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A severe case of Plasmodium falciparum malaria imported by a French traveler from Cameroon to French Guiana despite regular intake of Artemisia annua herbal tea

ABSTRACT

The use of herbal tea with Artemisia annua by travelers and traditional communities in Africa has increased in recent years as a supposed form of malaria prophylaxis, although its use is not recommended due to lack of efficacy. The risk of severe malaria complications that can lead to death is real regarding said behavior, and awareness needs to be raised. We report a case of severe Plasmodium falciparum malaria imported in the Amazon rainforest by a traveler returning from Cameroon who treated himself with Artemisia annua herbal tea.

Plasmodium falciparum; Artemisia annua; Prophylaxis; Amazonia; Severe malaria; Herbal tea

INTRODUCTION

Malaria is a life-threatening protozoan disease caused by Plasmodium sp. which is transmitted by a mosquito vector and is present in tropical regions of the world, including the Amazon rainforest and sub-Saharan Africa. P. falciparum is the most dangerous of the species and can progress to a severe clinical case and death. There were 241 million cases of malaria in 202011. World Health Organization. World malaria report 2021. [cited 2022 Oct 5]. Available from: https://www.who.int/teams/global-malaria-programme/reports/world-malaria-report-2021
https://www.who.int/teams/global-malaria...
.

Artemisia annua is a Chinese medicinal herb from the Asteraceae family that produces artemisinin, whose derivatives have been found to have antimalarial properties, such as artesunate, artemether and dihydroartemisinin. These artemisinin derivatives used in ACTs (Artemisinin-based combination therapies) have been WHO-recommended therapies for malaria since 200211. World Health Organization. World malaria report 2021. [cited 2022 Oct 5]. Available from: https://www.who.int/teams/global-malaria-programme/reports/world-malaria-report-2021
https://www.who.int/teams/global-malaria...
,22. World Health Organization. Consolidated guidelines for malaria. [cited 2022 Oct 5]. Available from: https://www.who.int/teams/global-malaria-programme/guidelines-for-malaria
https://www.who.int/teams/global-malaria...
. Lately, it has been suggested that A. annua infusion or herbal tea could be used as a natural anti-malarial prophylactic and curative treatment. It is common to read on social networks that WHO and the so-called “Big Pharma” would implement all possible means to prevent the diffusion of this so-called “natural treatment”. However, the dose of artemisinin absorbed when used in this way is inconsistent and there have been reports of treatment failures33. Lagarce L, Lerolle N, Asfar P, Le Govic Y, Lainé-Cessac P, de Gentile L. A non-pharmaceutical form of Artemisia annua is not effective in preventing Plasmodium falciparum malaria. J Travel Med. 2016;23:taw049.,44. Argemi X, Houze S, Noel H, Broca O, Chidiac C, Rapp C. Imported Plasmodium falciparum malaria following non-pharmaceutical forms of Artemisia annua prophylaxis. J Travel Med. 2019;26:taz073.. Furthermore, with the increase in artemisinin resistance in recent years, there is concern that the use of sub-therapeutic doses of artemisinin could create resistant parasites and accelerate global resistance to ACTs55. Pays JF. Menaces sur l’efficacité du traitement contre le paludisme. Bull Soc Pathol Exot. 2018;111:195-6..

We report a severe case of P. falciparum malaria in a young French patient who traveled to Cameroon and then to French Guiana, in the Amazon rainforest, using A. annua herbal tea as prophylaxis.

CASE REPORT

A 22-year-old student from Paris, France, with no previous medical history, was taken by local authorities to the health center in Saul (3°55’18’’N, 53°18’02’’W), a small village with around 100 inhabitants, located in the center of French Guiana, about 180 km southwest of Cayenne.

Saul is a popular tourist destination for hiking in the middle of the rainforest, which is only accessible by walking through the forest or by plane.

The patient was taken to the health center after he fainted during his walk. He was in poor general condition and manifested fever, vomiting and diarrhea

He had returned from a 4-month stay in Cameroon eleven days earlier, and was drinking A. annua herbal tea daily for malaria prophylaxis. He reported a first malaria episode in Cameroon which was treated with artesunate, and a second episode a month earlier which was treated with tablets that he could not identify. These malaria attacks occurred while he was taking an alternative treatment of A. annua herbal tea obtained from a local store in Cameroon. He strongly believed in the effectiveness of these tea infusions, and he associated these attacks with forgetting to take the decoction.

The symptoms started during his stopover in Paris, 5 days prior to the consultation at the Saul health center. He consulted a general physician 24 h later in Kourou (5°09’29.” N, 52°38’33” W), a city located 60 km from the capital of French Guiana (Cayenne), where he was diagnosed through thick and thin blood smears that were positive for P. falciparum. However, the patient left for Saul, without taking the prescribed medicine. He continued drinking A. annua herbal tea. As soon as he arrived in Saul, he started a walk in the deep forest. Three days later, he was found by the local police several kilometers away from the village, in a poor clinical condition. He was febrile and couldn’t walk anymore. The police carried him to the health center.

