Epidemiology and clinical features of severe imported falciparum malaria among adults upon hospital admission: a four-year retrospective single-center study in Moscow, Russia

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Malaria stands as the most widespread and deadly disease transmitted by vectors. Due to its potential for life-threatening complications, the World Health Organization (WHO) classifies it as a major public health issue [7, 30]. Malaria is endemic in 91 countries, and nearly half of the world’s population is at risk. The WHO African Region carries a disproportionately high share of the global malaria burden. In 2021, the Region was home to 95% of malaria cases. Nearly all malarial deaths are caused by Plasmodium falciparum (P. falciparum), and 95% of such cases also occur in Africa [30, 31, 32, 33, 34]. Malaria is considered one of the major causes of travelrelated morbidity and mortality, especially among non-immune travelers from nonendemic countries to the endemic regions. According to a multicenter study from the GeoSentinel surveillance network, malaria was the most frequent cause of fever in 21% of returning travelers, followed by dengue, typhoid fever, chikungunya and rickettsiosis [10]. Individuals traveling from regions without malaria transmission to areas where it is endemic face a heightened risk of contracting the disease due to their lack of immunity. Accessing quality medical care while abroad can also be challenging for these travelers if they become ill. Furthermore, returning travelers who develop malaria in malaria-free countries may encounter additional obstacles [7, 10, 12, 22]. Since 2010, no autochthonous cases in the Russian federation have been reported. In 2012, the country was included in the list of those officially acknowledged by WHO to be malaria-free [4]. A recent state report from Rospotrebnadzor “On the state of sanitary and epidemiological well-being of the population in the Russian Federation”, indicated that over the past ten years, between 57–132 imported cases of malaria have been detected annually in Russia [16]. Most of these cases were solely imported from the WHO African and Asian region, and more than 50% of these cases were caused by P. falciparum infection (Fig. 1). Diagnostic and therapeutic delays are associated with the emergence of severe illness, particularly in cases of P. falciparum malaria in non-immune travelers [14]. Some literatures have implicated lack of effective antimalarial drugs in the country, late presentations, incorrect and delayed diagnosis as the driving factors that increases severe P. falciparum malaria deaths in Russia [4, 18, 23]. Healthcare providers in non-endemic malaria countries might lack familiarity with diagnosing and treating malaria, leading to delayed identification and treatment potentially resulting in severe complications and increased mortality rates. Very few studies have analyzed the clinical and epidemiological profile of severe P. falciparum malaria in Russia. Research focusing on rare diseases like malaria in non-endemic regions is crucial for educating primary care physicians about its symptoms, diagnosis, and treatment. This increased awareness and knowledge can lead to improved patient outcomes. This study aimed to characterize the epidemiological patterns of imported severe malaria cases and investigate the most common serious clinical presentations observed at the time of hospital admission. The final objective being to delineate peculiar patterns of severe P. falciparum malaria symptomatology in the context of travelers who are non-immune to malaria. Understanding these patterns would contribute to improved patient care and treatment protocols.

 

Figure 1. Geographic distribution of imported malaria cases in the Russian federation from 2015–2024. Complied by [16]

 

Materials and methods

This study included imported malaria cases at the Infectious Diseases State Hospital (IDSH) No. 2 Moscow from 2020 to 2023. The medical records were retrospectively evaluated in this single-center investigation. The diagnosis of P. falciparum infection was confirmed through microscopic examination of both thick and thin blood smears of patients. This analysis was conducted by an experienced microbiologist. While rapid immunochromatographic tests were initially performed, definitive diagnosis relied on subsequent microscopic evaluation of peripheral blood smears in every case. Clinical data were retrospectively extracted from the medical records. This information encompassed patient demographics (age and sex), travel details (destination country and purpose of travel), pre-trip preventative measures taken, presenting symptoms, and parasite density upon presentation. The severity of malaria cases was assessed using the WHO established criteria (Table 1). The results were statistically analyzed using Microsoft Excel software. Continuous variables are presented as arithmetical means and standard deviation (SD) or with median and interquartile range (IQR) as appropriate. Categorical data were described with numbers and percent.

