destinations P. falciparum is responsible for most of the fatal cases. At different tourist destinations there are also different types of malaria. For example in the studies from Australia, New Zealand and Singapore there are rather low case fatality rates; 0.4%, 0.32% and 0.00% [15e17]. This may be due in part to the fact that the main travel destinations are Asian countries where P. vivax is more widespread then P. falciparum. In Germany where most malaria is imported from Africa, the proportion of P. falciparum is higher. This may also be a reason for a higher CFR in Germany [18,19]. This factor only has to be taken into account if the study is performed on all of the malaria cases from all malaria species and not just with P. falciparum.

4.2. Different populations The observational study from the UK and the study from Switzerland show clearly that persons who travel to visit friends and relatives and/or have previous exposure to malaria have a lower case fatality rate than tourists or travellers from non-endemic countries [20,21]. Therefore the percentage of persons who are travelling as “VFR” impacts the CFR. This means that countries with a high immigration rate from malaria endemic countries tend to have a lower CFR. In the UK study, there were 8937 individuals born in an endemic country with a CFR of 0.4% compared to 50 849 individuals born in non- endemic countries with a CFR of 2.4%. A recent paper from Pistone et al. shows the possible protective effect of persisting immunity [22]. In this study, VFR travellers suffered less often from severe and fatal malaria than travellers of European origin (p Z 0.02). This study suggests that some degree of immunity persists even after a long-term stay in a non-endemic country. In contrast, the German paper reported only on non-immune persons thus resulting in a higher CRF [18]. It has to be mentioned that it is difficult to accurately describe an individual as actually having “immunity” or “semi immunity”. These are terms of convenience used to describe populations who may actually have some degree of protection. We use residence in an endemic country or other characteristics as surrogate markers for actual measurable immunity. In fact, another explanation for this finding might be that the VFR population had a higher rate of sickle cell

Please cite this article in press as: Lu ¨thi B, Schlagenhauf P, Risk factors associated with malaria deaths in travellers: A literature review, Travel Medicine and Infectious Disease (2014), http://dx.doi.org/10.1016/j.tmaid.2014.04.014

63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 6

Risk factors for malaria deaths in travellers. Year

Name of the paper

Risks

Checkley et al.

2012

Risk factors for mortality from imported falciparum malaria in the United Kingdom over 20 years: an observational study

Christen et al.

2006

Deaths caused by malaria in Switzerland 1988e2002

Kain et al.

2001

Malaria deaths in visitors to Canada and in Canadian travellers: a case series

Krause et al.

2006

Chemoprophylaxis and malaria death rates

Legros et al.

2007

Newman et al.

2004

Risk factors for imported fatal Plasmodium falciparum malaria, France, 1996e2003 Malaria-related deaths among U.S. travelers, 1963e2001

Mu ¨hlberger et al.

2003

Age, careless use or non-use of effective chemoprophylaxis, being a tourist vs. VFR, not-African born, delay in seeking care, delay in treatment, wintertime presentation of infection, P. falciparum infection Age, careless use or non-use of effective chemoprophylaxis, delay in diagnosis, in-county infection, P. falciparum infection, infection acquired in Africa Age, careless use or non-use of effective chemoprophylaxis, false instruction of physician, delay in treatment, delay in diagnosis, begin of treatment in foreign country, pregnancy, non-access to parenteral treatment, in-county infection, P. falciparum infection, infection acquired in Africa Age, careless use or non-use of chemoprophylaxis, origin in non-endemic country, infection acquired in Africa, reported year Age, careless use or non-use of chemoprophylaxis, European origin, travel to East Africa Careless use or non-use of effective chemoprophylaxis, delay in seeking care, delay in diagnosis, no treatment, no possibility for right therapy, P. falciparum infection Age, careless use or non-use of effective chemoprophylaxis

Foca ` et al. Breslin et al.

2012 2013

Santos et al.

