The permanent and constant maintenance of an optimal level of vitamin D status is a difficult task to achieve but of paramount importance for a growing organism, starting with the first minutes of conception and intrauterine development, continuing with the postnatal period, until the end of life with beneficial impact not only on strengthening bone health and maintaining phosphocalcium homeostasis, but also on protection against various diseases and conditions, including infectious and parasitic diseases of all kinds [1]. Pediatricians were among the first to draw attention to the ability of vitamin D to reduce general (including infectious) morbidity. As early as the 1960s, Soviet researchers noted that prescribing vitamin D to young children (1 month to 3 years) suffering from rickets reduced the risk of morbidity and mortality from bronchopneumonia [2]. However, the associations between vitamin D deficiency and morbidity in older children remain poorly understood. Evidence-based medicine data indicate the importance of using vitamin D preparations for the prevention and treatment of tuberculosis, chronic bronchitis, and the prevention of infectious diseases and malaria [3]. The purpose of the article was to analyze the most relevant publications and inform practitioners of various specialties about the epidemiological situation in post-war Bessarabia regarding the high morbidity and mortality from malaria and the risk that we face in the future with global warming and the permanent presence of the vector of this potentially deadly disease against the background of a deficient vitamin D status.

For the secondary, qualitative, narrative synthesis study dedicated to malaria and vitamin D deficiency on population health, a search for the results of published primary studies was conducted, using the electronic databases Cochrane, PubMed, Scopus, and Web of Science. From 116 literary sources, 44 studies published between 1962 and 2025 in different languages (English, French and Romanian) were selected. Depending on the databases, different search keywords were used: for the PubMed database - "malaria" and "plasmodium infection"; for the others - "malaria", "vitamin D", "malaria-related morbidity", "vitamin D status", "malaria in Bessarabia", "malaria in Europe", "malaria in Ukraine", "malaria in Romania". Articles from electronic databases were imported into Endnote, eliminating 72 publications for the following reasons: mismatch between the title and the results, between the result presented in the abstract and the respective section of the article, by geographical region, duplicates. All references of relevant studies were checked to find potentially related articles.

The history of the morbidity and mortality of the Bessarabia population in the post-war malaria years. The phenomenon of epidemics in the Union of Soviet Socialist Republics (USSR) during the first post-war decade, represents an unexplored subject by both the Soviet historiography and the Republic of Moldova (Bessarabia). There are some exceptions: reports written by some epidemiologists that approach the subject from the perspective of public health. Multiple errors in the management of treatment and eradication of these diseases caused by the policy of the communist regime resulted in numerous human victims [1-3]. It is known that the sinister Bolshevik experiments of communalization of agriculture generated, in 1946-1947, mass starvation, which led to a dramatic increase in the level of morbidity and mortality of infectious diseases [1]. Malaria has played a major role in human history, causing harm to more people than perhaps any other infectious disease [4]. It is an infection that has made its way in Bessarabia for centuries on the lower course of the Prut, Dniester, R?ut and Bâc rivers, affecting mercilessly, year after year, tens of thousands of people and reaping thousands of lives [5].

Official Statistics of Malaria Morbidity and Mortality in Bessarabia

Malaria was one of the most widespread infectious diseases in Bessarabia over centuries. According to statistics, in 1910 – 89,450 cases were registered, in 1934-1939 approximately 90,000 cases were recorded annually (in 1938 – 96,000 cases) or 2,500 cases per 10,000 population, the disease having serious social consequences - 300 annual deaths from malaria [6,8]. According to archived data, in 1945, malaria’s incidence rate in the USSR was 580.2 per 10,000 inhabitants. The most affected cities being Bender and Tiraspol, in the territory east of Dniester River, with 2180 and 1230.3 cases per 10,000 residents. Among the administrative units in the former Bessarabia, the most cases were reported in the following counties: Orhei (672.7), Chisinau (449.7), and Balti (441.9), Cahul (426.7) cases 10,000 inhabitants [4]. Official statistics indicate a decrease in the incidence of malaria in 1946 in the entire republic, as well as in each individual county, reporting an index of 293 cases per 10,000 inhabitants [4]. This data does not reflect the real situation, but is rather a confirmation of the lack of complete data from districts and counties about the number of those affected by malaria [4]. On the other hand, the reports of the Ministry of Health from the Moldavian Soviet Socialist Republic (MSSR) indicate a significant increase in the number of cases starting with May 1946. [8] The morbidity of malaria increased during the war, and created an extremely difficult situation, which led to the inauguration of the Republican Combat Station of malaria in October 1944. It was meant to ensure the realization of antimalarial measures. In 1948 additional countermeasures against malaria were adopted. The Ministry of Health of the USSR sends special teams of doctors and a group of scientists of the Institute of Scientific Research in the Field of Malaria, medical parasitology, and helminthology, as aid to local health workers.