 

Table 1. WHO clinical and laboratory definitions of severe P. falciparum malaria. Complied by [32]

Clinical features of severe malaria

impaired consciousness (including unrousable coma)

prostration, i.e. generalized weakness so that the patient is unable to sit, stand or walk without assistance

multiple convulsions: more than two episodes within 24 h

deep breathing and respiratory distress (acidotic breathing)

acute pulmonary oedema and acute respiratory distress syndrome

circulatory collapse or shock, systolic blood pressure < 80 mm Hg in adults and < 50 mm Hg in children

acute kidney injury

clinical jaundice plus evidence of other vital organ dysfunction

abnormal bleeding

Laboratory and other findings

hypoglycemia (< 2.2 mmol/L or < 40 mg/dL)

metabolic acidosis (plasma bicarbonate < 15 mmol/L)

severe normocytic anemia (hemoglobin < 5 g/dL, packed cell volume < 15% in children; < 20% in adults)

hemoglobinuria

parasitemia (> 10% parasitemia)

hyperlactatemia (lactate > 5 mmol/L)

renal impairment (serum creatinine > 265 μmol/L

pulmonary oedema (radiological)

 

Ethics approval. All patient medical records include signed, informed consent forms permitting possible future data extraction for research purposes.

Results

Patients’ characteristics. During the study period a total of 32 patients were identified with severe imported malaria, as defined by the World Health Organization (WHO). Among the 32 analyzable cases, 28 (89%) were men and 4 (11%) were women; the median age was 38 years (IQR 30–48). A total of 29 (88.6%) cases were among patients of Russian origin, 2 (6.25%) and 1 (3.1%) had European and African origins, respectively. Nearly all acquired their infection in sub-Saharan Africa countries (Fig. 2). No patient used malaria chemoprophylaxis before, during or after visit to these countries. The median length of stay in endemic areas was 17 days (IQR 11–49) Median time from symptom onset to presentation was five days (IQR 4–6). Only one patient (of African origin) had a history of having received treatment for malaria in the past. Demographic data are shown in Table 2.

 

Figure 2. Countries where possible P. falciparum malaria infection occurred

 

Table 2. Demographics data of patients

Number of patients		32
Male, Female (%)		28 (89%), 4 (11%)
Age, median years (IQR)		38 (IQR 30–48)
Malaria chemoprophylaxis before travel		0
Malaria chemoprophylaxis during visit		0
Malaria chemoprophylaxis after travel		0
Reported previous malaria		1
Time from onset of symptom to seeking healthcare, median days (IQR)		3 (IQR 1.5–4.7)
Time from onset of symptom to hospital admission, median days (IQR)		5 (IQR 4.2–6.8)
Reason for travel	Tourism	19
	Business	9
	Visiting friends or relatives	3
	Other	1

 

Clinical characteristics. All, 100% (32/32) severe malaria cases were caused by P. falciparum species. The initial diagnosis at admission were as follows: malaria (43.7%), fever of unknown origin (28.1%), acute viral infections of the respiratory system (9.3%), acute gastroenteritis (9.3%), unspecified viral hepatitis (6.2%), and meningitis of unknown etiology (3.1%.). It should be noted that most patients (29/32; 90.6%) reported no co-morbidities at the time of admission. The most frequent symptom upon admission was fever (96.5%). Other subjective symptoms presented at the time of admission are shown in Fig. 3.

 

Figure 3. Subjective complaints upon hospital admission

 

Symptoms of severe malaria. At the time of hospital admission, hyperparasitemia (99%), impaired consciousness (98%), prostration (78.1%), and jaundice (52%) were the most frequent findings as described by the WHO criteria for severe malaria. 27 out of the total 31 patients (86.6%) who were experiencing altered consciousness exhibited a Glasgow Coma Scale (GCS) score below 11, indicating a marked compromised level of consciousness. A smaller proportion (4/31 or 4.3%) presented with a GCS score above 13 but displayed disorientation regarding time and location. Among the 17 patients (52%) presenting with jaundice, scleral icterus (yellowing of the whites of the eyes) was observed in 12 patients (70%), while cutaneous jaundice (yellowing of the skin) was present in only 1 (5%). Dark urine was reported in 7 patients (41%). Among the 25 patients (78.1%) who exhibited signs of prostration, 17 patients (68%) were conscious but unable to sit upright, while 9 patient (36%) were conscious but incapable of standing or walking even with assistance. Median parasitemia at admission, was 11.2% or 576 500 parasites/μL (IQR 6.6–23% or 192 782–1 087 000 parasites/μL). Seven (21.9%) had a parasitemia greater than 20% (> 1 000 000 parasites/μL). Parasite density was observed to be higher 12–24 hours following patient admission to the hospital. Concurrently, impaired consciousness and prostration also became more apparent during this time period, while the onset of jaundice typically occurred later during hospitalization, predominantly around the second day (Fig. 4) Individuals experiencing altered consciousness exhibited significantly elevated levels of parasites in their bloodstream when these neurological symptoms manifested, as compared to patients who presented with prostration and jaundice (Fig. 5).