There, the physical examination showed no sign of sepsis, bleeding, hypoglycemia or dyspnea. His neurological examination was normal. The malaria rapid diagnostic test was positive with 2 bands, Pf and PAN. Treatment was started with artemether/lumefantrine (20/120 mg) and the patient was then transferred by helicopter to a hospital in Cayenne (Centre Hospitalier de Cayenne Andree Rosemon) (4°56’13.6”N, 52°19’32.9”W).

Thick and thin blood smears were positive for P. falciparum with a parasitemia of 1.62% of erythrocytes. Other laboratory tests showed: hemoglobin 12.7 g/dL, white blood cell count 8 G/L, platelet count 19 G/L, alkaline reserve 20.8 mmol/L, urea blood level 16.4 mmol/L (normal 2.8-8.1 mmol/L), creatinine blood level 135 µmol/L (normal 59-104 µmol/L), bilirubin 45.8 µmol/L (normal < 21 µmol/L) and CRP 205.4 mg/L (normal < 5mg/L).

He had watery diarrhea but no more vomiting (he had received metoclopramide in Saul).

A new blood draw showed worsening of the renal function with creatinine dosed at 325 µmol/L and urea at 26.1 mmol/L for an estimated glomerular filtration rate of 22 mL/min/1.73 m2 (normal > 90 mL/min/1.73 m2). A dosage of lactate returned normal at 1.6 mmol/L. There were no other signs of severe malaria apart from the acute renal failure, established by the severely reduced glomerular filtration rate.

The treatment with artemether/lumefantrine (20/120 mg) was continued for a total of 3 days as recommended by the French guidelines66. Epelboin L, Rapp C, Faucher JF, Méchaï F, Bottieau E, Matheron S, et al. Management and treatment of uncomplicated imported malaria in adults: update of the French malaria clinical guidelines. Med Mal Infect. 2020;50:194-212.. It was decided not to switch treatment for IV artesunate (recommended treatment in severe malaria)77. Bruneel F, Raffetin A, Corne P, Llitjos JF, Mourvillier B, Argaud L, et al. Management of severe imported malaria in adults. Med Mal Infect. 2020;50:213‐25. because the patient’s clinical state was already improving after the first dose of artemether/lumefantrine.

Parasitemia on day 3 was still positive but had diminished considerably (only the thick blood smear was positive). A new control on day 9 came back negative. Stool cultures as well as stool parasitology were screened and no pathogens were found.

Symptoms improved rapidly and the patient was discharged 5 days after the beginning of treatment. Renal function improved significantly with IV saline solution (0.9/1,000) but creatinine levels remained above normal values (121 µmol/L) on day 10. Follow up was done in outpatient consultations on days 9 and 28 post treatment.

Despite the severity of his clinical condition and the manifest lack of efficacy of this alternative treatment, he was still convinced the herbal tea could work as a malaria treatment.

DISCUSSION

To our knowledge, this is the first case reported in South America of a P. falciparum attack in a patient undergoing A. annua herbal tea prophylaxis. Although Brazilian researchers in the Amazon have already tested its effects in vitro and found some efficacy on P. falciparum, it’s currently not supported by in vivo effects88. Lima RB, Rocha e Silva LF, Melo MR, Costa JS, Picanço NS, Lima ES, et al. In vitro and in vivo anti-malarial activity of plants from the Brazilian Amazon. Malar J. 2015;14:508.,99. Silva LF, Magalhães PM, Costa MR, Alecrim M, Chaves FC, Hidalgo AF, et al. In vitro susceptibility of Plasmodium falciparum Welch field isolates to infusions prepared from Artemisia annua L. cultivated in the Brazilian Amazon. Mem Inst Oswaldo Cruz. 2012;107:859-66.

Treatment and eradication of P. falciparum malaria has always been a challenge because of parasite adaptation capabilities and fast emerging resistance to treatments. Since the discovery of artemisinin, ACTs have become the new standard drugs for malaria. But in 2009, artemisinin resistance started to appear in Southeast Asia and it is now spreading to Africa1010. Fairhurst RM, Dondorp AM. Artemisinin-resistant Plasmodium falciparum malaria. Microbiol Spectr. 2016;4.. To prevent selective resistance from developing too fast, artemisinin derivatives are always associated with another molecule in ACTs and these are not recommended as prophylaxis22. World Health Organization. Consolidated guidelines for malaria. [cited 2022 Oct 5]. Available from: https://www.who.int/teams/global-malaria-programme/guidelines-for-malaria
https://www.who.int/teams/global-malaria...
.

A few years ago, the use of A. annua herbal tea as malaria “prophylaxis” and treatment started to become popular as a supposed cheaper, more natural medication, with a very oriented argument against the resistance to “Big Pharma”, the hegemony of WHO and the so-called Western countries. It’s used in traditional communities in Africa and can be bought online, without prescription, by travelers who want to go to malaria-endemic regions and want to take a presumed more natural treatment rather than the recommended one. An article published a few years ago1111. Gillibert A, