Unexpectedly long incubation period of Plasmodium vivax malaria, in the absence of chemoprophylaxis, in patients diagnosed outside the transmission area in Brazil

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• Malar J
• v.10; 2011
• PMC3120730

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Malar J. 2011; 10: 122.

Published online 2011 May 14. doi: 10.1186/1475-2875-10-122

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Background

In 2010, Brazil recorded 3343,599 cases of malaria, with 99. 6% of them concentrated in the Amazon region. Plasmodium vivax accounts for 86% of the cases circulating in the country. The extra-Amazonian region, where transmission does not occur, recorded about 566 cases imported from the Amazonian area in Brazil and South America, from Central America, Asia and African countries. Prolonged incubation periods have been described for P. vivax malaria in temperate climates. The diversity in essential biological characteristics is traditionally considered as one possible explanation to the emergence of relapse in malaria and to the differences in the duration of the incubation period, which can also be explained by the use of chemoprophylaxis. Studying the reported cases of P. vivax malaria in Rio de Janeiro, where there is no vector transmission, has made it possible to evaluate the extension of the incubation period and to notice that it may be extended in some cases.

Methods

Descriptive study of every malaria patients who visited the clinic in the last five years. The mean, standard deviation, median, minimum and maximum of all incubation periods were analysed.

Results

From the total of 80 patients seen in the clinic during the study time, with confirmed diagnosis of malaria, 49 (63%) were infected with P. vivax. Between those, seven had an estimated incubation period varying from three to 12 months and were returned travellers from Brazilian Amazonian states (6) and Indonesia (1). None of them had taken malarial chemoprophylaxis.

Conclusions

The authors emphasize that considering malaria as a possible cause of febrile syndrome should be a post-travel routine, independent of the time elapsed after exposure in the transmission area, even in the absence of malaria chemoprophylaxis. They speculate that, since there is no current and detailed information about the biological cycle of human malaria plasmodia’s in Brazil, it is possible that new strains are circulating in endemic regions or a change in cycle of preexisting strains is occurring. Considering that a prolonged incubation period may confer advantages on the survival of the parasite, difficulties in malaria control might arise.

The malaria incubation period is defined as the time elapsed between exposure to the infectious agent (through the bite of the Anopheles mosquito) and the manifestation of the first clinical sign or symptom. Usually, these periods vary depending on the species of Plasmodium causing malaria. The average incubation period is 9-14 days for Plasmodium falciparum, 12-17 days for infections by Plasmodium vivax and 18-40 days for infections caused by Plasmodium malariae [1].

The relapse patterns and variations in the length of the incubation period, including a delay of four months or longer, was first described by Korteweg in Holland between 1901 and 1902 (cited by Swellengrebel and De Buck [2]). Later, in 1935, Nikolaev proposed that there were two strains of P. vivax (cited by Tiburskaya [3]) with different incubation periods and gave the sub-specific taxonomic name of P. vivax hibernans to the variety with the longest incubation period. It was suggested that this sub-species had adapted to more northern latitudes where the anopheles vector was absent for much of the year. Shute (1946) [4] proposed that the sporozoite infective inoculum would be inversely related to the prepatent and incubation period. However, in Moscow, Tiburskaya [3] demonstrated situations in which the length of the incubation period did not depend on the number of inoculated sporozoites, but instead was determined by the inherent properties of the strains. It was also believed that strains with prolonged latency could be attributed either to the “senility” of the sporozoite towards the end of the season or to the low number of sporozoites in the infective bite [5].

According to Shute [5], the differences between the P. vivax strains could be explained by the assumption that, in varying proportions, all strains of P. vivax produce two types of sporozoites: one eliciting short prepatent periods (Type I) and the other lying dormant or developing slowly to give rise to long prepatent periods (Type II). In this model, the latter type would greatly predominate in “temperate strains”, but not in tropical ones. It was thought that relapses of P. vivax could in reality correspond to a delayed parasitaemia arising from Type II sporozoites. In the same year, Garnham stated that the length of the incubation period was considered the major biological difference between Dutch, Madagascar, and USSR strains, and although there was no evidence of specifically dormant forms, it was believed that if certain sporozoites failed to develop in the normal time, they could be reactivated by an unknown factor one year or more after inoculation [6].

In 1980, Warwick [7] proposed that the ambient winter temperatures could extend the incubation period of P. vivax in humans, based on the concept that temperatures persistently above a minimum of 23.9°C were required for sporozoite maturation [8], thereby limiting vector transmission in cold areas. Finally, in 2007, Nishiura et al in Korea [9] suggested that the incubation periods would likely reflect adaptation to the behaviour of the principal vector of the region, which hibernates during the winter season. Currently, several reports associate the extension of the incubation period to malaria prophylaxis among travellers [10,11].

The opportunity to study some cases of P. vivax malaria in Rio de Janeiro, where there is no vector transmission, has made it possible to detect and to evaluate certain peculiar aspects of the natural evolution of the disease in human beings. One main aspect was the extension of time required for the parasites to progress through liver schizogony and produce symptoms by their propagation in the bloodstream.

Plasmodium vivax infections with prolonged periods of incubation and no association with malaria prophylaxis in patients from the Amazon region in Brazil and in one patient from Indonesia are presented.

In addition to demonstrating an interesting clinical situation and the need for clinicians to consider the diagnosis of malaria in a patient presenting symptoms a long time after exposure, even in the absence of chemoprophylaxis, our cases raise questions regarding the understanding of the biology of the host/P. vivax interactions.

Design and study location

This is a descriptive study conducted at the Acute Febrile Disease Outpatient Clinics of IPEC, Fiocruz, a specialized post-travel care clinic located in Rio de Janeiro, from January, 2005, to February, 2010.

