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Clinical and Laboratory Features of Travel-Associated Malaria; a University Hospital Experience/Seyahat Iliskili Sitma Olgularinin Klinik ve Laboratuar Ozelliklerinin Degerlendirilmesi; Bir Universite Hastanesi Deneyimi.

1. Introduction

Malaria is a widespread protozoan disease and estimated globally over more than 1 billion people are at risk for malaria. According to the World Malaria Report 2016, 212 (148-304) million cases of malaria occurred worldwide in 2015 and it is estimated that there were 429 000 (235 000-639 000) malaria associated deaths globally in 2015 [1]. Malaria remains a continuing challenge because of the imported malaria cases in Turkey despite its eradication in 2011. According to the Turkey malaria report of 2017 the number of imported malaria cases was 209 in 2016. Local cases have not been reported since 2011 [2,3]. Turkey has recorded considerable progress towards malaria eradication and are now in the elimination stage of the World Health Organization (WHO) malaria control programme [4].

Malaria is a transnational problem and without global eradication anyone cannot be assumd to be safe. The economic reasons, 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 in primary care or emergency. Malaria should be primarily excluded because of its severe clinical course particularly in the nonimmune. In this case biomarkers such as CRP were useful indicators to assess the acute malaria infection and also the progression of the disease [5].

2. Materials and Methods

We conducted a retrospective study between 2008 and 2017 in Ondokuz Mayis University Hospital which is one of the referral centers for malaria cases in the Black Sea region. Microscopically confirmed malaria cases by thin and thick peripheral blood smears were included the study. The demographic, clinical and laboratory features (complete blood count, biochemistry) of the patients were obtained from hospital health records. We were not able to obtain exact data regarding parasite density. The reasons for travel, destination, duration, history of malaria, history of receiving malaria prophylaxis were all recorded.

The data were collected and evaluated. SPSS version 21 was used to analyze data. Results were presented as mean [+ or -] Standard deviation and median (min-max). A value of P < 0.05 was considered as statistically significant.

3. Results

We identified 20 malaria cases, all males, median age of 35 (19-56) confirmed by thin and thick blood smear. All the patients had travel history to African countries for job. Sudan (n=4), Guinea (n=4), Ghana (n=4), Mozambique (n=2), Gabon (n=1), Nigeria (n=1), Mali (n=1), Rwanda (n=1), Kenya (n=1), Uganda (n=1). The median duration of travel was 78 (6-545) days. All were Turkish citizens. The median time from initiation of symptoms until diagnosis was seven (4-55) days. The preliminary diagnosis of the patients was commonly fever. Seven had obvious history of visiting malaria endemic countries and had friends with malaria experience history during their visit. Therefore their initial diagnosis approaches to the malaria besides fever. One had fever, abdominal tenderness and leukopenia so has been considered as typhoid fever. The second case had a history of animal husbandry and consumption of diary foods without pasteurization so hospitalized with the preliminary diagnosis of brucellosis.The remained 11 had no specific diagnosis on admission, were hospitalized to investigate fever etiology.Malaria prophylaxis has been recommended to five patients but we learned that four of them did not take prophylaxis. The main diagnostic method was thin and thick blood staining. Half of the patient's data record do not include the information regarding thick blood films. The others revealed no trophozoite on their thick blood staining and two of them have been diagnosed only by thin blood smear. Only one patient had history of receiving prophylaxis to prevent malaria. Fever was the most common symptom presented in 95% of patients, followed by chills (65%), fatigue (60%), and unconsciousness (15%). Diarrhea was present in three (0.6%) cases. A previous history of malaria was reported in 29% of patients reported here.

Hepatomegaly was present in 25 %, splenomegaly in 45%. Plasmodium falciparum was the most common causative agent (80%). P. vivax was present in three (15%) cases and P. malariae in one case (5%).

Hemoglobin levels of the 10 (50%) patients were below the reference value (11.9-14.6g/dL) on admission. The platelet count was low in 19 cases. Eight out of 19 cases platelet count was less than 50000/ul on admission. WBC ranged between 1680-11400/ul and 40 % of cases revealed leucopenia. The other abnormal laboratory findings were anemia (45%) elevated AST (45%), elevated ALT (50%), hyperbilirubinemia (40%)(Table 1). CRP was higher than 100 mg/dl in 75% of patients. Except two patients who had pneumonia as a co-existing disease, all the other repeating CRP levels decreased. Five out of 14 patients control CRP level became normal within 10 (4-30) days. There was no statistically significant correlation between CRP and duration of hospital stay (r = 0,364, P = 0,126). The average CRP levels of the cases with relapse and/or recrudescence were 133mg/dl ([+ or -]84).

