Malaria remains the most important parasitic disease in the world, with an estimated 216 million new clinical cases and 655,000 deaths in 2010. Falciparum malaria occurs in 87 of the 106 countries where malaria is endemic, including 43 African countries.
In Europe, where malaria was eradicated, the reestablishment of local transmission remains a risk, as evidenced by Plasmodium vivax outbreaks in Greece in 2010 to 2012. In addition, imported malaria is an important public health problem with over 6,000 confirmed cases imported into the European Union (EU) in 2010.[1, 3] Imported malaria caused by Plasmodium falciparum is associated with significant fatality rates; the case fatality is overall 1% in Europe, but it varies among different countries. In Poland the number of reported malaria cases remains low compared to countries of Western Europe. Since the 1990s, the number of reported cases has not exceeded 40 per year. Despite the small number of recorded cases, the fatality rate in Poland is more than 10-fold higher than the EU average. Although deaths do not occur every year, this phenomenon raises serious concerns.
A number of factors are associated with a fatal outcome in patients with malaria, including the infecting Plasmodium species, increased age, delayed diagnosis and treatment, and failure to use chemoprophylaxis.[5-7] It is also increasingly recognized that imported malaria is not a homogeneous category. Recent studies examined different patient groups, including immigrants from malaria-endemic countries visiting friends and relatives (VFRs) in their country of origin, people born and living in an endemic area traveling to nonendemic countries, refugees from endemic countries, and people originating from nonendemic countries including military personnel, students, people temporarily working in malaria-endemic countries, missionaries, and tourists.[3, 8-10]
Some sources report that the total proportion of recorded malaria cases among VFRs in Europe has recently increased from 14% to 86%.
The aims of this study were to assess epidemiological aspects of malaria in Poland between 2003 and 2011 and to analyze factors related to case fatality and severe disease, that could explain the excessive number of malaria-related deaths in Poland.
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The included data from malaria cases were collected through the routine mandatory surveillance system in Poland between 2003 and 2011. The system is comprehensive and based on reporting by clinicians. All cases were laboratory-confirmed and met the EU case definition for reporting communicable diseases to the community network.
The most recent definition, which has been in force in Poland since 2009, includes both clinical (ie, fever) and laboratory criteria (ie, demonstration of parasites in blood films, detection of Plasmodium nucleic acid in blood samples, or detection of Plasmodium antigen). The previously existing case definition did not include Plasmodium antigen detection or the presence of symptoms. Patients with relapsing or recrudescent malaria were counted once. In addition to the clinical report additional epidemiological data were collected by the local epidemiologist on a standardized form.
Severe cases were defined according to the World Health Organization (WHO) criteria. In 5 of 44 cases classified as severe, sufficient data were not available and classification was based on clinical judgment by the treating physician.
Statistical analysis was performed using EpiInfo 3.5.3 and STATA 10. The chi-square test or Fisher's exact test was applied for univariable analysis and the log-binomial model was used for multivariable analysis of factors associated with severe form of falciparum malaria. Factors with a p value of <0.1 in univariable analysis were included in the model. Significance was defined as p value ≤0.05.
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A total of 189 confirmed malaria cases were recorded in Poland between 2003 and 2011. All cases were imported from malaria-endemic countries, and the annual number of cases ranged from 11 to 35.
Most of the patients were male (74%), and the median age was 36 years (range 9 months-73 years). The most frequently reported reasons for travel to malaria-endemic countries were work (40%) and tourism (38%). Missionaries represent 29% of all occupational visitors, and the majority of missionaries worked in Africa (91%). People originating from malaria-endemic countries, who were classified in different population categories, accounted for 12% of cases. Patient demographics for the included cases are summarized in Table 1.