Selection of patients

All malaria patients presenting clinical signs or symptoms of malaria and positive thick blood smears were enrolled in the study. The following variables of interest were recorded: estimated incubation period, place and year of infection, date of diagnosis, previous malaria history and year of the first malarial infection. No patients had malaria prophylaxis, had not received blood transfusions nor had close contact with a person with malaria after departure from the endemic area. No patients had haemoglobinopathies. Because it was not possible to determine the date of exposure to the infective mosquito bites, the minimum incubation period was estimated based on literature (9 days for P. falciparum and 12 days for P. vivax) [1]. The maximum was estimated by the interval between the day of the return from the malaria transmission area until the first day of symptoms. The mean, standard deviation, median, minimum and maximum of all incubation periods are shown in Table . Each patient gave fully informed consent. Children were not included.

Table 1

Time between the day of the return from the malaria transmission area and the first day of onset of symptoms of malaria cases diagnosed in the Acute Febrile Diseases Clinic, Rio de Janeiro (2005 until January 2010)

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d = days; h = hours

The project was submitted and approved by the Ethical Committee in Research of the Instituto de Pesquisa Clínica Evandro Chagas (IPEC), Fiocruz (number 0020. 0.009.000-07), maintaining strict secrecy and confidentiality of the information obtained.

Detection and quantification of malaria parasites

Thin and thick blood smears were stained with Giemsa and analysed by light microscopy using an immersion oil lens (X100 objective magnification) to identify the parasite species and determine the density of Plasmodium asexual and sexual stages, according to standard procedures [12]. Each smear was evaluated separately by two expert microscopists who had been blinded to the clinical status of the patients.

Data analysis

All information was recorded on a standardised form for study and subsequently entered into a database using Statistical Package for Social Sciences (SPSS). SPSS-WIN 16.0 was also used for data analysis.

During the study period, 80 malarious patients were diagnosed and treated. Of them, 50 (62.5%) presented with P. vivax malaria, 20 (25%) with P. falciparum malaria, eight (10%) with mixed (P. vivax/P. falciparum) infection and two (2.5%) with P. malariae. All patients were travellers, most of them (51) from the Amazon region, in Brazil; 17 travelled from Africa, 11 were from South and Central America, and one was from Indonesia.

Time between the day of return from the malaria transmission area and the first day of onset of symptoms recorded for all patients diagnosed in the Acute Febrile Diseases Clinic Rio de Janeiro (2005 until January 2010) was four times longer for P.vivax than for Plasmodium falciparum and is illustrated in Table . The estimated mean incubation period for all cases was 31 days (SD 51 days), with a median of 12 days and extreme values of 9 and 360 days.

An estimated incubation period longer than 90 days was observed in seven (14%) of the patients with P. vivax malaria (Figure ). The average incubation period (147 days) among this group was about twelve times longer than the classical period described in the literature (12 days). Malaria was contracted during visits to the Amazonian region (in six cases) and Indonesia (in one). Their details are described in Table . There were no differences in clinical presentation between individuals with P. vivax infection with different incubation periods. No patient had undergone malaria chemoprophylaxis or had taken any pharmacological drug that could inhibit the parasite’s development.

Open in a separate window

Estimated incubation period in days for each P. vivax infected patient.

Table 2

Patients with P. vivax infection and estimated incubation period ≥ 90 days

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NA = non aplicable

This is the second report of prolonged incubation period of malaria in patients without chemoprophylaxis coming from an endemic area in Brazil. A recent paper by one of the authors of this report (Tauil PL) described three cases of vivax malaria originating from the Amazon region and diagnosed in Brasilia, Federal District, six months after departure from the endemic region in 2008 [13]. Two of those patients were infected in the same town (São Gabriel da Cachoeira, Amazonas State, Brazil), as one of the patients in the present study. Some of the cases in this study were detected in 2005 and 2006, prior to the cases detected in Brasilia and reported by Tauil et al [13]. All possible current explanations for these prolonged periods (use of malaria prophylaxis or other pharmacological drugs that would inhibit the Plasmodium development; blood transfusions; close contact with a person with malaria after departure from the endemic area or haemoglobinopathies) were eliminated. The observation of a longer incubation period (≥90 days) in 14% of the P. vivax malaria patients seen at IPEC, in Rio de Janeiro, may indicate the importance of monitoring these characteristics worldwide, as it may represent an evolutionary change in P. vivax behaviour. The average incubation period of P. vivax malaria presented here was approximately twelve times longer than the classical period described in the literature. In this study, the extended incubation time occurred in both prime-infected (130 days) and non-prime-infected (131 days) patients, so the possibility of relapse among non-prime-infected patients cannot be ruled out. However, in two patients previously infected with malaria, the period between the last infection and the current clinical manifestation was five and six years, by far exceeding the maximum period of relapse reported for P. vivax (three years) [14]. Cities such as Rio de Janeiro, as well as areas in the northern hemisphere without disease transmission may be considered strategic places for monitoring incubation period, clinical cures and treatment failure in cases of malaria, facilitating the identification of the above features without misinterpreting variations as the result of new infections.

During the five years of surveillance (2005-2010) no seasonal differences in the prevalence of clinical P. vivax malaria diagnosed outside the endemic area were observed between these cases with prolonged incubation periods. Regardless, the postulate that extended incubation periods may represent an adaptation of the species to overcome cold temperatures, thereby conferring advantages for the survival of the parasite, does not seem to fit the reality of tropical areas, where the temperature is rarely below 10°C. Although the role of strain-specific variation in prolonged incubation periods has been questioned by some authors [9], it is possible that new strains of Plasmodium are circulating in tropical areas, especially in the Amazon, which is a region frequently visited by foreigners and which has seen the movements of troops.