All the patients were hospitalized for treatment of malaria and to follow up complications with median stay of 5 (3-13) days. All received combination regimen (Table 2). The mean duration of therapy was 5 ([+ or -]2) days. Two patients had received concomitant antibiotic therapy for additional diagnosis of pneumonia. Three out of 20 patients infected with P falciparum were followed up in intensive care unit until their vital signs become stabile.

Eight cases with relapse and/or recrudescence were re-hospitalized and re-treated. A total of six falciparum malaria cases re-hospitalized with recrudescence and two vivax malaria cases (lack of primaquine in their initial therapy regimen) with relapse and they were 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 worst symptoms within a month from their first admission. Before relapse and/or recrudescence patients were treated with artemether lumefantrine (2/8), atovaquone-proguanil (2/8), artesunate (2/8) and two out of eight patients data are not available were treated in countries where they acquired malaria.

4. Discussion

This study demonstrates that majority of the patients did not visit the endemic areas with antimalarial prophylaxis whereas the general principle of the prophylaxis is taking pills before, during and after the travel to minimize the exposure and malaria risk. The goal of malaria prophylaxis is to prevent malaria and its related complications. Obtaining health information for travelers, receiving appropriate prophylaxis regimen and the use of personal protective measures should be combined for effective protection against malaria. Turkey's General Directorate of Health for Borders and Coasts provide information for travelers and also provide drugs for chemoprophylaxis [6]. Receiving drugs for prophylaxis was just reported in one case, the rare usage is similar with the other studies [7]. Some of the travelers who experienced malaria before prefer to keep medications until they become infected. However the acquired immunity is lost quickly so they are in same risk with the others. A clinician has responsibilities of completely evaluating returned travelers from endemic malaria zones. A high index of suspicion is required to ensure prompt diagnosis of malaria [5]. The common symptoms of the patients in this study were fever(95%), chills(65%) and fatigue(60%). Patients with malaria may present with a wide variety of clinical symptoms [8-10]. 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 travel region, duration of travel, destination conditions, and receiving 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 it is considered that this epidemic led to ignore the care and treatment of the malaria [13]. The cessation of malaria prevention precautions and also inadequate diagnosis and treatment during the epidemic may cause acceleration of the number of malaria cases. Ebola may be associated with bleeding from skin, mucous membranes and different body parts. 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 didn't encounter any patient infected with Ebola virus during the outbreak. However a suspected Ebola case from Nigeria approached with expanded precautions and following examinations revealed malaria [14].

We hospitalized most of the patients (65%) with different pre-diagnosis other than malaria in spite of their travel history to the endemic regions. Rapid identification and treatment of patients with severe and progressive condition may decrease the risk of mortality and morbidity [11,16-19].

We missed the diagnosis of 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]. The 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 travel history of malaria endemic area. The other reason can be caused by 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 shows decrease under therapy [7]. Its prognostic role for assessing malaria severity and also for follow-up has been shown. CRP levels > 35 mg/L was highly sensitive in predicting mortality [15]. All of the CRP levels were high in this study and also in 75% of patients CRP level was over than 100 mg/dl. Almost all (13/14) control CRP levels decreased under treatment. Otherwise all the cases with relapse and/or recrudescence presented with elevated CRP levels.

Relapses entity 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 present because of antigenic variations or infection with different strains [20]. P. vivax, P. ovale, P. knowlesi malaria can be treated either with an artemisinin derivatives or chloroquine if susceptible. Primaquine is suggested to prevent relapses. P. falciparum acquired in an area where chloroquine resistance is found, artemisinin based combination therapies are strongly recommended drugs [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 related to recrudescence [21]. However artemether lumefantrine has been administered with a total of 6 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 therecrudescence 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 could be 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 experienced specialist refers the patient. In this case besides obtaining accurate medical history, the dose, frequency and duration of the drugs should be identified. History of malaria is an important clinical clue for the patients with relapse and/or recrudescence presented with fever in malaria free countries [23].