Table 1. Patient characteristics and the clinical course of the disease
|Characteristic||Number (%)||Number of deaths (case fatality %)||p Value||Number of severe malaria (%)||p Value|
|Total||189 (100)||5 (2.6)|| ||44 (23)|| |
|Male||139 (74)||5 (3.6)||0.211||34 (25)||0.369|
|Female||50 (26)||0||10 (20)|
|Mean (STD)||37 (12.79)|| || ||42 (12.5)|| |
|Median (IQR)||36 (28–48)||42 (21)|
|19–50||146 (77)||4 (2.7)||30(21)|
|>50||36 (19)||1 (2.8)||14 (39)|
|Tourists||71 (38)||4 (5.6)||0.447||15 (21)||0.107|
|Immigrants||13 (7)||0||1 (8)|
|Professional and laborers (temporarily employed)||66 (35)||0||20 (30)|
|Sea or air crew||10 (5)||0||5 (50)|
|Students||12 (6)||0||1 (8)|
|Unknown||17 (9)||1 (5.9)||2 (12)|
|Area of origin|
|Malaria-endemic country||22 (12)||0||0.537||2 (9)||0.072|
|Poland or other nonendemic country||167 (88)||5 (2.99)||42 (25)|
|Area of exposure|
|Africa||137 (73)||4 (3.2)||0.7091||39 (29)||0.0084|
|Other||50 (26)||1 (2.1)||5 (10)|
|Species of Plasmodium|
|P. falciparum, including mixed with falciparum||118 (62)||5 (4.2)||0.092||38 (32)||0.0004|
|Other species||44||0||3 (6)|
|Yes||62 (33)||1 (1.6)||0.384||15 (24)||0.321|
|No||69 (37)||3 (4.3)||22 (32)|
|Unknown||59 (31)||1 (1.7)||7 (12)|
|Time from onset to diagnosis (days)|
|<4||79 (43)||0||0.001||15 (19)||0.059|
|4–7||50 (27)||5 (10.5)||18 (36)|
|>7||56 (30)||0||11 (20)|
Most of the cases were presumably acquired in Africa (72%), most commonly in Nigeria, Cameroon, and Uganda. During the study period, the proportion of cases imported from other continents increased from 17% in 2003 to 36% in 2011. Among non-African countries the most frequently mentioned countries of exposure were India and Papua New Guinea. Overall P. falciparum malaria constituted over 60% of cases. Persons traveling to Africa were more likely to be infected with P. falciparum than others (76% vs 28%, p < 0.001; Table 2).
Table 2. Number of cases by Plasmodium species and area of exposure
| ||Total||P. falciparum||P. vivax||P. ovale||P. malariae||Mixed||Plasmodium spp.|
Of the 189 cases, 62 patients (33%) reported using chemoprophylaxis, but only 6 of them complied with medication regimens appropriate to their destination. Common errors included discontinued use of the drug immediately after leaving the endemic area and failure to initiate chemoprophylaxis early enough.
Delayed diagnosis (≥4 days) was found in 57% of the included cases and in 50% of cases caused by P. falciparum. Overall, the median time from onset of symptoms to diagnosis was 4 days (range 0–74); in patients with falciparum malaria this time was 3.5 days (range 0–74) and in vivax malaria this time was 6.5 days (range 0–34). A total of 42% of delayed diagnoses were caused by patients seeking medical attention too late. Incorrect medical diagnosis during the initial presentation occurred in 30% of all delayed diagnoses, and in 14% (15 cases) both delayed presentation to medical service and misdiagnosis occurred. In the remaining cases delayed diagnosis was related to onset of the disease during return travel. Incorrect diagnoses included viral infection (ie, influenza-like illness), respiratory tract infection (ie, patients treated with antibiotics), bronchitis, sepsis, and one case in which leukemia was suspected because of pancytopenia.
Severe malaria occurred in 23% (44/189) of all reported cases, and five deaths were reported, generating a case fatality rate of 2.6%. Outcome was not reported in 16 cases, mostly due to refusal of hospitalization or leaving the hospital prior to the end of treatment. Univariable analysis revealed that severe disease was significantly associated with increased age, the infecting species of Plasmodium (ie, infection with P. falciparum) and area of exposure, with exposure in Africa associated with severe disease. The association between severe disease and exposure in Africa may be due to the more frequent occurrence of P. falciparum in Africa. Severe disease was also more frequent among patients originating from nonendemic countries and patients whose diagnosis was delayed, although the significance of these factors was borderline (Table 1). Case fatality rates displayed similar patterns, but only delayed diagnosis was statistically significant.