2012

Shingadia et al. Badiaga et al.

2011 2005

Corne et al.

2004

Scho ¨neberg et al.

2003

Scho ¨neberg et al.

2003

Bryam et al. Bruneel et al.

1998 2003

Co infection with HIV; Confection with HIV and pregnancy Careless use or non-use of chemoprophylaxis, pregnancy, P. falciparum infection No immunity, delay in diagnosis

Careless use or non-use of effective chemoprophylaxis, delay in treatment, sub Saharan infection, no immunity Careless use or non-use of effective chemoprophylaxis, delay in seeking care, delay in treatment, delay in diagnosis

Careless use or non-use of effective chemoprophylaxis Careless use or non-use of effective chemoprophylaxis, delay in treatment, bacterial co-infection

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Delay in treatment Careless use or non-use of effective chemoprophylaxis, no immunity

B. Lu ¨thi, P. Schlagenhauf

Age as a risk factor for severe manifestations and fatal outcome of falciparum malaria in European patients: observations from TropNetEurop and SIMPID surveillance data Clin Infect Dis Malaria and HIV in adults: when the parasite runs into the virus. Malarial cases presenting to a European urban emergency department Severe imported malaria in an intensive care unit: a review of 59 cases UK treatment of malaria. Severe imported malaria: Clinical presentation at the time of hospital admission and outcome in 42 cases diagnosed from 1996 to 2002 Severe imported malaria in adults: a retrospective study of 32 cases admitted to intensive care units Malaria surveillance in Germany 2000/2001–results and experience with a new reporting system Data from the paper above; incidence and deaths in Germany from malaria 1990e2001 Report of the Australian malaria register for 1992 and 1993 The clinical spectrum of severe imported falciparum malaria in the intensive care unit: report of 188 cases in adults

MODEL

Author

+

Please cite this article in press as: Lu ¨thi B, Schlagenhauf P, Risk factors associated with malaria deaths in travellers: A literature review, Travel Medicine and Infectious Disease (2014), http://dx.doi.org/10.1016/j.tmaid.2014.04.014

Table 2

63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 1993 1991

Malaria imported in the United Kingdom in 1991 Malaria imported in the United Kingdom in 1989 and 1990

Buck et al.

1994

Wiselka et al. Mazaudier et al.

1990 1990

Lobel et al.

1985

Prognostic factors in malaria tropica-results of a 1963e1988 evaluation study in Germany Malaria In Leicester 1983e1988: A review of 114 cases Imported malaria in Bordeaux in 1989. Epidemiologic, clinical and therapeutic study of 71 cases Fatal malaria in US civilians

Mu ¨hlberger et al.

2003

Oh et al.

1999

McNeeley et al.

1998

Stoppacher et al.

2003

Romi et al.

2010

Cullen et al.

2013

Malaria deaths in the United States: case report and review of deaths, 1979e1998 Incidence of malaria and risk factors in Italian travellers to malaria endemic countries Malaria surveillance–United States, 2011

Mali et al. Mali et al.

2012 2011

Malaria surveillance–United States, 2010 Malaria surveillance–United States, 2009

Mali et al. Mali et al.

2010 2009

Malaria surveillance–United States, 2008 Malaria surveillance–United States, 2007

Mali et al.

2008

Malaria surveillance–United States, 2006

Thwing et al.

2007

Malaria surveillance–United States, 2005

Skarbinski et al.

2006

Malaria surveillance–United States, 2004

Eliades et al.

2005

Malaria surveillance–United States, 2003

Filler et al.