Conclusion

Fever is the most common finding in the returning traveler from malaria endemic area. However to prevent misdiagnosis and rule out other diseases the main step is a high index of clinical suspicion. CRP can be a useful biomarker to follow-up patients infected with malaria. Occupational travelers particularly, should be informed to seek medical care in case of fever during or after travel. And the physicians should consider the possibility of malaria when patients have a history of visiting malaria-endemic countries. Thus we can avoid lots of redundant tests to differentiate illnesses and loss time to evaluate potentially serious diseases.

Conflict of interest

None to declare.

References

[1.] World Health Organization (WHO) World Malaria Report 2014. Available at http://apps.who.int/iris/bitstream/10665/252038/1/9789241511711-eng.pdf?ua=1 Accessed September 11, 2017.

[2.] Turkish Statistical Institute http://www.turkstat.gov.tr/VeriBilgi.do?alt_id=39 Accessed March 20, 2016.

[3.] Turkish Ministry of Health Health Statistics Yearbook 2014. Available at https://sbu.saglik.gov.tr/Ekutuphane/kitaplar/EN%20YILLIK.pdf Accessed September 25, 2017.

[4.] Eliminating Malaria The long road to malaria elimination in Turkey. Available at http://apps.who.int/iris/bitstream/10665/94961/1/9789241506403_eng.pdf Accessed September 25, 2017.

[5.] Stauga S, Hahn A, Brattig NW, Fischer-Herr J, Baldus S, Burchard GD, Cramer JP. Clinical relevance of different biomarkers in imported plasmodium falciparum malaria in adults: a case control study. Malar J. 2013;12:246.

[6.] Turkey's General Directorate of Health for Borders and Coasts. Available at http://www.hssgm.gov.tr/EN/ Accessed September 4, 2017.

[7.] Chen LH, Wilson ME, Schlagenhauf P. Prevention of malaria in long-term travelers JAMA. 2006;296:2234-2244.

[8.] Kain KC, Harrington MA, Tennyson S, Keystone JS. Imported malaria: prospective analysis of problems in diagnosis and treatment. Clin Infect Dis. 1998;27:142-149.

[9.] World Health Organization. Guidelines for the treatment of malaria. 3rd Edition. Available at http://apps.who.int/iris/bitstream/10665/162441/1/9789241549127_eng.pdf?ua=1&ua=1 Accessed August 30, 2017.

[10.] Allan PJ, Tahir HIS. How easily malaria can be missed J R Soc Med. 2006;99:201-202.

[11.] Lopez Del Prado GR, Hernan Garcia C, Moreno Cea L, Fernandez Espinilla V, Munoz Moreno MF, Delgado Marquez A, Polo Polo MJ, Andres Garcia I. Malaria in developing countries. J Infect Dev Ctries. 2014;8:1-4.

[12.] Feder HM Jr, Mansilla-Rivera K. Fever in returning travelers: a case-based approach. Am Fam Physician. 2013;88:524-530.

[13.] Walker PG, White MT, Griffin JT, Reynolds A, Ferguson NM, Ghani AC. Malaria morbidity and mortality in Ebola-affected countries caused by decreased health-care capacity, and the potential effect of mitigation strategies: a modelling analysis. Lancet Infect Dis. 2015;15:825-832.

[14.] Suspected Ebola patient leaves Turkey after being diagnosed with Malaria Available at http://www.hurriyetdailynews.com/suspected-ebola-patient-leaves-turkey-after-being-diagnosed-with-malaria.aspx?pageID=238&nID=70423&NewsCatID=341 Accessed May 28, 2016.

[15.] Office of the Nations High Comissioner for Refugees. 2015 UNHCR country operations profile - Turkey http:// http://www.unhcr.org/tr/en/refugees-and-asylum-seekers-in-turkey Accessed October 11, 2017.

[16.] Doolan DL, Dobano C, Baird JK. Acquired Immunity to Malaria. Clin Microbiol Rev. 2009;22:13-36.

[17.] Centers for Disease Control and Prevention. CDC Traveler's health. Available at http://wwwnc.cdc.gov/travel Accessed September 19, 2017.

[18.] World Health Organization. WHO Travel and health http://www.who.int/topics/travel/en/ Accessed September 19, 2016.