Among The Factors That Had a Negative Impact on the Fight against This Epidemic Was the Very Low Level of Hospitalization

The situation in this chapter was somewhat different for patients from Chisinau and the other three main cities (Balti, Bender, Tiraspol), although even they were not hospitalized entirely due to lack of beds. In 1946, in the main cities of the USSR, 5,227 patients (8.1%) were hospitalized out of a total of 64,527 referrals. In the city of Chisinau 702 people (26.6%) were hospitalized out of a total of 2636 addresses; in Balti - 228 (17.9%) out of 127; Bender 235 (18.8%) out of 15477. In other districts the percentage of hospitalizations varied between 3-5% [4]. Most patients, however, "were treated at home" [4].

The Prophylactic and Anti-Epidemic Measures Undertaken during the Soviet Period on the Territory of Bessarabia

According to the data of the Ministry of Health of the SSR in 1946, 44737 sick people underwent pharmacological prophylaxis [7]. In the 1940s, the malaria treatment protocol in the USSR prescribed the antiparasitic drug called akrikhin [4]. This drug, characterized by its bitter taste, was the most effective remedy against malaria at that time. Without having serious side effects, its only drawback was the property of coloring the skin yellow, however the hue would disappear after the treatment stopped. Generally, in the early years of the epidemic (1945-1949), chemoprophylactic treatment included a random small number of people. In the rural regions, campaigns for chemoprophylaxis among malaria patients were carried out by volunteers recruited from the state institutions, collective and state farms. These volunteers distributed akrikhin pills to the homes of the sick, which were often not administered according to medical prescriptions. In some cases, the antimalarial stations themselves would organize inadequate chemoprophylaxis, which led to its ineffectiveness [4]. Considerable efforts and resources were directed to combat the disease vectors Thus, in 1948, treatment with DDT was initiated, yielding significant epidemiological effect, while the areas around rivers and ponds were treated with hexachloran [4,6]. In the following year, they treated the ponds and water basins along the lower reaches of the Prut and Dniester rivers, as well as an area of 3-5 km around these bodies of water, thus aiming to protect a population of 50,000 people [6]. In 1948, 82,813 new cases were recorded. In the following year, the number of patients dropped to 31251, of which only 15601 were new cases. It should be mentioned that by 1950 the number of antimalarial stations in the republic had risen to 63, therefore, increasing the efficiency of the efforts to combat the disease. In 1953 malaria morbidity recorded a sudden decrease, with only 890 cases having been detected [6].

The Risks for the Reappearance of New Indigenous Outbreaks in the Republic of Moldova

During the year 1954, Moldova had no reported cases of malaria in most districts, whereas the few remaining districts collectively reported 237 new cases. As a result, 1953 was marked as the year that malaria was effectively eradicated as a widespread disease in Moldova. The last registered case of malaria was in 1960 and this fact was confirmed by laboratory findings, obtained after a medical examination of the local population, conducted in the same year. The results show that among the 104,944 people examined for malaria in 1955 and the 63,859 examined in 1960, only one carrier of parasites was detected [6]. Although 1960 was considered the year of elimination of indigenous malaria cases, this achievement cannot be considered a complete eradication of malaria in the Republic of Moldova. Considering that there are approximately 100 endemic countries globally, recent data from the CDC reveals an annual tally of 350-500 million recorded cases of malaria, resulting in over a million deaths. Alarmingly, a significant portion of these fatalities comprises young children from South Africa. Subsequently, as a result of global immigration, there has been an increase of malaria cases in the Republic of Moldova in recent years, a majority of them being imported. In the 1990s, 1 to 8 cases were recorded annually. The numbers increased from 27 to 47 cases in 2007, The majority of cases were detected in natives returning home from different jobs in Sudan, Cameroon, Congo, Gabon, Angola, Equatorial Guinea, Iraq, Afghanistan, and the Russian Federation [8].