Fever is one of the most common clinical signs in returning travellers [15-20]. The incubation periods of potential pathogens should be considered when formulating differential diagnoses. The geographic location(s) visited, the traveller’s activities and the frequency of specific diseases in the region are usually taken into account. According to the observations reported here, malaria should be considered among the diseases with longer incubation periods (weeks to months after return), even in patients without malaria chemoprophylaxis.

It is classically considered that the co-existence of short and long-term incubation periods may imply that prolongation of this phase is either a genetically regulated feature of parasites or is controlled within Anopheles spp. by mechanisms yet to be defined. Therefore, new molecular tools need to be used for investigation of biological characteristics and origin of the Plasmodium strains that presents a prolonged incubation time in Brazilian patients that have never visited the temperate zone.

Plasmodium vivax, responsible for 86% of malaria cases in Brazil [21], has long been neglected and mistakenly [22]. The change in incubation period reported here is particularly important in theory, because it raises the possibility of changes in the biology and evolution of this organism, entering into strategic debates taking place on malaria epidemiology and control; and in practice because malaria is one of the most important infectious diseases among travellers and a long incubation period is one of the causes of missing early malaria diagnosis.

The authors declare that they have no competing interests.

PB – responsible for conception and design of the work, interpretation of data and drafting the manuscript.

APC – analyzed data, made the literature review and helped drafting the manuscript.

RSP – helped analyzing the data and reviewed the text.

CSB – responsible for the production of data and helped reviewing the text.

SS – carried out the parasitological examinations and helped in the literature review.

PLT – helped in interpretation of data, literature review and reviewing the manuscript.

CTDR – helped in the design of the work and reviewed the text up to the final version to be published.

All authors read and approved the final manuscript.

This work was supported by CGLAB from the Secretaria de Vigilância em Saúde to the Centro de Pesquisa Diagnóstico e Treinamento em Malária (CPD-Mal), Fiocruz, Ministério da Saúde, Brazil.

• Warrell DA. In: Essential Malariology. 4. Warrell DA, Gilles HM, editor. New York: Oxford University Press; 2002. Clinical features of malaria; p. 192. [Google Scholar]
• Swellengrebel N, De Buck A. Malaria in the Netherlands. Scheltema and Holkema, Amsterdam; 1938. pp. 1–267. [Google Scholar]
• Tiburskaya NA. Features specific to the Moscow strain of P. vivax. Trop Dis Bull. 1962;59:228. [Google Scholar]
• Shute PG. Latency and long-term relapses in benign tertian malaria. Trans R Soc Trop Med Hyg. 1946;40:189–200. doi: 10.1016/0035-9203(46)90056-9. [PubMed] [CrossRef] [Google Scholar]
• Shute PG, Lupascu G, Branzei P, Maryon M, Constantinescu P, Bruce-Chwatt LJ, Draper CC, Killick-Kendrick R, Garnham PC. A strain of Plasmodium vivax characterized by prolonged incubation: the effect of numbers of sporozoites on the length of the prepatent period. Trans R Soc Trop Med Hyg. 1976;70:474–481. doi: 10.1016/0035-9203(76)90132-2. [PubMed] [CrossRef] [Google Scholar]
• Garnham PCC, Bray RS, Bruce-Chwatt LJ, Draper CC, Killick-Kendrick R, Sergiev PG, Tiburskaya NA, Shute PG, Maryon M. A strain of Plasmodium vivax characterized by prolonged incubation: morphological and biological characteristic. Bull World Health Organ. 1975;52:21–32. [PMC free article] [PubMed] [Google Scholar]
• Warwick R, Swimer GJ, Britt RP. Prolonged incubation period of imported P. vivax malaria in London. J R Soc Med. 1980;73:333–336. [PMC free article] [PubMed] [Google Scholar]
• Shute PG, Maryon M. Imported malaria in the United Kingdom. BMJ. 1969;2:781–785. doi: 10.1136/bmj.2.5660.781. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
• Nishiura H, Lee HW, Cho SH, Lee WG, In TS, Moon SU, Chung TG, Kim TS. Estimates of short- and long-term incubation periods of Plasmodium vivax malaria in the Republic of Korea. Trans R Soc Trop Med Hyg. 2007;101:338–343. doi: 10.1016/j.trstmh.2006.11.002. [PubMed] [CrossRef] [Google Scholar]
• Schwartz E, Parise M, Kozarsky P, Cetron M. Delayed onset of malaria: implications for chemoprophylaxis in travellers. N Engl J Med. 2003;349:1510–1516. doi: 10.1056/NEJMoa021592. [PubMed] [CrossRef] [Google Scholar]
• Greenwood T, Vikerfors T, Sjöberg M, Skeppner G, Färnert A. Febrile Plasmodium falciparum malaria 4 years after exposure in a man with sickle cell disease. Clin Infect Dis. 2008;47:39–41. doi: 10.1086/590250. [PubMed] [CrossRef] [Google Scholar]
• Brasil Ministério da Saúde. Manual de diagnóstico laboratorial da malária. Brasília: Ministério da Saúde; 2005. p. 112. [Google Scholar]
• Tauil PL, Luz FCO, Oliveira APL, Deckers FAL, Santos JB. Vivax malaria with long incubation period, detected in the Federal District: three case reports. Rev Soc Bras Med Trop. 2010;43:213–214. doi: 10.1590/S0037-86822010000200023. [PubMed] [CrossRef] [Google Scholar]
• Fairhurst RM, Wellems TE. In: Mandell, Douglas and Bennett’s Principles and Practice of Infectious Diseases. 7. Mandell GL, Bennett JE, Dolin R, editor. New York: Churchill Livingstone; 2009. Plasmodium species (Malaria) pp. 3437–3462. [Google Scholar]
• O’Brien D, Sean T, Brown GV, Torresi J. Fever in returned travelers: review of hospital admissions for a 3-year period. Clin Infect Dis. 2001;33:603–609. doi: 10.1086/322602. [PubMed] [CrossRef] [Google Scholar]
• Magill AJ. Fever in the returned traveler. Infect Dis Clin North Am. 1998;12:445–69. doi: 10.1016/S0891-5520(05)70013-1. [PubMed] [CrossRef] [Google Scholar]
• Felton JM, Bryceson AD. Fever in the returning traveller. Br J Hosp Med. 1996;55:705–711. [PubMed] [Google Scholar]
• Humar A, Keystone J. Evaluating fever in travellers returning from tropical countries. BMJ. 1996;312:953–956. [PMC free article] [PubMed] [Google Scholar]
• Doherty JF, Grant AD, Bryceson AD. Fever as the presenting complaint of travellers returning from the tropics. QJM. 1995;88:277–281. [PubMed] [Google Scholar]
• Saxe SE, Cardner P. The returning traveler with fever. Infect Dis Clin North Am. 1992;6:427–439. [PubMed] [Google Scholar]
• Oliveira-Ferreira J, Lacerda MV, Brasil P, Ladislau JL, Tauil PL, Daniel-Ribeiro CT. Malaria in Brazil: an overview. Malar J. 2010;9:115. doi: 10.1186/1475-2875-9-115. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
• Galinski MR, Barnwell JW. Plasmodium vivax: who cares? Malar J. 2008;7(Suppl 1):S9. doi: 10.1186/1475-2875-7-S1-S9. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