Because of the different clinical courses observed in falciparum malaria and other types of malaria, we focused on risk factors for severe disease among falciparum malaria cases (Table 3). Age was the most important predictor of severe disease with an adjusted rate ratio (aRR) for age >50 years versus age ≤50 years of 1.74 [95% confidence interval (CI) 1.07–2.83]. Delayed diagnosis was also significantly associated with severe disease with a rate ratio (RR) for ≥4 days versus <4 days of 1.71 (95% CI 1.0–3.0). The association of severe disease with origin from nonendemic countries was borderline significant with an RR for Poland or other nonendemic country versus endemic country of 2.8 (95% CI 0.8–10.6) in univariable analysis.
Table 3. Risk factors for severe malaria in falciparum malaria in Poland
|Factor||N||Number of severe (%)||RR (95% CI)||p Value||aRRa (95% CI)||p Value|
|Total||118||38 (32)|| || || || |
|Male||91||30 (33)||1.11 (0.58–2.13)||0.47|| || |
|Female||27||8 (30)||Reference|| || || |
|Age group (year)|
|>50||24||13 (54)||2.04 (1.24–3.35)|| ||1.74 (1.07–2.83)|| |
|Area of origin|
|Poland or other nonendemic country||102||36 (35)||2.8 (0.8–10.6)|| ||2.7 (0.7–10.50)|| |
|Area of exposure|
|Africa||104||35(34)||1.57 (0.56–4.44 )||0.358|| || |
|Other||14||3(21)||Reference|| || || |
|Yes||40||12 (30)||1.4 (0.78–2.48)||0.257|| || |
|No||48||20 (42)||Reference|| || || |
|Unknown||30||6 (20)||—|| || || |
|Delay from onset to diagnosis (day)|
|≥4||59||24 (41)||1.71 (1.0–3.0)|| ||1.63 (0.96–2.78)|| |
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The results of this study highlight the high case fatality (2.6%) and the high proportion of severe clinical forms of malaria (23%) in Poland. These high rates compare unfavorably to the rates observed in Western European countries, where the incidence of malaria is much higher than in Poland.[3, 5, 7, 13]
We note that both the case fatality and the proportion of severe cases are lower among persons originating from malaria-endemic areas than among other population groups (0% vs 3% and 9% vs 25%, respectively). These differences were not statistically significant, most likely due to the small number of malaria patients born in endemic countries in Poland. These results merit further investigation. Differences in the clinical course of malaria related to the area of origin have been described in previous studies of imported malaria and may partially explain the relatively high case fatality in Poland. In Poland, tourists and occupational travelers of Polish origin comprise the majority of the cases (88%), while in the Western European countries most of the imported malaria cases occur in immigrants, especially VFRs.[3, 5, 7, 14] This finding could be due to the relatively low rate of immigration from malaria-endemic countries to Poland, which generates a small number of VFRs exposed to malaria in their country of origin. In addition, studies from European countries indicate that although the overall case fatality and proportion of severe cases are much lower than those observed in Poland, with a similar frequency of falciparum malaria, analyses that are restricted to nonimmune travelers, especially in regions where malaria is less frequently seen, indicate rates similar to or higher than those observed among Polish nationals.[5, 15, 16] Higher mortality is also observed in ship crews, for whom additional risk factors were identified (ie, the limited availability of medical care during the cruise and the language barrier during anamnesis), but in most studies, adult VFRs remain a group of low mortality. The milder clinical course of malaria among patients originating from endemic countries has recently been attributed to past malaria exposures. Residents of malaria-endemic countries acquire semi-immunity after prolonged and intense malaria exposure, and this immunity may persist after they leave malaria-endemic areas. However, the mean time required to lose this semi-immunity has not yet been established. Persisting semi-immunity does not protect against infection, but it seems to protect against severe clinical course, complications, and death.[5, 6, 18] Our results are consistent with the above findings. Interestingly, one of the two persons with severe malaria who originated from endemic areas was born in Ghana and visited relatives 19 years after leaving the endemic area. There were no data available concerning the duration of stay outside the endemic area for the second patient, who was an immigrant from Kenya. Further, this patient's exact place of origin could be a nonendemic area of Kenya.