 

Figure 4. Timeframe of severe P. falciparum malaria manifestation upon hospital admission

 

Figure 5. Parasitemia at the time of occurrence of symptoms of severe P. falciparum malaria

 

Discussion

Previous studies examining severe malaria cases in non-endemic areas have largely concentrated on epidemiological patterns, as well as characterizing patient symptomatology and complications during hospitalization [13, 17, 19, 25]. This research examined not only the epidemiological patterns of occurrence for severe imported malaria but also the prevalent symptoms observed in patients at the time of hospital admission. Despite the limited duration of our study, we were unable to identify potential changes in in the epidemiological patterns of imported P. falciparum malaria in the Russian Federation. As previously stated, the majority of imported malaria cases originate from travelers visiting malaria-endemic regions in Africa. A review of malaria cases introduced into the Russian Federation over the past ten years as seen in Fig. 1 demonstrates a clear trend: the majority of these cases stem from regions where P. falciparum, P. vivax and P. ovale are prevalent. Consequently, the possibility of mixed-species Plasmodium infections must be carefully considered. While documented instances of mixed infections in Russia remain limited, underdiagnosis is a potential concern. This may be attributed to the prevalent use of traditional microscopic and rapid diagnostic tests, which may not reliably detect mixed infections. Notably, polymerase chain reaction (PCR) assays have demonstrated superior sensitivity in identifying malaria parasites at the species level, including in mixed-species Plasmodium infections. The recent implementation of PCR testing in Russia represents a significant step towards more accurate malaria diagnosis. It is noteworthy that none of the participants in the study received malaria chemoprophylaxis. A study by Krause G. et al. demonstrated that malaria chemoprophylaxis significantly reduced fatality rates among nonimmune malaria patient [85]. Another systematic review and meta-analysis which characterized the epidemiological status of malaria deaths showed that the proportion of adequate chemoprophylaxis was low among patients with severe imported malaria [28]. Therefore, the findings of this study may serve to optimize pre-travel consultation practice. In the Russian Federation, mefloquine chemoprophylaxis is the most frequently prescribed and preferred medication for individuals planning travel to malaria-endemic regions. Malaria imported to nonendemic settings, especially P. falciparum malaria, is sometimes initially overlooked and the delayed diagnosis is responsible for every year of preventable deaths [1]. The World Health Organization (WHO) advocates swift access to suitable anti-malarial treatment, preferably within the initial 24 h of first symptoms (fever), as severe complications of malaria can occur within hours or days [30]. The availability of effective antimalarial drugs is crucial for not only preventing the disease’s spread, especially in endemic areas but also reducing malaria deaths in edemic and non-endemic areas. Artemisinin-based combination therapies (ACTs) are the current standard for treating Plasmodium falciparum malaria. The availability and proper use of these drugs are vital, alongside monitoring for drug resistance to ensure treatment remains effective. Both previously published studies [4, 18, 23] and the internal analysis of malaria incidence carried out at the tertiary infectious diseases hospital in Moscow indicated above demonstrated that there are no effective, registered antimalarial drugs available in the Russian Federation. This lack of approved medications represents a major contributing factor to the limited readiness of the healthcare system for prompt management and treatment malaria in Russia, and it significantly contributes therapeutic delays. Our investigation revealed that over 80% of patients were hospitalized more than five days after experiencing initial symptoms. This delayed hospitalization, as highlighted by published research on severe falciparum malaria Russia, is a crucial factor contributing to the development of disease progression and associated complications [18]. A review of data from Russia revealed that only 48% of patients seeking medical care for malaria in 2015–2016 were correctly diagnosed initially. Diagnostic errors, which accounted for most cases, arose from several key factors:

• delayed seeking of care: both patients and doctors often had low awareness of malaria risks and its diverse symptoms;
• incorrect pathogen identification: this included errors such as confusing P. vivax with P. ovale;
• laboratory errors: these errors were caused by insufficient knowledge of parasite morphology and improperly prepared specimens [4, 18, 23].