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A 4-Day Incubation Period of Plasmodium falciparum Infection in a Nonimmune Patient in Ghana: A Case Report

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Open Forum Infect Dis. 2019 Jan; 6(1): ofy169.

Published online 2019 Jan 17. doi: 10.1093/ofid/ofy169

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Plasmodium falciparum can cause severe infection and has the shortest incubation period compared with all the other Plasmodium species. Incubation periods of 9–14 days for the immune and 6–14 days for the nonimmune have been reported for P. falciparum. However, an incubation period of less than 5 days has not been reported, as of yet. This report presents a case of a 23-year-old nonimmune female who presented with signs and symptoms 4 days after being bitten by mosquitoes while visiting Ghana. The patient was successfully treated with a 1-day course of parenteral artesunate, followed by a 3-day course of oral artemisinin combination therapy.

Keywords: artesunate, Ghana, incubation period, Malaria, nonimmune, Plasmodium falciparum, West Africa

Plasmodium falciparum is one of the prominent Plasmodium species, transmitted by malaria-causing vectors, in Ghana [1, 2]. This Plasmodium species is responsible for the majority of the uncomplicated and severe malaria cases that are reported in clinics and hospitals throughout Ghana [3]. Among the 5 species of Plasmodium that cause human infection, P. falciparum causes the most severe form of malaria [4]. Like the other species, P. falciparum is transmitted by the bite of an infected female Anopheles mosquito; however, it has a relatively shorter incubation period than the others [5]. The incubation period for P. falciparum is 9–14 days, whereas those of P. vivax and P. malariae are 12–17 days and 18–40 days, respectively [5]. Though a shorter incubation period of 6 days for P. falciparum has been reported, especially in the nonimmune [4], an incubation period of less than 5 days has not been reported in literature. Presented here is a case of a 4-day incubation period of P. falciparum infection in a nonimmune patient in Ghana.

A 23-year-old female medical student from the United Kingdom presented to a local hospital 5 days after arriving in Ghana, with a 24-hour history of fever, chills, bodily pains, vomiting, and diarrhea. She reported a recent incident of several mosquito bites while she was sitting outside the first night she arrived in the country. The patient had never visited Africa before this trip. She had been taking 250 mg of mefloquine once a week for malaria prophylaxis but admitted to not being compliant with her medication. The patient admitted to being a cigarette smoker and to smoking about 3 packs per week. Since the onset of her symptoms, she had vomited twice and passed loose, nonbloody stool 4 times. Upon examination, the patient exhibited several insect bite marks bilaterally on the legs and a temperature of 37.8°C; she was not dehydrated, pale, or in respiratory distress. She had a flat abdomen but reported mild epigastric tenderness. Breath sounds were clear bilaterally; in addition, heart sounds were clear, with no rubs, murmurs, or gallops. The patient was conscious and oriented to time, place, and person. Her full blood count investigation revealed a hemoglobin level (Hb) of 12.3 g/dL; white blood cell count (WBC) of 8.2 × 10⁹ µL with differentials (neutrophils 50%, lymphocytes 30%, monocytes 20%, and basophils 0%) and platelets of 158 × 10⁹ uL. A rapid diagnostic test (RDT) was positive for malaria parasites, and malaria parasites were also seen on blood film microscopy, with a parasitemia level of 2+. Urine pregnancy test was negative, and urinalysis showed no signs of infection. The patient was diagnosed with malaria and was immediately started on artesunate injection, 160 mg Q12H. The patient was also placed on 500 mL 5% dextrose normal saline infusion, alternating with 500 mL ringers lactate infusion, for 24 hours. The patient’s fever, vomiting, and diarrhea subsided 24 hours after commencing treatment. The patient was subsequently placed on oral, adult-course artemether lumefantrine (80/480 mg, repeated every 8 hours for the first day, then twice daily for the next 2 days) and paracetamol (acetaminophen) 1 g every 8 hours for 3 days. The patient’s condition improved, and she was discharged 3 days after. The patient was re-examined a week later and found to be recovering well, with resolution of her symptoms. Before leaving Ghana, 6 weeks post–hospital admission, there was no parasite observed in her blood film microscopy, and RDT was negative.

Our patient had not visited Africa or any other malaria-endemic region of the world. Therefore, she had no form of immunity against malaria. She manifested febrile symptoms 4 days after the mosquito bites, which infected her with the malaria parasite, as evidenced by the positive P. falciparum–specific RDT.