Other factors, such as sickle cell anemia which may modify the malaria form in Africans and uncertainty of data regarding usage of chemoprophylaxis, may also contribute to a less severe disease course among patients originating from endemic countries. This last explanation is unlikely to play a role in our data, because chemoprophylaxis was used less frequently among immigrant VFRs.[9, 13, 16, 19]
Although the number of semi-immune individuals in the total number of imported cases is important, it is not the only factor affecting the case fatality rate. In regions where the number of imported malaria cases is high, the mortality is less than 1%, even if nonimmune persons predominate and the rate of severe disease course is high.[5, 13, 20] This finding indicates the crucial role of awareness of malaria among both doctors and patients, and the role of experience in the diagnosis and treatment of malaria. In Poland, where there are only a small number of imported cases, this expertise may be lacking. Most delays in diagnosis occurred due to late presentation to health care and lack of proper diagnosis in a primary health care setting. In these cases, malaria was not considered in the initial differential diagnosis and symptoms were not linked to recent travel, especially during the flu season.
In our study, delayed diagnosis predicted fatal outcome and severe course of falciparum malaria, although this association was only borderline significant in the adjusted analysis, possibly due to the small sample size. The time from onset to diagnosis is of paramount importance to public health as it can be reduced by interventions that target both travelers and primary care physicians. In contrast, we observed that the median delay in diagnosis in Poland is similar to what was observed in other countries.
The association of delayed diagnosis with severe disease may be explained by the observation that malaria severity is correlated with increasing parasitemia over time, especially among nonimmune patients.[6, 21] Nevertheless, the risk of severe disease and death appears to have more complex determinants. Recent studies indicate that severe malaria is an immune-mediated disease caused by an imbalance between proinflammatory and anti-inflammatory cytokines.[22-25]
Although the lack of chemoprophylaxis or the improper use of chemoprophylaxis was not a predictive factor of severe course, most cases could be attributed to inadequate chemoprophylaxis. This finding underscores the importance of prevention using barrier methods and chemoprophylaxis. Although the total incidence of malaria in Poland is not high, this rate should be compared to the frequency of travel of the Polish population to endemic countries. On the basis of data from the Institute of Tourism (IT) and the Civil Aviation Authority of the Republic of Poland, the average number of trips to endemic countries from 2005 to 2011 was approximately 80,000 per year (range 40,000–145,000), which is a modest number compared with some countries in Western Europe.
Our study has several limitations. First we used the routine surveillance data, which suffers from low case ascertainment. If reporting is associated with clinical course and only more severe cases are reported to surveillance, our findings could be biased. There are currently no data available to confirm or reject this hypothesis.
Conclusions concerning the impact of semi-immunity on malaria severity are impeded by the lack of available data concerning the duration of immigration after leaving the endemic area, which may influence the persistence of semi-immunity.
Additionally, some limitations are associated with severity classification. Our study was based on clinical presentation, as determined and recorded by the treating physicians, and in some cases, it was not possible to apply the strict WHO definition. However, where data were available, classification is consistent with the WHO's criteria for severe malaria. In contrast, in four patients with hyperparasitemia >5%, the clinical course was determined by the physician to be moderate. These cases were not included as severe cases in the analysis.
It should be noted that even in neighboring European countries, imported malaria is not a homogeneous disease. Characteristics of the course of malaria in different countries, and even regions of the same country, may depend on the historical links to malaria-endemic countries, the number of immigrants, tourist traffic, duration and style of travel, and the structure of the population suffering from malaria. The incidence of imported malaria in a country affects malaria awareness among both travelers and general practitioners. It is important to remind physicians that malaria may pose a threat to any patient with an exposure history, even if travel was some time ago.