Our study explored the possible syndromes that might precede the development of severe malaria outside of a hospital setting. According to our observation, initial symptoms of falciparum malaria require differentiation from other acute infectious diseases. The failure to consider malaria in the initial differential diagnosis proved fatal. This is illustrated by three fatal imported malaria cases in 2017 involving Russian tourists returning from Goa, who were misdiagnosed with influenza, respiratory infections, acute viral hepatitis, or acute gastroenteritis without being tested for malaria. Similar atypical malaria presentations were documented in a systematic review by Zaki et al. [36].

An internal, currently unpublished observations from a tertiary infectious diseases hospital in Moscow highlighted several barriers to timely malaria diagnosis in the Russian Federation. These include inconsistent epidemiological history taking due to language barriers and limited clinical vigilance, the absence of registered rapid diagnostic tests or antimalarial drugs, and the lack of molecular diagnostic capacity at the laboratory level. Samples must be referred to the central reference laboratory for PCR confirmation, leading to delays that complicate prompt public-health response. To enhance diagnostic accuracy, sustained clinical suspicion and meticulous collection of travel history are essential. Most of the severe P. falciparum malaria cases were within the middle age group did not present with additional underlying health conditions. This is in contrast to a study that found obesity and diabetes as risk factors for severe Plasmodium falciparum malaria [35]. The patients analyzed in this study had WHO severity criteria that classified them as having severe or complicated malaria: upon admission, the patient exhibited pronounced symptoms of impaired consciousness and prostration. The clinical hallmark of cerebral malaria is impaired consciousness and prostration, though these findings are more common in children. Protocol for managing cerebral malaria (for example the Airway Breathing and Circulation approach) should be initiated if symptoms occur [32]. Malaria complications may increase the risk of developing hypoglycemia, particularly those associated with impaired consciousness. Hypoglycemia is an independent risk factor for death in severe malaria and a recognized adverse treatment effect of parenteral quinine [24]. If possible, hypoglycemia should be confirmed, ideally by a rapid test. The WHO handbook on the management of severe malaria recommends that standard treatment of hypoglycemia consists of intravenous dextrose. Jaundice is one of the common manifestations of severe malaria in adults and its incidence vary from 10–45% in different regions. Our patients exhibited signs of clinical jaundice, though it was not readily noticeable upon initial examination. The presence of jaundice signifies a more critical stage of malaria, increasing the likelihood of complications. Jaundice combines with evidence of other vital organ dysfunction vital is recognized as a hallmark of severe malaria based on WHO severe malaria treatment guidelines [32]. Multiple factors contribute to jaundice in severe malaria. These include hemolysis of parasitized and nonparasitized red blood cell, hepatic dysfunction and possibly an element of microangiopathic hemolysis associated with disseminated intravascular coagulation. Management of jaundice in severe malaria is not different from management the other severe malaria symptoms which involves prompt administration of an adequate dose of antimalarials injection [26]. High parasitemia significantly contribute to mortality from falciparum malaria, but the relationship between parasitemia and disease outcome is influenced by the prevalence of malaria in a region. In areas with low malaria transmission, mortality begins to increase when parasite densities exceed 100 000 parasites per microliter (approximately 2.5% parasitemia) [28]. Conversely, in regions with high transmission rates, considerably higher parasite levels may be tolerated without severe consequences. Some studies from non-endemic malaria countries, does not completely share the same parasitemia criteria. In French guidelines, the severity threshold for parasitemia in severe malaria is > 5%, contrarily to > 10% identified in an investigation conducted in the International Health Department of the Hospital Clinic of Barcelona (Spain), from 2005 to 2023 [3]. In our study, the severity threshold for parasitemia was also more than 10%, which represents an extremely high value. However, the threshold varies from 2% to 4% among European guidelines [2, 5, 9, 15, 21]. The World Health Organization acknowledges “uncomplicated hyperparasitemia” as a category requiring closer monitoring but not necessarily indicative of severe disease [33]. However, it is important to note that measuring peripheral parasite counts alone does not fully capture the pathogenic mechanisms of P. falciparum malaria [29]. Therefore, there is an urgent need for biomarkers that can more accurately correlate with organ damage, disease severity, and life-threatening outcomes. Parenteral artesunate has a become the choice treatment of cases of high parasitemia malaria due to a Parasite clearance time and increased cure rate. Parenteral artesunate has a become the choice treatment of cases of high parasitemia malaria due to a reduced parasite clearance time and increased cure rate [20, 37]. Comprehensive supportive care plays a crucial role in treating severe malaria cases due to its multi-organ impact and potential for life-threatening complications such as severe anemia, acute respiratory distress, and metabolic imbalances (Table 3). Optimal management involves close monitoring of vital signs, identification and correction of reversible factors contributing to acidosis, and tailored fluid therapy to mitigate risks of complications such as pulmonary edema. Continuous observation and evaluation of hydration status are imperative to ensure the best possible outcomes for patients receiving intensive care. In addition to primary antimalarial treatments, adjunctive therapies such as the use of immunomodulators, exchange transfusion, antioxidants etc., have been explored as a means to enhance treatment effectiveness and mitigate complications associated with malaria. While there exists a substantial body of literature on this subject, many clinical trials exhibit methodological limitations, including open-label designs, lack of randomization, and small sample sizes. To definitively establish the efficacy of these interventions, rigorous research is crucial. This necessitates large-scale, multicenter trials employing double-blind, controlled methodologies [6, 11, 27]. In summary, the findings and analysis of this study provide a strong basis for further investigation. Additionally, this study’s results have significant implications for healthcare practitioners in non-endemic settings. This includes general practitioners, primary care physicians, paramedics, and ambulance personnel. These professionals can use the findings to promptly identify patients who may have severe malaria. This study’s primary limitation stems from its small sample size and short observation period. Consequently, larger-scale investigations are warranted to establish a comprehensive understanding of the recurring patterns associated with severe imported malaria cases in the Russian Federation. The findings emphasize the crucial role that antimalarial medication and prompt medical attention play in both preventing malaria and mitigating its severity. Prompt diagnosis and treatment of P. falciparum malaria is crucial, as delays in identification can lead to more severe illness. Our investigation also highlights the necessity of improving pre-travel consulting procedures.