Mosquito species - the potential for malaria transmission to be reintroduced in Moldova, Ukraine, and Romania. In the Republic of Moldova, the primary vector responsible for malaria spreading is the female Anopheles mosquito [6]. Until 1950, massive outbreaks of malaria were experienced with development of 5 to 6 generations of An. maculipennis s.l. per year with peak abundance in July-August due to favorable climatic conditions [9]. The agents behind malaria were P. vivax, P. falciparum and P.malariae. Anopheles messeae and An. maculipennis s.s. were considered the most important vectors [8]. Furthermore, the lack of immunity against malaria, led to minor flares of these diseases [4]. In Europe, a minimum of four possible mosquitos have been identified as vectors [4,10]. Despite the eradication of malaria in the 1960s and 1970s across the European continent, the anopheline vectors are still present, as reported in more than 20 European countries Anopheles atroparvus is one of the predominant potential vectors of malaria [11,12]. As of now, the majority of cases reported in Europe have been acquired by travelers in endemic areas, however, the possibility of acquiring malaria by locally infected mosquitoes has been insufficiently investigated, despite occasional autochthonous malaria cases being reported in several European countries [12]. Anopheles atroparvus can be found from south-eastern Sweden all the way to Portugal along the Atlantic coasts, as well as around the Baltic and Mediterranean Seas, and has a patchy distribution in southern and south-eastern Europe [12]. Its distribution does not overlap with that of Anopheles labranchiae [17]. It is suggested that the species is absent from southern Italy and Greece. Distinguishing adult forms of Anopheles atroparvu from other sibling species within Anopheles maculipennis complex is practically unattainable [11]. The easiest way to morphologically identify them is by examining their eggs [14]. Eggs of Anopheles atroparvus have an upper surface softly patterned with wedge-shaped dark marks on a pale background [14]. In the Republic of Moldova, the current mosquito population remains under-researched. For a better understanding of the mosquito fauna, collections were made from early April to mid-November between 2008 and 2012 [13].

A total of 10,923 larval specimens and 8,246 adult mosquitoes were collected from 20 regions across Moldova [13]. The survey identified 36 species, thereby increasing the country’s known mosquito fauna to 40 species, these comprised representatives of 9 genera and 11 subgenera [13]. Seven species are reported as new national records: Anopheles pseudopictus, Anopheles melanoon, Aedes geminus, Culex torretium, Culiseta longiareolata, Coquillettidia buxotoni and Uranotaenia unguiculata [13]. A countrywide field survey of immature mosquitoes was conducted in Moldova with the aim to evaluate the species composition of Culicidae in different larval habitats and their distribution throughout the country [14]. Altogether, samples were collected from 259 likely larval habitats across 53 localities, resulting in 9,456 specimens collected. Among the collected specimens, twenty species from the Anopheles, Aedes, Culex, Culiseta, and Uranotaenia genera were collected. The mean species abundance in aquatic habitats ranged from 1.00 to 4.00, and it was higher in swamps, flood plains, ditches and large ground pools, while being lower in rivers, streams, tree-holes, and containers [14]. In a sole type of aquatic habitat, a number of six mosquito species were identified. “Anopheles maculipennis. s.l., Culex pipiens pipiens L., and Culex modestus Ficalbi presented with larger numbers and widely distributed species representing over 80% of the identified specimens” (Sulescu, et.al, 2015) [14]. Findings demonstrated the simultaneous incidence of Cx. p. pipiens and Culex torrentium Martini in both natural and rural environments [14]. In summary, the previous analysed area has undergone major ecological modifications since the preceding studies in the 1950s, which could be a reason why Culex theileri Theobald is nearly extinct in Moldova [14]. The larval abundance of Anopheles maculipennis s.l., previously reduced with DDT control in the 1950s, had returned to the levels observed in the 1940s [14]. Over the years, the measures taken in the fight against malaria vectors have decreased significantly, leading to an important increase in the number of mosquitoes per square meter. This phenomenon, in combination with a rise in imported cases of malaria caused by intensive migration to malaria endemic areas, constitute a risk of the reintroduction of malaria transmission in Moldova [14,15].

The current epidemiological situation regarding malaria incidence in Moldova, Ukraine and Romania. The Republic of Moldova hasn’t had any indigenous malaria cases for more than half a century, however there were cases of imported malaria. In the last 3 years (2019-2021), 7 cases of malaria were registered: 3 cases in 2019; 2 cases in 2020 and 2 cases in 2021 [16]. Out of all the imported cases, the majority of infections (93.9%) were proven to be with P. falciparum. Infections with P. ovale constituted 4.0% and with P. vivax-3.2% [16]. The geographical location and climatic conditions (temperate climate, presence of Anopheles mosquitoes, and intense migration of the population, especially to endemic areas) put the Republic of Moldova among the countries with increased risk of malaria transmission [16]. These therefore endanger the status of Moldova as a malaria free country. The majority of imported cases in Ukraine, a neighboring country, are from the tropical region of Africa, clinically manifesting as the most severe status of the disease, however being beneficial from an epidemiological point of view, as the mosquitoes found in Ukraine are not susceptible to tropical African malaria [16]. Citizens of Ukraine don't consider the dangers of traveling to tropical countries for holidays, which leads to deaths caused by malaria.