The virulence of P. falciparum is seen in the severity of the disease [4, 6]. It has also been reported to have a short incubation period and life cycle [4, 6]. The life cycle begins with the bite from an infected female Anopheles mosquito. The sporozoites’ journey through the liver to the red blood cells which is marked by 2 important periods in the life cycle: the prepatent period (from sporozoite entry to parasite detection in the blood) and the incubation period (sporozoites to the manifestation of symptoms) [4]. The duration of these periods, especially the incubation period, is usually influenced by the level of immunity of the infected patient, antimalarial prophylaxis, and previous malaria treatment [4, 7]. The nonimmune state of our patient would have been responsible for the unusually short incubation period noted in this case [4]. Though she was on mefloquine prophylaxis, which is specific to P. falciparum [8], she was not consistent in taking the course. Though the patient had a short incubation period, her symptoms were not severe, probably because she reported to the hospital as soon as the symptoms began. She presented with the typical malarial symptoms of fever, chills, vomiting, and diarrhea [9]. The physical findings were also not remarkable, which is not uncommon, even in nonimmune patients [4]. The laboratory results also reflect the unremarkable nature of this infection, as all blood cells (leukocytes, red cells, and platelets) were within normal reference range. Usually, more severe infections, especially in the nonimmune, present with thrombocytopenia, anemia, and neutrophilia with band formation [10]. RDT was used as a diagnostic tool to diagnose malaria in this patient, and the positive RDT was confirmed with microscopy, which is indeed the best practice in laboratory diagnosis of malaria [11–13]. Though the patient did not present with severe malaria and, as per the World Health Organization guidelines, being nonimmune is not a criterion for treatment with intravenous artesunate [14], the decision to start the patient on parenteral antimalarial was because of the vomiting, as she might not have been able to tolerate oral medication. Artesunate was the parenteral antimalarial drug of choice for this patient. It is a very efficacious drug, whose rapid parasite clearance, lack of or minimal clinical side effects, and an easy administration made it a better option than quinine [15, 16].

P. falciparum malaria typically manifests within 2 months of exposure to mosquito bites and generally presents clinically in travelers after their return from an endemic region [17]. Unlike the typical incubation period, this case highlights the successful management of P. falciparum infection occurring in a nonimmune patient 4 days after being bitten by mosquitoes. The patient was successfully treated with a 1-day course of parenteral artesunate, followed by a 3-day course of oral antimalarial artemisinin combination therapy.

Potential conflicts of interest. All authors: no reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

1.
Malaria, D. F. I. D. Country Profiles. 2011. Available at: https://www.unicef.org/health/files/Annual-report-accounts-2011-12.pdf

2.
Owusu EDA, Brown CA, Grobusch MP, Mens P.
Prevalence of Plasmodium falciparum and non-P. falciparum infections in a highland district in Ghana, and the influence of HIV and sickle cell disease. Malar J 2017; 16:167. [PMC free article] [PubMed] [Google Scholar]

3.
World Health Organization. World Malaria Report 2015. Geneva, Switzerland: WHO Press, World Health Organization; 2015. [Google Scholar]

4.
Trampuz A, Jereb M, Muzlovic I, Prabhu RM.
Clinical review: severe malaria. Crit Care 2003; 7:315–23. [PMC free article] [PubMed] [Google Scholar]

5.
Brasil P, de Pina Costa A, Pedro RS, et al..
Unexpectedly long incubation period of Plasmodium vivax malaria, in the absence of chemoprophylaxis, in patients diagnosed outside the transmission area in Brazil. Malar J 2011; 10:122. [PMC free article] [PubMed] [Google Scholar]

6.
Hayward RE, Tiwari B, Piper KP, et al..
Virulence and transmission success of the malarial parasite Plasmodium falciparum. Proc Natl Acad Sci U S A 1999; 96:4563–68. [PMC free article] [PubMed] [Google Scholar]

7.
Taylor TE, Strickland GT..
Malaria in Hunter’s Tropical Strickland, GT. Hunter’s Tropical Medicine and Emerging Infectious Diseases, Ed. 8. Philadelphia, PA: WB Saunders; 2000. ISBN: 0721662234; Record Number: 20013047493. [Google Scholar]

8.
Schwartz E.
Prophylaxis of malaria. Mediterr J Hematol Infect Dis 2012; 4:e2012045. [PMC free article] [PubMed] [Google Scholar]

9.
Genton B, D’Acremont V.
Clinical features of malaria in returning travelers and migrants. In: Schlagenhauf P, ed. Travelers’ Malaria. Hamilton, Ontario: BC Decker Inc; 2001:371–92. [Google Scholar]

10.
D’Acremont V, Landry P, Mueller I, et al..
Clinical and laboratory predictors of imported malaria in an outpatient setting: an aid to medical decision making in returning travelers with fever. Am J Trop Med Hyg 2002; 66:481–6. [PubMed] [Google Scholar]

11.
Lee SH, Kara UA, Koay E, et al..
New strategies for the diagnosis and screening of malaria. Int J Hematol 2002; 76:291–3. [PubMed] [Google Scholar]

12.
Endeshaw T, Gebre T, Ngondi J, et al..
Evaluation of light microscopy and rapid diagnostic test for the detection of malaria under operational field conditions: a household survey in Ethiopia. Malar J 2008; 7:118. [PMC free article] [PubMed] [Google Scholar]

13.
Tangpukdee N, Duangdee C, Wilairatana P, Krudsood S.
Malaria diagnosis: a brief review. Korean J Parasitol 2009; 47:93–102. [PMC free article] [PubMed] [Google Scholar]

14.
World Health Organization. Guidelines for the Treatment of Malaria. Geneva, Switzerland: WHO Press, World Health Organization; 2015. [Google Scholar]

15.
Day N, Dondorp AM.
The management of patients with severe malaria. Am J Trop Med Hyg 2007; 77:29–35. [PubMed] [Google Scholar]

16.
Zoller T, Junghanss T, Kapaun A, et al..
Intravenous artesunate for severe malaria in travelers, Europe. Emerg Infect Dis 2011; 17:771–7. [PMC free article] [PubMed] [Google Scholar]

17.
Dauby N, Figueiredo Ferreira M, Konopnicki D, et al..
Case report: delayed or recurrent Plasmodium falciparum malaria in migrants: a report of three cases with a literature review. Am J Trop Med Hyg 2018; 98:1102–6. [PMC free article] [PubMed] [Google Scholar]

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What you need to know about malaria

Ministry of Health of the Astrakhan Region

Center for Medical Prevention

Memo for the population.