[19.] Paul R, Sinha PK, Bhattacharya R, Banerjee AK, Raychaudhuri P, Mondal J. Study of C reactive protein as a prognostic marker in malaria from Eastern India. Adv Biomed Res. 2012;1:41.

[20.] Omonuwa S, Omonuva S. Malaria recurrence caused by Plasmodium falciparum. J Am Board Fam Pract. 2002;15:159-60.

[21.] Worldwide Antimalarial Resistance Network (WWARN) AL Dose Impact Study Group. The effect of dose on the antimalarial efficacy of artemether-lumefantrine: a systematic review and pooled analysis of individual patient data. Lancet Infect Dis. 2015;15:692-702.

[22.] Galappaththy GN, Tharyan P, Kirubakaran R. Primaquine for preventing relapse in people with Plasmodium vivax malaria treated with chloroquine. Cochrane Database Syst Rev 2013; 10: CD004389. doi: 10.1002/14651858.

[23.] Caskurlu H, Pakir E, Colak A. Evaluation of malaria cases in individuals after traveling to endemic regions of the world. Turk J Med Sci. 2014;44:168-170.

Ilkay Bozkurt, Meltem Karslioglu, Saban Esen

(1) Ondokuz Mayis University School of Medicine, Clinical Microbiology and Infectious Diseases Department, Samsun, Turkey

Correspondence:Dr Ilkay Bozkurt, Ondokuz Mayis University School of Medicine, Clinical Microbiology and Infectious Diseases Department, Samsun

Phone: + 90 362 3121919 Mobile: + 90 505 6746597

Fax: + 90 362 4576041

E-mail: drilkaybozkurt@gmail.com

30.12.2017

29.08.2018

DOI: 10.4274/mjima.2018.26
Table 1. Laboratory characteristics of patients with malaria

Variable                         N       Mean[+ or -] Standart
                                 tested  deviation


White blood cells on admission   20        5 [+ or -] 2.8
(thousand/[micro]ul)
Platelets on admission           20       68.4 [+ or -] 43.0
(thousand/[micro]l)
Admission hemoglobin(g/dl)       20       12.4 [+ or -] 2.8
Bilirubin (total, mg/dl)         20        2.1 [+ or -] 1.7
Aspartate amino transferase      20       58 [+ or -] 42
(U/L)
Alanine amino transferase (U/L)  20       45 [+ or -] 29
Creatinin (mg/dl)                20        0.9 [+ or -] 0.4
C-reactive protein on            19      151.7 [+ or -] 85.8
admission(mg/dl)
Control C-reactive               14       34.9 [+ or -] 61.6
protein(mg/dl)

Variable                         Median           Normal
                                 (Min-Max)        range


White blood cells on admission    5 (1.7-11.4)      3.7-9.7
(thousand/[micro]ul)
Platelets on admission           64 (20-187)      179-373
(thousand/[micro]l)
Admission hemoglobin(g/dl)       12.8(6.2-16.2)    13.3-17.2
Bilirubin (total, mg/dl)          1.1(0.7-5.3)      0.1-1.5
Aspartate amino transferase      44(13-168)         8-46
(U/L)
Alanine amino transferase (U/L)  39(8-112)          0-40
Creatinin (mg/dl)                 0.8(0.4-2.53)     0.4-1.4
C-reactive protein on            140(14-325)      < 3.36
admission(mg/dl)
Control C-reactive                 9.5(0-177)     < 3.36
protein(mg/dl)

Table 2. Malaria species and administered drugs

Malaria species  Treatment

Plasmodium       * Artemisinin combination therapy (9/20)
falciparum       * Quinine based regimen(2/20)
                 * Mefloquine(3/20)
                 * Atovaquone-proguanil(2/20),
P. vivax         * Atovaquone-proguanil and chloroquine(1/20)
                 * Quinine based regimen and primaquine (2/20)
Plasmodium       * Quinine based regimen(1/20)
malaria
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Title Annotation:Research article
Author:Bozkurt, Ilkay; Karslioglu, Meltem; Esen, Saban
Publication:Mediterranean Journal of Infection, Microbes and Antimicrobials
Article Type:Report
Geographic Code:7TURK
Date:Jan 1, 2018
Words:3097
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