Summary

Introduction: Malaria remains an ongoing challenge despite the fact that it seems to have been eradicated in Turkey since 2011. This study aimed to evaluate the status of antimalarial prophylaxis, clinical and laboratory profile of imported malaria cases admitted to a university hospital in a period of 10 years.

Materials and Methods: Patients with malaria hospitalized in a university hospital between the years 2008 and 2017 were evaluated retrospectively. Data were obtained from the hospital database. Thin and thick blood smears were examined for diagnosis. Sociodemographic features, epidemiological, clinical, and laboratory findings as well as response to various treatments were evaluated.

Results: A total of 20 patients (all male) were diagnosed with imported malaria. The median age of the patients was 35 (19-56) years. The median length of travel was 78 (6-545) days. Plasmodium falciparum was the most common causative agent (80%). Only one patient had received malaria prophylaxis previously. Fever was the most prominent symptom (95%). C-reactive protein (CRP) levels were higher than 100 mg/dl in 75% (n=15) of patients. Eight cases were re-hospitalized with relapse and/or recrudescence. CRP levels in patients with relapse and/or recrudescence were significantly higher. All the patients received combination regimen. The most commonly used anti-malarial drugs were artemisinin derivatives.

Conclusion: Before visiting malaria-endemic regions it is essential to obtain information about preventive measures and chemoprophylaxis. Sick patients should be monitored until full resolution of symptoms and also peripheral blood smear should be performed due to the high rate of relapses. CRP can be a useful biomarker in follow-up of patients infected with malaria.

Introduction

Malaria is a transnational problem and without global eradication nobody can be considered safe. Economic factors, lack of antimalarial drugs, increased drug resistance, weak health systems and poor surveillance systems are the main challenges particularly in sub-Saharan countries contrary to opportunities in controlling and eliminating malaria in developed and developing countries[1]. Each year, almost 25-30 million travelers visit malaria-endemic sites. Travel-associated malaria is a serious problem in this population[4]. Fever in the traveler returning from an endemic region is the most common clinical presentation to primary care facilities or emergency service. Malaria should be primarily excluded because of its severe clinical course particularly in non-immune individuals. In this case, biomarkers, such as CRP, are effective in assessing acute malaria infection and also the progression of the disease[5]. This study aimed to evaluate the status of antimalarial prophylaxis, clinical and laboratory profile of imported malaria cases admitted to a university hospital in a period of 10 years.

Methods

Statistical Analysis
SPSS version 21 was used for statistical analysis. The results were presented as mean±standard deviation and median (min-max). A value of less than 0.05 was considered statistically significant.

Results

Plasmodium falciparum was the most common causative agent (80%). P. vivax was present in three patients (15%) and P. malariae in one (5%).

Hemoglobin levels on admission were below the reference value (11.9-14.6 g/dl) in 10 (50%) patients. Nineteen patients had a low platelet count. Platelet count on admission was less than 50000/uL in eight of these 19 patients. White blood cell count ranged between 1680/ul and 11400/ul while 40% of patients had leucopenia. The other abnormal laboratory findings were anemia (45%) elevated aspartate transaminase (45%), elevated alanine aminotransferase (50%), and hyperbilirubinemia (40%) (Table 1). C-reactive protein (CRP) level was higher than 100 mg/dl in 75% of patients. Except two patients, who had pneumonia as a co-existing disease, the control CRP levels got also decreased in whom at least two CRP measurements were performed. In five out of 14 patients, the CRP level became normal within 10 (4-30) days. There was no statistically significant correlation between CRP level and length of hospital stay (r=0.364, p=0.126). The average CRP level in patients with relapse and/or recrudescence was 133 mg/dl (±84).

Table 1: Laboratory characteristics of patients with malaria

All the patients were hospitalized for the treatment of malaria and follow-up of the complications with a median length of hospital stay of 5 (3-13) days. All received combination regimen (Table 2). The mean duration of therapy was 5 (±2) days. Two patients received concomitant antibiotic therapy for additional diagnosis of pneumonia. Three out of 20 patients infected with P. falciparum were followed up in the intensive care unit until their vital signs became stable.

Table 2: Malaria species and administered drugs

Eight patients with relapse and/or recrudescence were re-hospitalized and re-treated. A total of six patients with falciparum malaria with recrudescence and two patients with vivax malaria (lack of primaquine in their initial therapy regimen) with relapse were re-hospitalized and re-treated. One out of eight patients with falciparum malaria was admitted to the hospital two months later and the others presented with similar or worse symptoms within a month from their first admission. Before relapse and/or recrudescence, the patients were treated with artemether lumefantrine (2/8), atovaquone-proguanil (2/8), artesunate (2/8). Data on the treatment in two out of eight patients were not available since they were treated in countries where they acquired malaria.