The outbreak of war in Ukraine, coupled with significant migration to Romania, with imported cases only, and to other countries where the malaria vector is still present (Belarus, Bulgaria, France, Greece, Italy, Portugal, and Spain) significantly increases the risk of re-emergence of malaria [18].

Malaria incidence statistics on the continent of Asia, Africa and Europe. Africa continues to bear the heaviest burden due to malaria. According to the World Malaria Report 2022, published by WHO, in 2021, Africa accounted for 96% of all cases of malaria (238 million cases) and 98% of all malaria-related deaths (603,877 deaths) [17]. Almost 77% of these deaths involved children under the age of 5 [24]. Globally, malaria is the cause of death of 8% of children younger than 5, nevertheless in Sub-Saharan Africa a disproportionate 17% of fatalities in children below the age of 5 were attributed to malaria. Since 2000, the incidence has decreased by 37% and its mortality by 59% [17]. As a result, 1.5 billion malaria cases and 10.6 million malaria deaths have been avoided over the past two decades in Africa [17].

Malaria mortality increased by 7.4% in 2020, but decreased by 3.4% in 2021 [17]. In 2021, out of the 4,856 malaria reports documented in the EU/EEA, more than 99% (4 855 cases) were confirmed [17]. France reported the highest number of cases, followed by Germany, Italy, Spain, and Belgium [17]. The 2022 African report also indicated that from the year 2015 to 2019, the total report rate remained steady, varying between 1.2 and 1.3 per 100,000 individuals [17]. The lowest notification rate was observed (0.3 per 100 000) in 2020 followed by an increase in 2021 (0.6 cases per 100 000 population) [17]. In 2021, Luxembourg had the highest report rate (4.4 per 100 000 population), succeeded by Iceland, with 1.9 per 100 000 population, then Sweden, with 1.4 per 100 000, and Norway with 1.3 per 100 000 population [17]. Among 4 257 imported cases, 99.7% were associated with travel [17]. Among the ones labeled as acquired within the EU, 4 cases were established in Greece and 9 cases in France [18, 19]. Three of the cases in Greece were related to P. falciparum transmission in a hospital in the Attica region [19]. In 2021, almost every malaria case stated by EU/EEA countries was imported, most likely due to the socio-economic and historical ties of some of those countries with endemic regions of the African and American continents [19].

The literature suggests that a significant proportion of imported malaria cases in the EU/EEA occur among recent immigrants from malaria-endemic countries and settled migrants who travel to visit friends and relatives in malaria-endemic countries [20]. The COVID-19 pandemic was potentially responsible for the decline in the number of reports in 2020, due to the restrictions in traveling, significant behavioral changes in the overall populational, and tourism to endemic regions. The increasing number of cases in 2021 probably reflects the lifting of those travel restrictions [18, 20].

According to the WHO, 2023, the South-East Asia Region had nine malaria endemic countries in 2022, accounting for 5.2 million cases and contributing 2% of malaria cases globally [21]. Sri Lanka was confirmed to be malaria free in 2016 [21]. In 2021, for the first time, Thailand had zero local deaths, and in 2022, there was just one declared death due to a P. knowles infection [30]. In 2022, Timor-Leste reported zero indigenous cases for the second consecutive year, while Bhutan and Nepal reported zero indigenous cases for the first time [21]. Between 2019 and 2022, there was an increase of more than 500 000 cases in Myanmar due to the political and social instability in the country, with a sevenfold increase in cases, from 78,000 to 584,000 cases [21].

Malaria and Vitamin D

Research on the role of vitamin D in malaria traces back to the late 1950s and the 1980s, when some studies showed promising results indicating a potential antiplasmodial activity of active vitamin D [31]. These discoveries have inspired the researchers to further explore this correlation.

The Pathophysiological Mechanism. Modern Views.

Research since the 1950s has suggested a potential antiplasmodial role for active vitamin D [31]. Vitamin D modulates both innate and adaptive immunity through defensins, cathelicidin, lactoferrin, reactive oxygen species, and inhibition of phospholipid biosynthesis. In malaria, inadequate vitamin D status may exacerbate disease severity by impairing immune regulation, increasing inflammation, and limiting control of Plasmodium infections [23,24].

