Imported Plasmodium falciparum malaria in Istanbul,Turkey: risk factors for severe course and mortality

Abstract

We describe the epidemiological, clinical features and risk factors for the morbidity and mortality of imported Plasmodium falciparum malaria cases during the last 10 years in Istanbul, Turkey. The epidemiological, clinical and laboratory data of cases in six tertiary care hospitals in Istanbul between 2002 and 2012 were analysed. Seventy patients (65 males, five females; median age 37; range: 14–84) were included. Sixty-five (93%) patients had travelled to African countries and the remaining five to other malarious countries. Seventeen (24%) had a history of previous malarial episodes; eight (13%) developed recrudescence during the first month; 22 (31%), 17 (24%), 20 (29%) and three (4%) cases had cerebral malaria, cholestatic icterus, malarial hepatitis and respiratory distress syndrome on admission, respectively. Six of 12 patients with severe falciparum malaria died. Clinically, the presence of alteration in mental status, icterus, hypoglycaemia, disseminated intravascular coagulation and malarial hepatitis were statistically significant for the development of severe malaria and mortality. Recrudescence should not be forgotten, especially in uncomplicated cases.

Keywords

malaria icterus cholestasis

Introduction

Malaria is endemic throughout most tropical countries. Sporozoite forms of five Plasmodium species (Plasmodium falciparum, P. ovale, P. vivax, P. malariae and P. knowlesi) cause malaria via a bite from the female Anopheles mosquito. P. vivax malaria has been endemic in certain parts of Turkey for many years. However, the successful ‘National Malaria Elimination Program’ carried out country-wide during the last decade has almost eliminated the disease.¹ According to the World Health Organization (WHO) malaria report 2011, 81% (178 million cases) of the 216 million malarial cases reported in 2010 occurred in Africa, and an estimated 655,000 people died from malaria in 2010.² Increased travel to falciparum malaria-endemic countries has become an important health problem threatening non-endemic countries (e.g. Europe and USA), particularly in cases of non-adherence to prophylactic measures. In the surveillance study of the travel-associated diseases in Europe by Gautret et al., the highest increase in prevalence was reported in P. falciparum malaria (PFM) cases, which comprised 6% of all travel-associated morbidities.^3,4 PFM had rarely been reported in Turkey. However, due to the rapidly growing relationships between countries and the lack of appropriate prophylactic measures, exotic infections emerged in continents that had previously been free from such diseases. We describe the epidemiological and clinical features of patients with PFM who were followed-up in two university hospitals and three education and research hospitals in Istanbul, Turkey, within the last 10 years in order to determine the risk factors for morbidity and mortality.

Methods

Patients

Turkey has initiated an active campaign against malaria and all suspected or documented cases are reported to the head of department for the Fight Against Malaria (HDFAM) organization. This institution is responsible for the confirmation of the diagnosis of malaria by examination of peripheral blood smears, recording of epidemiologic data and the provision of antimalarial drugs.

The study included all the secondary and tertiary care centres in Istanbul, Turkey. All cases diagnosed with PFM were managed at the hospitals where they were admitted and were then notified to the HDFAM. According to the HDFAM records, in Istanbul 115 cases were reported to have PFM from 2002 to 2012. We contacted the infectious diseases specialists working at the centres where the patients had been treated. They were asked to fill in the epidemiologic (age, gender, nationality, country visited, history of prophylaxis, prior malarial episode), clinical (symptoms and signs), laboratory and treatment data from patient records on an excel file retrospectively. The data in the medical records of 70 (60.8%) of the 115 patients were available for comprehensive review and were, therefore, included in our study. Subjects younger than 15 years were excluded. Diagnosis was established by the demonstration of the parasites on Giemsa-stained thin and thick preparations of peripheral blood smear.

Definitions

Severe PFM defines the malarial infection in patients with indications of intensive care unit (ICU) admission.⁵ Cerebral malaria defines the co-existence of severe PFM and encephalopathy ranging from blurred consciousness to delirium or comatose clinical picture (i.e. Glasgow Coma Scale <11) with or without concomitant convulsions.⁶ Malarial hepatitis refers to elevated transaminases [especially alanine aminotransferase (ALT) more than three times the upper limit of normal] and conjugated hyperbilirubinaemia which normalizes after anti-malarial treatment in patients with malaria or hepatitis with disseminated P. falciparum infection proven at autopsy provided that viral or drug-related hepatitis had been ruled out.⁷ Recrudescence refers to relapse due to inadequate or ineffective treatment for PFM in the previous month.⁸

Data analysis

Patients’ data were analysed by the statistical package Stata 12 (StataCorp 2011, Stata Statistical Software: Release 12; USA, Texas: StataCorp LP). Dichotomous variables were compared by chi-square test or Fisher’s exact test where appropriate. Continuous variables were compared using the t-test or unequal variances t-test. Two-sided significance was assessed at P value less than 0.05.