WHAT YOU NEED TO KNOW ABOUT MALARIA!

MALARIA is a severe parasitic disease widespread in countries with a tropical and subtropical climate (Asia Minor and Southeast, Africa, South America) and in neighboring countries (Azerbaijan, Armenia, Uzbekistan, Tajikistan, Georgia ). Malaria is characterized by attacks of fever (fever), anemia, enlargement of the liver and spleen .

Infection occurs when bitten by malarial mosquitoes. There are 4 types of malaria: tropical, three-day, four-day and oval malaria. The most severe is the tropical form, common in African countries.

According to the World Health Organization, at present, 82 countries of the world are highly endemic for malaria and are in the process of fighting it, and only 16 countries have achieved the elimination of malaria in their territories through anti-epidemic (preventive) measures, and 27 countries have received the status of ” free from malaria”, confirmed by the WHO certificate. Russia is represented in the group of countries directing efforts to prevent local transmission of malaria.

Malaria is transmitted from a sick person to a healthy person through the bites of female mosquitoes. In addition, there are two more ways of infection – through blood transfusion and intrauterine, when a woman with malaria infects her unborn child. Entered into the human body during the bite of malarial mosquitoes, the parasites circulate in the blood, and then are carried to the liver, in the cells of which they begin their development.

The incubation period (the period from the moment of infection to the onset of the first clinical symptoms) ranges from 7 days to 1 month (in case of a tropical form of malaria, the incubation period can last up to 3 years).

Signs of the disease – the disease begins acutely: weakness, severe headache, chills appear. Then recurring attacks of fever begin, in which the body temperature rises to 40 ° and above, and lasts for several hours. The fever is accompanied by severe chills; at the end of the attack marked sweating. Attacks are repeated regularly – after a certain time (every other day, two or three days later). When such attacks occur, you should immediately seek medical help.

Tropical malaria the most severe form of malaria. The incubation period most often ranges from 8 to 16 days. Headache, fatigue, nausea, loss of appetite may occur 3-4 days before the development of the first clinical signs. The initial stages of the disease are characterized by severe chills, a feeling of heat, severe headache. In the absence of timely treatment, a fatal outcome occurs. Recovery depends on the correct selection of antimalarial drugs and the equipment of the clinic.

Malaria parasites are found in the blood of a sick person and can only be detected by examining the blood under a microscope. Treatment of this dangerous disease is carried out taking into account the type of pathogen and its sensitivity to chemotherapy drugs.

Prevention of malaria.

All travelers to tropical countries in Africa, Southeast Asia, Central and South America are recommended to carry out specific prophylaxis of malaria by taking antimalarial chemicals. More detailed advice on dosages and regimens for taking antimalarial drugs can be obtained from the offices of infectious diseases in polyclinics at the place of residence.

It must be remembered that during a stay in a malaria-affected country and within 3 years after returning home, in case of any increase in temperature, you should immediately contact a medical institution, informing the doctor about the fact of staying in tropical countries endemic for malaria .

In addition to taking antimalarial drugs, it is necessary to remember about personal non-specific prevention of malaria: the use of repellents (mosquito repellents), in the absence of air conditioning in places of accommodation, windows and doors should be blocked, electric fumigators should be used to kill mosquitoes.
People living in areas endemic for malaria should observe the following recommendations during their stay in the outbreak:

• dress in tight, as close as possible, light-colored clothing when leaving the house after sunset;
• apply repellents to exposed areas of the body;
• sleep in rooms that exclude the penetration of blood-sucking insects;
• before going to bed, treat the room with an insecticidal spray or use fumigators;
• in the presence of a large number of mosquitoes and the impossibility of screening the windows, organize sleep under a canopy made of gauze and treated with insecticide.

Remember! Only early detection of malaria patients will help them recover and prevent the spread of infection among the surrounding population!

Follow all the rules for malaria prevention! Take care of yourself!

The material was prepared by
editorial and publishing department
GBUZ JSC “Center for Medical Prevention”
2015.

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Malaria: symptoms, pathogens, treatment, doctor’s advice0005

• What is malaria
• Exciters
• Varieties
• Symptoms
• Diagnostics
• Treatment
• Inoculation
• Prophylaxis
• Malaria in Russia
• Expert commentary

What is malaria

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Malaria is one of the most common infectious diseases in the world. It is caused by plasmodia parasites carried by malarial mosquitoes. The incubation period of the disease can last from 11 days to several months. The main symptom is regular bouts of severe fever that occur every two to three days. In severe forms, the disease can lead to dangerous organ damage.

Even 80 years ago, malaria was spread all over the globe. However, thanks to the development of the economy and medicine, today the disease has been defeated in half the countries of the world and is rampant only in hot developing countries. Scientists believe that humanity will be able to completely defeat malaria by 2050, although this will require spending an additional $2 billion a year to fight it [1].

According to WHO, about 228 million people fall ill with malaria each year, of which 400,000 die. 94% of malaria cases are reported in Africa, half of them in six countries: Nigeria, Congo, Tanzania, Burkina Faso, Mozambique and Niger. Children from six months to five years of age, who are completely immune to the disease, suffer the most from malaria. They account for two thirds of malaria deaths.