Vitamin D influences T-helper (Th) cell balance, promoting Th2 and regulatory T cell (Treg) activity while inhibiting Th1 and Th17 proinflammatory cytokines (TNF-α, IL-1, IL-2, IFN-γ) [25,26]. Experimental studies in mice show that vitamin D supplementation reduces Th1 responses, enhances Treg activity, and maintains blood–brain barrier integrity during cerebral malaria (CM), leading to lower mortality and severity [24,35]. Vitamin D also supports calcium-phosphate homeostasis, reduces oxidative stress, and modulates immune cell migration and cytokine production, all contributing to protective effects in malaria [26-28].

Vitamin D Deficiency in Malaria-Endemic Areas

Vitamin D deficiency is widespread globally and contributes to bone disorders and increased susceptibility to infectious diseases, including severe malaria [29–30]. Serum 25(OH) D levels are used to assess status: deficiency <30–50 nmol/L, insufficiency 50–75 nmol/L, sufficient ≥75 nmol/L [31,32]. Prevalence varies by region: highest in the Eastern Mediterranean, significant in Europe, Southeast Asia, and Western Pacific. Risk factors include limited sunlight exposure, skin pigmentation, age, and inadequate supplementation, especially in infants and young adults [31-33]. Seasonal variations affect levels, with winter–spring associated with higher deficiency rates.

Correlation with Malaria Morbidity and Mortality

Cerebral malaria (CM), primarily caused by P. falciparum, is characterized by coma and high mortality if untreated (up to 100%) and persists as a major cause of childhood morbidity in endemic regions [34,35]. Severe malaria is associated with excessive Th1 responses and dysregulated Treg activity, leading to inflammation and neurocognitive impairment [34]. Vitamin D modulates these responses, reducing Th1-driven inflammation, enhancing Treg function, and increasing IL-10 production, thus mitigating CM severity [35]. Supplementation studies in mice demonstrate improved survival and reduced neurological damage, supporting a potential preventive role of vitamin D in malaria-endemic regions [24,35].

Malaria Prevention

Prevention relies on protection against Anopheles mosquito bites and chemoprophylaxis [38-40]. Protective measures include wearing appropriate clothing, using insect repellents (DEET, picaridin), bed nets (preferably permethrin-treated), and permethrin-treated clothing. Chemoprophylaxis selection depends on age, travel destination, local drug resistance, and medical history. Regular updates from health authorities are essential. For infants, special precautions apply regarding repellent use, breastfeeding, and prophylactic drug exposure [38-44].

Management of Vitamin D Deficiency

Vitamin D deficiency affects over 1 billion people globally, with ~50% of the population insufficient [39-43]. Risk factors include limited sun exposure, dark skin, age, obesity, and certain medications. Infants and breastfed children require supplementation (400 IU/day), especially during winter months or in regions with limited sunlight [43]. Toxicity is rare but possible at serum 25(OH) D >88 ng/mL, leading to hypercalcemia and renal complications. Monitoring serum calcium is recommended in high-dose therapy or patients with malabsorption [41-43].

Vitamin D deficiency is highly prevalent worldwide, including in malaria-endemic areas. Evidence suggests that adequate vitamin D status may reduce malaria severity and CM-related mortality. Combined with chemoprophylaxis, immunization, and vector-control measures, ensuring optimal vitamin D levels could enhance malaria prevention and treatment strategies. Sporadic malaria cases in Eastern Europe (Moldova, Ukraine, and Romania) further underscore the importance of research into vitamin D’s role in malaria control and public health interventions.

None declared.

Authors’ Contributions

AV, CV, LS and IR designed the study and wrote the manuscript; AR, CV collected the data; AV and RI revised the manuscript critically; CV, AV, IR collected and carried out the analysis of the literary sources; CV, IR and SL collected and conducted the analyses of the literary sources; CV, IR and AV collected and effected the analysis of the literary sources. All the authors revised and approved the final version of the manuscript.

Acknowledgements and Funding

No external funding

Provenance and Peer Review

Not commissioned, externally peer reviewed.

Authors’ ORCID ID

Alexandru Voloc – https://orcid.org/0000-0001-8882-3164

Irina Rusu – https://orcid.org/ 0000-0002-2759-3171

Larisa Spinei - https://orcid.org/0000-0002-5370-9801

Chiril Voloc – https://orcid.org/0000-0002-3428-9880

Aliona Rotari – https://orcid.org/0000-0002-3214-846X

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