2003

Malaria surveillance–United States, 2001

Imported falciparum malaria in Europe: Sentinel surveillance data from the European network on surveillance of imported infectious diseases Imported malaria in a Singapore hospital: clinical presentation and outcome Malaria surveillance in New York City: 1991e1996

Careless use or non-use of effective chemoprophylaxis, delay in diagnosis Age, careless use or non-use of effective chemoprophylaxis, delay in diagnosis Delay in diagnosis Careless use or non-use of effective chemoprophylaxis, delay in seeking care, delay in diagnosis, no effective treatment, delay in treatment No immunity

Careless use or non-use of effective chemoprophylaxis, noninformed physicians Age, careless use or non-use of effective chemoprophylaxis, delay in treatment, misdiagnosis

Careless use or non-use of effective chemoprophylaxis, delay in seeking care, delay in diagnosis, delay in treatment Delay in seeking care, delay in treatment, pregnancy Careless use or non-use of effective chemoprophylaxis, delay in seeking care, delay in diagnosis, delay in treatment Delay in diagnosis and treatment Careless use or non-use of effective chemoprophylaxis, delay in seeking care, delay in diagnosis, delay in treatment Careless use or non-use of prophylaxis, delay on diagnosis and treatment Careless use or non-use of effective chemoprophylaxis, delay in seeking care, delay in diagnosis, delay in treatment, pregnancy Careless use or non-use of not effective chemoprophylaxis, delay in seeking care, delay in diagnosis, delay in treatment, pregnancy Careless use or non-use of effective chemoprophylaxis, delay in seeking care, delay in diagnosis, delay in treatment, pregnancy Careless use or non-use of effective chemoprophylaxis,

7

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Bradley et al. Bradley et al.

Careless use or non-use of effective chemoprophylaxis, delay in diagnosis

MODEL

Malaria imported in the United Kingdom in 1992 and 1993

+

1994

Risk factors associated with malaria deaths in travellers

Please cite this article in press as: Lu ¨thi B, Schlagenhauf P, Risk factors associated with malaria deaths in travellers: A literature review, Travel Medicine and Infectious Disease (2014), http://dx.doi.org/10.1016/j.tmaid.2014.04.014

Bradley et al.

63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 8

Author

Year

Name of the paper

2002

Malaria surveillance–United States, 1999

Holtz et al.

2001

Malaria surveillance–United States, 1998

Williams et al.

1999

Malaria surveillance–United States, 1995

Kachur et al.

1997

Malaria surveillance–United States, 1994

Barat et al.

1997

Malaria surveillance–United States, 1993

Calleri et al.

1998

Severe and complicated falciparum malaria in Italian travelers

Kriechbaum et al.

1996

The epidemiology of imported malaria in New Zealand 1980-92.

Moore et al.

1994

Spinazzola et al.

2007

Apitzsch et al.

1998

Imported malaria in the 1990s. A report of 59 cases from Houston, Tex. Imported malaria at Italy’s National Institute for Infectious Diseases Lazzaro Spallanzani, 1984-2003 Imported malaria in Germany in 1996

Cohen et al.

2005

Increased prevalence of severe malaria in HIV-infected adults in South Africa

delay in seeking care, delay in diagnosis, delay in treatment, pregnancy Careless use or non-use of effective chemoprophylaxis, delay in seeking care, delay in diagnosis, delay in treatment, pregnancy Careless use or non-use of effective chemoprophylaxis, delay in seeking care, delay in diagnosis, delay in treatment, pregnancy Careless use or non-use of effective chemoprophylaxis, delay in seeking care, delay in diagnosis, delay in treatment Careless use or non-use of effective chemoprophylaxis, delay in seeking care, delay in diagnosis, delay in treatment Careless use or non-use of effective chemoprophylaxis, delay in seeking care, delay in diagnosis, delay in treatment Age, careless use or non-use of effective chemoprophylaxis, infection acquired in Africa, being a tourist vs. VFR, non immigrant Careless use or non-use of effective chemoprophylaxis, travelling to high risk areas Careless use or non-use of effective chemoprophylaxis, delay in diagnosis, misdiagnosis Age, careless use or non-use of effective chemoprophylaxis, delay in seeking care, delay in diagnosis Careless use or non-use of effective chemoprophylaxis, delay in diagnosis, misdiagnosis HIV in non-immune persons

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Newman et al.