Results

The median age of 70 patients (65 men, 5 women) was 37 (range: 15–84). Nine (13%) were foreigners and the rest were Turkish citizens. Sixty-five (93%) had visited African countries and the remaining five travelled to countries outside Africa (Saudi Arabia, Yemen, Pakistan, India and Iran).The time interval between the onset of fever and the diagnosis was less than 2 weeks. The most characteristic presenting symptom in all patients was fever. The characteristics of patients, clinical signs and symptoms and laboratory data are summarized in Table 1.

Table 1.

Characteristics, clinical and laboratory findings of plasmodium falciparum patients.

Characteristics (n = 70)	n	%
Age (mean ± SD)	36.57 (±11.14)
Male	64	91.43
Travel region
Africa	64	91.43
Others	6	8.57
Duration of travel (mean ± SD)	103.88 (±202.01)
Chemoprophylaxis
Received (mean ± SD)	5	7.14
WBC <4000 cell/mm³	25	35.1
Hemoglobin <12 mg/dL	44	62.86
PLT <100000 cell/mm³(n = 69)	58	84.06
Total Bilirubin >1.5 mg/dL	38	54.29
Direct Bilirubin >2.5 mg/dL	17	24.29
Creatinine >1.5 mg/dL	14	20
ALT >60 IU	32	45.71
AST >60 IU	39	55.71
LDH >400 IU (n = 63)	46	73.02
Gastrointestinal symptoms	23	32.6
Hepatomegaly	32	45.71
Splenomegaly	49	70
Icterus	24	34.29
Cerebral Malaria	22	31.43
Coma	7	10
Confusion	14	20
Convulsions	1	1.43

SD, standard deviation; WBC, white blood count; PLT, platelet

Seventeen (24%) patients had a history of a prior malarial episode – nine within the previous month (recrudescence). Only one with a previous malarial infection had the severe form of the disease. Twenty-two (31%) had cerebral malaria (14 blurred consciousness, 7 comatose, 1 convulsion); 17 (24 %) had cholestatic icterus; 20 (29%) had malarial hepatitis; 16 (23%) had hypotension (i.e. mean arterial pressure less than 70 mmHg); 12 (17%) had hypoglycaemia (i.e. glucose level less than 70 mg/dL); five (7%) had disseminated intravascular coagulation (DIC); three (4%) had adult respiratory distress syndrome (ARDS). Twelve (17.2%) who had indications for ICU admission were considered to be suffering from severe malaria and six (8.57%) died from malaria. The density of parasitaemia was not detected in all cases but it was >5% in those with severe PFM.

A comparison of the demographic, clinical characteristics and laboratory findings of the patients in terms of outcomes is shown in Table 2.

Table 2.

Comparison of characteristics, demographic and laboratory findings of Plasmodium falciparum patients in terms of outcomes.

Variables*	Died (n = 6)		Survived (n = 64)		P
Variables*	n	%	n	%	P
Age	35.67 ± 6.89	36.66 ± 11.49	0.761
Male gender	5	83.33	59	92.19	0.428
Duration of travel	108 ± 141.07	103.48 ± 207.82	0.945
Prophylaxis	0	0	5	7.81	1
Cerebral malaria	6	100	1	1.56	<0.001
MAP	62.77 ± 13,88	81.57 ± 12.13	0.018
DIC	4	66.67	1	1.56	<0.001
ARDS	1	16.67	2	3.12	0.239
Icterus	6	100	18	28.57	0.001
Cholestatic icterus	6	100	11	17.19	<0.001
Malarial hepatitis	6	100	23	35.93	<0.001
Hypoglycaemia	3	50	9	14.06	0.026
Urea (mg/dL)	149.17 ± 116.96	41.26 ± 33.48	0.073
Creatinine (mg/dL)	2.71 ± 2.15	1.37 ± 1.28	0.19
ALT (IU)	86.83 ± 41.68	82.8 ± 98.14	0.85
AST (IU)	142.17 ± 38.82	83.13 ± 89.18	0.009
Total bilirubin (mg/dL)	9.13 ± 5.45	2.9 ± 3.48	0.036
Direct bilirubin (mg/dL)	6.23 ± 3.93	1.27 ± 1.57	0.027
INR	1.18 ± 0.16	1.17 ± 0.24	0.945
Haemoglobin (mg/dL)	10.1 ± 2	11.11 ± 2.45	0.285
Glucose (mg/dL)	75.67 ± 21.51	91.03 ± 26.13	0.145
PLT (cells/mm³)	24000 ± 15475.79	97610.94 ± 214287.4	0.01
WBC (cells/mm³)	16266 ± 7495.51	5102.34 ± 2355.28	0.014
LDH (IU)	641.5 ± 243.17	678.27 ± 425.15	0.794
Recrudescence	1	17	8	12.5	0.999

Continuous variables are presented as mean ± SD.