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Tourists and travelers are often infected with malaria. According to WHO, about 10,000 people annually bring the disease from foreign trips.

Malaria

The disease is carried by mosquitoes of the genus Anopheles, infected with malarial plasmodia, protozoan parasites, which are the direct causative agents of the disease. Malarial mosquitoes live mainly in swamps and in small stagnant water bodies, including puddles. Many countries have eradicated malaria through massive swamp draining campaigns.

Two hundred species of malarial mosquitoes can be found all over the planet, with the exception of deserts and territories of the Far North. In Russia, the species Anopheles Messeae is common. However, he stopped carrying the disease over 50 years ago. Today, malaria can only be contracted from Asian and African species of malarial mosquitoes.

First, the malarial mosquito drinks the blood of a person infected with malaria. Plasmodium enters his intestines. It then bites another person and transfers the parasite larvae to them. Those first enter the liver, where they grow and develop. When Plasmodium become adults, they pass from the liver into the bloodstream, after which the first symptoms of malaria appear in humans. Some varieties of Plasmodium can doze in the liver for a long time.

Malaria can also be transmitted from person to person without the involvement of mosquitoes: from mother to child (very rare), through blood transfusion and by sharing injection needles.

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Types of malaria

Of the several hundred malarial plasmodia, only five are dangerous to humans. Each one causes a different kind of disease.

Three-day malaria

Plasmodium vivax causes three-day malaria (vivax-malaria) – a relatively mild form with a long course. It is characterized by the fact that malarial attacks of fever occur every two days, often at the same time of the day, from 11 am to 4 pm. Another variety of the pathogen, P. ovale, causes ovale malaria, which is similar to three-day malaria.

P. Vivax is distributed in Tajikistan, Afghanistan, Pakistan and Nepal, as well as in Central America and northern South America. Previously, this particular type of plasmoid was common in Europe and Russia. P. ovale is found mainly in Africa, where the Plasmodium that causes dengue is found.

Four-day malaria

P. malariae causes four-day malaria, in which attacks occur every 70-72 hours. This form is not as severe, but in rare cases it can cause serious damage to the kidneys – nephrological syndrome. Plasmodium of this type can live hidden in the human body for decades even after recovery. They cause a fairly rare type of malaria found in India, Indonesia, Cambodia and Laos.

Tropical malaria

P. falciparum causes tropical malaria. This is the most dangerous type of the disease, and at the same time the most common – it accounts for more than 90% of infections. Attacks occur irregularly, and the disease affects the vessels, which can lead first to hypoxia, and then to organ failure. This type of illness dominates all of Africa, and in countries such as India, Vietnam, and Thailand, it occurs about as often as three-day malaria.

Malaria Knowlesi

The possibility of human infection with P. knowlesi was discovered only in 2004 – it was previously thought that it only infects macaques. This type of malaria develops the fastest and is therefore very dangerous if treatment is delayed [2]. The features of the course of this type of malaria are still poorly understood, but researchers call this form no less severe than tropical [3]. This type of malaria is common in Southeast Asia, primarily in Malaysia, the Philippines and Indonesia.

Symptoms of malaria

Most often, the first symptoms of malaria appear 11-30 days after infection, although both types of Plasmodium that cause the three-day form can sleep in the liver for up to 15 months.

At the first stage of the disease, pathogens multiply and accumulate in the blood, and the symptoms resemble general poisoning – a person is shivering, nauseous, he experiences weakness, body aches and pain in the joints and limbs. Distinguishing malaria from other infectious diseases at this stage is very difficult.

When there are many Plasmodium in the blood, the peak of the disease sets in, which consists of recurring malarial attacks, or paroxysms. Depending on the type of disease, attacks occur every other day or every two to three days.

An attack lasts from 15 minutes to two hours. Symptoms resemble the flu: the temperature rises sharply to 39-41 °, the pressure drops, breathing quickens. A person is sick or vomits, he may become delirious. Then the temperature drops sharply, the patient feels severe weakness and quickly falls asleep. Rashes similar to herpes may appear on the lips. Waking up, a person feels healthy, but after a while the attack is repeated. When the patient begins to recover, the attacks become less severe and eventually disappear altogether.

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In all patients with malaria, by the fifth or seventh day of illness, the liver and spleen become enlarged, and in addition, anemia (anemia) develops.

According to the clinical picture, malaria is divided into uncomplicated and severe, in which the disease causes not only attacks, but also damage to organs.

The main complications of malaria include:

Nephrotic syndrome

This is a dangerous, almost untreatable kidney disease that can occur with four days of malaria.

Cerebral malaria

Brain damage, which most often develops due to inadequate treatment. It begins with headache and mild impairment of consciousness, and if left untreated can lead to coma and death.

Algid malaria

Toxic shock that occurs due to the huge amount of parasites in the blood. It begins with symptoms of severe intoxication, can lead to coma and death.

Hemoglobinuric (blackwater) fever

An extremely serious complication of dengue fever, which most often occurs when treatment is started late. After taking drugs, there are too many dead plasmodia and dead red blood cells in the human blood at the same time, which die due to drugs. The most characteristic manifestations are vomiting of black bile and black urine. Some studies have associated this complication with quinine, a drug used to treat severe forms of malaria.

Tears and organ failure

Malaria can severely damage the kidneys, liver or spleen, the latter to the point of rupture.

Diagnosis of malaria

The vast majority of Europeans are diagnosed with malaria after visiting tropical countries where the disease is present.

In its early stages, malaria develops in the same way as many other infectious diseases. The main method of accurate diagnosis is blood smear microscopy, which allows detecting parasites. Only after their identification, the doctor can make a final diagnosis.