Risks

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Please cite this article in press as: Lu ¨thi B, Schlagenhauf P, Risk factors associated with malaria deaths in travellers: A literature review, Travel Medicine and Infectious Disease (2014), http://dx.doi.org/10.1016/j.tmaid.2014.04.014

Table 2 (continued )

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Risk factors associated with malaria deaths in travellers trait compared to the European travellers. Thus it may bet hat it was their inherent genetic polymorphism that protected them rather than antibodies or some aspect of their cell mediated immunity. Another risk factor for mortality due to malaria is the presentation of patients to general practitioners (GPs) who may not have a high awareness of imported diseases such as malaria. It also may contribute that the awareness to report malaria cases can vary from country to country, in some countries the reporting system is inadequate, in others there is a tendency to report only fatal cases which also skews the CFR.

5. Risk factors associated with fatal malaria Although risk factors vary from paper to paper, the following factors are consistently reported in association with death from malaria.

5.1. Co morbidities This review does not contain a list of relevant co morbidities or clinical symptoms, which lead to a higher CFR, but it has been repeatedly reported in the literature that coinfection with HIV results in more severe illness (OR 4.82), also splenectomised patients or a co-infection with Mycobacterium tuberculosis can lead to a more severe disease [23e26].

5.2. Pregnancy Pregnancy correlates with a three fold higher risk of developing severe malaria. The Infection is dangerous for the mother and the foetus and the therapy can be more complicated [27,28]. Different fatal case reports underline these statements [29e31].

5.3. Age as a risk factor In various studies, an older age is significantly associated with a higher CFR [20,21,32,33]. In the UK, a significantly increased risk of malaria deaths was seen in persons aged over 50 years (p < 0.001) and an even stronger risk in persons aged over 65 (p < 0.001) [20]. According to the TropNetEurop and SMIPID surveillance data, the risk in elderly patients is almost six times higher in persons who are sixty years of age or older than in younger people. In their surveillance the case fatality rate was shown to rise with every decade. In the study from Switzerland, the mean age of fatal cases is 51.6 years, 10e15 years above the age of the non-fatal cases. In the German study, the age of the cases wasn’t divided into groups but into a continuous variable, which avoided any kind of classification bias. Their Odd’s Ratio was 1.06 with a p value smaller then 0.001. In the French study, the OR increases with every decade by 1.78 (p < 0.001). The four previously mentioned studies are based on P. falciparum cases only. The exact reason is unclear but it is unlikely that this is only because of existing co-morbidities in older persons. In Africa, fatal malaria occurs mainly in children under 5 or until they acquire a protective semi-immunity. Travellers to malaria

9 endemic areas generally do not have any semi-immunity [1]. In non-endemic countries, the case fatality rate of imported malaria in children is low, ranging from 0 to 0.33 [34]. In the British study there are no deaths in children under 5 and a case fatality rate of 0.33% in children aged >5e18 years (p Z 0.54).

5.4. Malaria species as a risk factor P. falciparum is responsible for most of the fatal malaria infections. In the UK study, the case fatality rate of P. falciparum was 0.73%, the case fatality rate of other species was 0.05%. In the US study from 2004, 93% of the deaths were attributed to P. falciparum infections giving P. falciparum a CFR of 1.3% P. vivax 0.06% Plasmodium malaria 0.3% and Plasmodium ovale 0.3% [8]. Therefore the type of species is a main risk factor. Nine studies listed in this paper concern P. falciparum infections only. In general, there are only a few fatal cases of malaria caused by species other than P. falciparum. Recently published literature suggests that the risk of fatal illness due to P. vivax infection is greater that commonly accepted [35].

5.5. Chemoprophylaxis as a risk factor In the Swiss study from Christen et al. 95% of all fatal cases had not taken chemoprophylaxis or had taken an inappropriate drug or were non-compliant with the chemoprophylaxis regimen. In the UK study, the case-fatality-rate in nonAfrica-born Individuals, infected with P. falciparum, changes from 0.6% for travellers who correctly used chemoprophylaxis to 1.4% for those who took any kind of prophylaxis (even if it was incorrect or if adherence was inadequate) to 3.5%, for those who took no prophylaxis at all. In the French study, based on P. falciparum cases, the OR rises from the correct drug usage, to 1.90 in persons who took ineffective drugs, to 2.07 in persons who took no antimalarials at all (p Z 0.04). In the German study from Krause et al. the risk of dying for non-immune persons with P. falciparum who took any chemoprophylaxis was two thirds that of those who had not taken any chemoprophylaxis (p Z 0.042). Furthermore, taking chemoprophylaxis lowers the mortality even if it fails to prevent the disease. It lowers the parasitemia and therefore the risk of getting a severe or deadly malaria infection. This is rather important because in the UK study only one third of the travellers took chemoprophylaxis and of these, only one out of six took a regimen which is effective in Africa. The spread of P. falciparum drug resistance underlines the need for general practitioners to be up-to-date with the latest chemoprophylaxis recommendations.

5.6. Immunity and “reason for travel” as risk factors There is a higher case fatality rate for non-immune travellers compared to semi-immune travellers, non-African born travellers compared to African born travellers, and tourists compared to travellers who visit friends and relatives (VFR). In the Swiss study, the risk of dying from malaria in Europeans compared to non-Europeans is more than

Please cite this article in press as: Lu ¨thi B, Schlagenhauf P, Risk factors associated with malaria deaths in travellers: A literature review, Travel Medicine and Infectious Disease (2014), http://dx.doi.org/10.1016/j.tmaid.2014.04.014

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10 8 times higher (p < 0.001). In The UK studies, individuals born in Africa are responsible for most of the malaria cases in the UK but their case fatality rate is 0.4 compared to non African born individuals who have a CFR of 3.0 (odds ratio crude: 6.2 adjusted for age: 4.2 p < 0.001). This may be due to a partial immunity, which remains even after a long time. A recent paper from Moncunill shows that the percentage of antibodies in immigrants are the same between individuals living up to five years abroad and individuals living more than five years abroad. But also that immigrants without malaria had lower IgGs to all tested malaria antigens than individuals with a life long exposure to malaria [36]. In the French study, the OR from European travellers is 6.79 compared to African travellers (p < 0.001). Other studies have similar results [18,33,37e39]. In the UK study, there were still significant differences in individuals born in the UK and visiting friends and relatives and the tourist group. This may be a result of those with an African heritage or staying with an African family know the early symptoms and have a greater knowledge about malaria and how to act if symptoms occur. Other factors such as genetic polymorphisms may also contribute.

5.7. Sex as a risk factor Although sex is not explicitly mentioned as a risk factor of dying from malaria, in the studies included in this review, men are always at higher risk. In the study from Mu ¨hlberger et al. almost 65% of all the malaria cases are male [32]. In the French study, the sex ratio between the genders was M:F Z 1.7 and in the fatal cases the sex ratio was even higher (M:F Z 3.3), the French study however rules the factor “sex” out after controlling in multivariate analyses for ethnic origin and age [33]. In the Swiss study, more than 75% of all fatal cases are men [21]. It is unclear how sex impacts the CFR but most of the fatal cases are men, this could be due to behavioural factors as “ taking no chemoprophylaxis” “poor personal protection measures” or “delay in seeking care” but also there are different biological responses to infections between the sexes which have to be taken into account. A paper of Schlagenhauf et al. supports this thesis. It indicates that men and women have different travel related morbidity, due to different biological responses and social and cultural issues [21,40].