MAP, mean arterial pressure; DIC, disseminated intravascular coagulation; ARDS, acute respiratory distress syndrome; ALT, alanine transaminase; AST, aspartate transaminase; INR, international normalization ratio; PLT, platelet; WBC, white blood count; LDH, lactate dehydrogenase.

Parenteral quinine dihydrochloride or artemether were the first-line drugs in complicated cases and oral artemether lumefantrine or mefloquine were the treatment modalities for uncomplicated cases.

Discussion

Malaria surveillance is carried out both actively and passively in Turkey. The HDFAM has reported that 155,234 blood specimens were screened of which 439 (0.28%) were diagnosed as malaria between 2002 and 2012 in Istanbul. Of these 324 (73.8%) and 115 (26.2%) cases were caused by P. vivax and P. falciparum, respectively. The total number and the proportion of imported PFM cases has increased when compared with the number reported between 1981 and 2000.⁹

WHO has described and published the diagnostic criteria for PFM (first in 1990 and revised in 2000).⁶ Severe PMF refers to the clinical picture complicated by: metabolic acidosis; severe hypoglycaemia; anaemia and bleeding; respiratory and renal insufficiency; and dysfunction of the central nervous system. Low level of parasitaemia (<0.1% infected erythrocytes) and mild clinical findings are the characteristic features of uncomplicated PFM. WHO specified the cut-off levels of infected erythrocytes in regions with low and high transmission rates of malaria as >5% and >10%, respectively, and recommended that hyperparasitaemia, together with a severe clinical course, should be considered as predictors of severe malarial infection.¹⁰

This is a retrospective file analysis study. Objective evaluation criteria for each patient had not been kept in a standard format. In our health care system, intensive care unit indications (mechanical ventilation, need for inotropic support and coma) are very restricted. Therefore, we identified the main criterion for severe malaria as an intensive care unit indication. As the data regarding the density of parasitaemia were lacking for some of the patients, we could not report the ratio for all patients.

Older age was reported as a risk factor of severe falciparum malaria in non-immune patients in previous studies.^11,12 As our citizens usually visited Africa for business, the mean age of the patients refers to young people. In a comparative analysis, age was not a risk factor for severity or mortality.

Cerebral malaria is an encephalopathic condition with impaired consciousness, delirium, seizures and, rarely, focal neurologic signs.¹³ In our patients, the presence of central nervous system dysfunction due to sepsis, bacterial meningitis, viral encephalitis and hypoglycaemia was ruled out. All of the blood and cerebrospinal fluid cultures obtained from patients with cerebral malaria remained sterile. Cerebral malaria, defining the co-existence of severe PFM and central nervous system dysfunction, has been found to be statistically significant for severe P. falciparum infection and fatality (P = 0.001).

Jaundice is usually secondary to intravascular haemolysis during the course of PFM. It also develops after differential interference contrast (DIC) and direct hepatocyte damage.⁷ Marsh et al. investigated the risk factors of increasing mortality in African children with malaria and found that 4.7% had jaundice and the relative risk was found to be 4.46 (2.2–9.4).¹⁴ A study from the USA reported 188 severe PFM cases that were categorized as severe and less severe forms and jaundice was present in 55% and 32%, respectively. The authors emphasized that the presence of jaundice alone was not a strong prognostic marker.¹⁵ In our study, 24 (34%) had clinical jaundice. Of these, 17 (71%) presented with cholestatic jaundice. Malarial hepatitis was detected in 29 (41.4%). The presence of cholestatic jaundice and malarial hepatitis was statistically significant for severe PFM and related mortality (P < 0.05).

Re-emergence of malaria occurs as a result of relapse or recrudescence after treatment. P. vivax and P. ovale have hypnozoite forms and may cause relapse within months of the initial successful treatment. P. falciparum is the usual cause of recrudescent infections as it can remain in blood stream due to ineffective treatment or host immunity.^8,16 In our patients, 10 (14.2 %) had an average of 11 prior malarial attacks treated within the previous 64 days (7–180 days) before the last presentation; nine of them had received their last malarial episode within the previous month (recrudescence). Three patients had received previous treatments of 3-day artemether-lumefantrine and two had received quinine. The treatments of other cases had not been documented.

However, we have retrospectively evaluated the records of the patients with PFM who were managed in various hospitals over a period of 10 years. Therefore, possible subjective parameters in the determination of ICU indications of the patients must be taken into account. Well-designed prospective studies are necessary in order to evaluate the predictors of mortality and morbidity in patients with PFM.

Conclusion

In clinical practice, the presence of changes in mental status, icterus, hypoglycaemia, DIC and malarial hepatitis were statistically significant for the development of severe malaria and mortality. Patients returning from malarious areas, particularly those indicating ICU admission as a suggestible severity criterion, should be promptly managed due to the high mortality rate in cases of delayed diagnosis. We suggest that patients with a history of prior diagnosis and treatment of PFM should be carefully monitored for recrudescence, particularly for the first month after treatment.

Footnotes

Declaration of conflicting interests

None declared.

Funding

This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

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