Discussion

Patients with malaria may present with a wide variety of clinical symptoms[8-10]. The common symptoms in patients in this study were fever (95%), chills (65%) and fatigue (60%). Partial immunity against Plasmodium spp. may cause subclinical symptoms or asymptomatic parasitemia in endemic areas. On the other hand, non-immune people tend to have more severe clinical picture[10]. All of our cases lived in non-endemic areas and also all were previously healthy. The risk for a traveler is related to destination, length of stay, destination conditions, and chemoprophylaxis[11]. Other travel-related illnesses may appear with similar symptoms such as Ebola virus disease, chikungunya virus infection, dengue, typhoid fever and yellow fever[12]. Ebola had substantial effect on the number of malaria cases during the recent Ebola outbreak in Western African descent because this epidemic led to ignore the care and treatment of malaria[13]. Cessation of malaria prevention precautions and also inadequate diagnosis and treatment during the epidemic might have caused an increase in the number of malaria cases. Ebola spreads through direct contact with the blood, secretions, organs and other bodily fluids of infected people (through broken skin or mucous membranes). Although it may be rarely seen in severe form of malaria, hemorrhagic symptoms are prominent in Ebola. In the presence of suspicion, immunoassay and nucleic acid tests may be useful for differential diagnosis. We did not encounter any patient infected with Ebola virus in Turkey during the outbreak. However, a Nigerian woman who was travelling on Turkish Airlines and was suspected of having Ebola was approached with expanded precautions and following examinations revealed malaria[14].

A clinician has the responsibility of completely evaluating travelers returning from malaria-endemic zones. A high index of suspicion is required to ensure prompt diagnosis of malaria[5]. We hospitalized most of the patients (65%) with different pre-diagnosis other than malaria in spite of their history of travel to the endemic regions. Rapid identification and treatment of patients with severe and progressive conditions may decrease the risk of mortality and morbidity[11, 15-19].

We missed the diagnosis in one patient who had recently returned from Nigeria. He was re-admitted to the infectious diseases clinic when his symptoms deteriorated after 11 days. High number of cases with misdiagnosis has been reported in the literature[8]. False-negative results may lead to delay in starting appropriate therapy[7]. This can be prevented by repetitive Giemsa staining in patients presenting with fever and a history of travel to malaria-endemic areas. The other reason of misdiagnosis may be patients presenting with unusual symptoms[8, 9].

CRP has recently started to be investigated in malaria cases. CRP increases in patients infected with Plasmodium spp. and decreases under therapy[7]. Its role in assessing malaria severity and also for follow-up has been shown. It has been reported that CRP levels >35 mg/L were highly sensitive in predicting mortality[15]. CRP levels were high in all the patients in this study and they were over 100 mg/dl in 75% of patients. Almost in all patients (13/14) CRP levels decreased under treatment. Furthermore, all the cases with relapse and/or recrudescence presented with elevated CRP levels.

Relapse in patients infected with P. vivax is a well known entity but recurrence may occur due to inappropriate or inadequate treatment choices in falciparum malaria. Sometimes recrudescence may be observed because of antigenic variations or infection with different strains[20]. P. vivax, P. ovale, P. knowlesi malaria can be treated either with an artemisinin derivative or chloroquine if susceptible. Primaquine is suggested to prevent relapses. If P. falciparum is resistant to chloroquine, artemisinin-based combination therapies are strongly recommended[7]. Infrequent use of these drugs in our series was probably the reason why we encountered relapses in 40% of patients. The other reason for the vivax malaria cases may be the rare appearance of P. vivax in endemic areas. The dose of artemisinin derivates particularly artemether lumefantrine has been found to be related to recrudescence[21]. However, in our study, artemether lumefantrine was administered with a total of six oral doses in 3-day treatment schedule. The two cases with falciparum malaria remained unclear because they had been treated in countries where they acquired malaria. We included those cases in the recrudescence group, however, as they may have been re-infected in their second attack. The two relapse cases with vivax malaria had been treated without primaquine which is required for the hypnozoite forms that remain dormant in the liver and can cause a relapse. The main reason is probably the lack of initial primaquine treatment in vivax malaria cases because primaquine is the only antimalarial agent that prevents relapses in vivax malaria[22]. All the patients recovered with no long-term sequelae. One was transferred to another hospital with the consent of his family. The diagnosis and treatment of relapse and/or recrudescence may be delayed until the patient is referred to a experienced specialist. In this case, besides obtaining accurate medical history, the dose, frequency and duration of the drugs should be learned carefully. History of malaria is an important clinical clue for the patients with relapse and/or recrudescence presenting with fever in malaria-free countries[23].

Conclusion

Ethics
Ethics Committee Approval: Retrospective study.
Informed Consent: Retrospective study.
Peer-review: Externally and internally peer-reviewed.

Authorship Contributions
Concept: İ.B., Design: İ.B., Data Collection or Processing: M.K., Analysis or Interpretation: İ.B., M.K., Literature Search: İ.B., M.K., Ş.E., Writing: İ.B., M.K., Ş.E.

Conflict of Interest: No conflict of interest was declared by the authors.

Financial Disclosure: The authors declared that this study received no financial support.