 

Table 3. Clinical management of severe manifestations and complications of P. falciparum malaria Complied by [32]

Manifestation or complication	Immediate management
Coma (cerebral malaria)	Maintain airway, place patient on his or her side, exclude other treatable causes of coma (e.g., hypoglycemia, bacterial meningitis), intubate if necessary
Convulsions	Maintain airways; treat promptly with intravenous or rectal diazepam, lorazepam or midazolam. Check blood glucose
Hypoglycemia	Check blood glucose, correct hypoglycemia and maintain with glucose-containing infusion. Although hypoglycemia is defined as glucose < 2.2 mmol/L, the threshold for intervention is < 3 mmol/L for children < 5 years and adults
Severe anemia	Transfuse with screened fresh whole blood
Acute pulmonary oedema	Prop patient up at an angle of 45°, give oxygen, give a diuretic, stop intravenous fluids, intubate and add positive end-expiratory pressure or continuous positive airway pressure in life-threatening hypoxemia
Acute kidney injury	Exclude pre-renal causes, check fluid balance and urinary sodium; if in established renal failure, add hemofiltration or hemodialysis, or, if not available, peritoneal dialysis
Spontaneous bleeding and coagulopathy	Transfuse with screened fresh whole blood (cryoprecipitate, fresh frozen plasma and platelets, if available); give vitamin K injection
Metabolic acidosis	Exclude or treat hypoglycemia, hypovolemia and septicemia. If severe, add hemofiltration or hemodialysis
Shock	Suspect septicemia, take blood for cultures; give parenteral broad-spectrum antimicrobials, correct hemodynamic disturbances

About the authors

Karl Ch. Emerole

Peoples' Friendship University of Russia (RUDN University)

Author for correspondence.
Email: emerole_k@pfur.ru
ORCID iD: 0000-0002-0636-2710

PhD (Medicine), Associate Professor, Department of Infectious Diseases, Epidemiology and Phthisiology

Russian Federation, Moscow

Maria V. Bogdanova

Infectious Diseases Clinical Hospital No. 2 , Moscow

Email: bolnica2@yandex.ru

Infectious Disease Physician, 4th Infectious Disease Department

Russian Federation, Moscow

Mvuania N. Vellynance

Peoples' Friendship University of Russia (RUDN University)

Email: vellynancentonde@gmail.com

PhD Student, Department of Infectious Diseases, Epidemiology and Phthisiology

Russian Federation, Moscow

References

Supplementary files