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Less accurate methods of immunological diagnostics are used, in which blood is searched for specific antibodies or antigens of Plasmodium.

There are also rapid tests for parasite antigens, but they are not very accurate.

Treatment of malaria

In Russia and other non-endemic countries for malaria, it is treated only in a hospital.

To cure the disease, it is necessary to kill the plasmodia in the blood. For this, antiparasitic drugs are used.

The most common treatment for uncomplicated malaria today is combination therapy. Most often, it contains artemisinin or its derivatives – this is an antiparasitic drug that is made from wormwood (artemisia). It is effective against all types of malarial plasmodia, but treatment with it alone often leads to relapse. Therefore, artemisinin is supplemented with other, more specific antimalarial drugs. In addition, if mass treatment of malaria with only artemisinin, Plasmodium will inevitably develop resistance to it over time, and humanity will be almost defenseless against the disease. In Russia, drugs based on artemisinin are not registered. Malaria ovale is treated with a combination of primaquine and chloroquine.

Main drugs used in the treatment of malaria:

• chloroquine;
• hydroxychloroquine;
• primaquine;
• quinine;
• mefloquine;
• artemisinin;
• artesunate;
• artemether;
• arteeter;
• proguanil;
• tetracycline;
• doxycycline.

The choice of remedy depends on the form of malaria and also on the region in which the infection occurred [4]. For example, the malarial plasmodia of Afghanistan and Pakistan have developed resistance to chloroquine, while the Thai and Myanmar parasites have also developed resistance to mefloquine [5].

In the treatment of malaria with complications, antimalarial drugs are supplemented with specific drugs for the affected organs.

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Malaria vaccine and malaria immunity

The only working malaria vaccine, RTS,S, was created in the late 1980s, but only received EU approval in 2015. It has a rather low efficiency – RTS,S provides 27% protection against all forms of malaria and 58% from severe ones [6]. Today, it is being vaccinated in children in countries where malaria is most common, and is not available to travelers and residents of developed countries.

People living in countries where malaria is present may have an innate immunity to it. West African and African American populations have the Duffy gene, which makes them immune to infection with three-day malaria. Other genetic factors may make them more resistant to tropical malaria as well. Also, the risk of getting malaria is lower in people suffering from sickle cell anemia, a rare genetic disease that also occurs mainly in blacks [7].

After an illness, a person develops unstable acquired immunity, which grows stronger with each repeated infection. In an immunocompetent patient, malaria can be almost insidious, with very low levels of parasites in the blood. In societies where people are constantly exposed to malaria and are infected with it several times a year, many develop strong immunity to the disease by the age of puberty [8].

Malaria prophylaxis

Prevention of malaria mainly comes down to protection from mosquito bites. WHO recommends wearing full-body clothing and using insect repellents on the skin and living quarters. Of the repellents, it is best to use products that contain DEET, IR3535 or icaridin. International organizations distribute mosquito nets impregnated with mosquito repellents in countries with malaria – they are considered one of the most convenient, simple and effective ways to protect against the disease [9].

There is also a group of antimalarial drugs that are effective in preventing the disease. Doctors advise taking antimalarial drugs before traveling to a malarial country, as well as during travel and for some time after it. In Russia, mefloquine and chloroquine are most often prescribed. Only a doctor can choose the right drug.

Rospotrebnadzor recommends that tourists returning from countries with malaria monitor their temperature for three years after their trip.

Malaria in Russia

From prehistoric times to the middle of the 20th century, malaria was common throughout the world (except for the Far North), including most of Russia.

In Rus’, the disease was called “shaking”, “pale” or “death”. In the mid-1930s, a large-scale malaria epidemic swept through the Soviet Union, which affected the Volga region, the Urals and Ukraine. However, industrialization, the drainage of swamps and the development of medicine gradually helped to cope with malaria. At 19In 1962, the authorities announced that the disease was completely defeated.

After the collapse of the Soviet Union, the disease returned to Central Asia. In the 2000s, the majority of infections imported into Russia were associated with migrants from Tajikistan, Azerbaijan and Uzbekistan. However, the situation there quickly improved – today the only post-Soviet state where endemic malaria is present is Tajikistan, but it is also close to completely defeating the disease [10].

For the last decade, 80-120 cases of malaria have been registered in Russia per year. All of them are imported, most often from Africa, as well as from India, Thailand, Latin America and the countries of the Middle East [11].

In 2020, Tanzania became the main supplier of malaria to Russia, one of the few countries that did not close the borders to tourists. According to the head of Rospotrebnadzor Anna Popova, 11 cases of malaria were imported from there. Two patients are known to have died.

Expert comments

Anna Tsygankova, Senior Consultant, BestDoctor Medical Company

How toxic are malaria drugs? What side effects can they have?

Side effects may occur with all medicines. In the case of malaria chemoprophylaxis, drugs are used that are supposed to kill the parasite, and they are quite toxic. However, there is a concept of risk-benefit, that is, chemoprophylaxis for a European is potentially much less harmful than malaria. All registered prophylactic drugs have undergone post-marketing studies and have proven their effectiveness and safety. Mild nausea, occasional vomiting, and frequent loose stools should not lead to discontinuation of prophylaxis, but if these symptoms persist, medical advice should be sought. A rare complication (1 in 10,000 travelers) has been described when taking mefloquine: the development of neurological symptoms, seizures, and psychosis.

Can the complications of malaria lead to fatal organ dysfunction, disability or disability?

If you seek medical help in time and start treatment, then malaria disappears completely. Severe forms of the disease are individual, in some cases they lead to death. Four-day malaria has a specific complication. It may not cause acute symptoms, but low levels of parasitemia (the presence of Plasmodium in the blood) may persist for many decades and lead to immune complex-mediated nephritis with the development of nephrotic syndrome.