5.8. Delay in seeking care, delay diagnosis and delay treatment as risk factors In the US study, 37.4% of the persons who died waited longer than one day after symptom onset, with a median of 4.5 days before seeking care. 67.8% of the persons did not obtain a correct diagnosis on the same day, with a range of 1e17 days to achieve the correct diagnosis. In 17.9% of the fatal cases the diagnosis was made only at the autopsy. Of the persons who died but had the opportunity to receive therapy, 5.5% had a delay of 12e24 h and another 16.5% never received therapy. 10.0% did not receive appropriate treatment. Some 8.9% received exchange transfusion therapy. In the paper of Santos et al. the mean time between arrival and diagnosis in individuals who survived was 8 days. In fatal cases it was 16 days. So late diagnosis is

B. Lu ¨thi, P. Schlagenhauf associated with a fatal outcome (p Z 0.027). In the UK, 26% of the fatal cases died at home or in an ambulance. This can be related to a late diagnosis or the long time lag before seeking medical care. It was also shown, in the UK study, that the case fatality rate was higher in regions where malaria is less often seen than in regions where malaria presents frequently (adjusted OR for age 18.2 between the region with the most and least malaria was seen p < 0.001), this may be attributed to the fact that the awareness of malaria is lower in certain regions. Also there was a peak in the CFR in December, even after correcting with purpose of travel and other factors. This may be correlated with longer time till seeking medical care and less available medical staff in hospitals and doctor’s offices. In the Swiss study, there were 11 cases of unusual transmission (including airport malaria) of which two ended fatally, the high CFR of these 18.2% may be related to a late diagnosis because of a missing history or a history that did not point to a possible malaria (Table 3).

5.9. Region visited as risk factor In the French study, travelling to East Africa is individually associated with a higher CFR compared to travel to West Africa (OR 3.39 p Z 0.02). In the UK study the CFR is also higher but it is explained with a higher number of tourists and a lower use of chemoprophylaxis. In the Swiss study, all imported infections were acquired in Sub-Saharan Africa, especially in Kenya, a typical tourist destination rather than a VFR destination. 15 out of 27 fatal cases were infected in Kenya (including one case who also visited Uganda). The German study from Krause et al. associates a significant relationship between “infection acquired in Africa” and fatal cases.

6. Conclusions This review shows that malaria must be treated as a serious, life-threatening tropical disease. With more awareness and knowledge of this potentially fatal imported tropical disease, risk factors such as “delays in diagnosis and treatment” can be minimized. Furthermore, failure to use appropriate chemoprophylaxis in high transmission malaria endemic areas is a major risk factor and is cited frequently in many papers. Chemoprophylaxis is underused in many cases. Even when correctly prescribed for the intending travellers, it can be used incorrectly by the

Table 3 Summary of top risk factors for fatal malaria in travellers. Top risk factors Non-use or incorrect use of appropriate chemoprophylaxis Age Delay in seeking care, delayed diagnosis, delayed administration of the correct treatment Non-immunity and travelling as a tourist Sex Malaria species e Plasmodium falciparum Sex

Please cite this article in press as: Lu ¨thi B, Schlagenhauf P, Risk factors associated with malaria deaths in travellers: A literature review, Travel Medicine and Infectious Disease (2014), http://dx.doi.org/10.1016/j.tmaid.2014.04.014

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Risk factors associated with malaria deaths in travellers travellers themselves. This underlines the need for all relevant parties, pre-travel health advisors, the travel industry and travellers themselves to be up to date on malaria risk and prevention practices appropriate for the travel destination. The main risk factors for malaria deaths are: “age”, “wrong or no usage or incorrect chemoprophylaxis”, “delay in consulting a doctor”, “delay in diagnosis”, “delay in treatment” and “sex”. We conclude that many of the main risk factors for malaria deaths in travellers can be mitigated by correct interventions before and after travel. Q3

Funding None.

Conflict of interest None declared.

Uncited references [41e62].

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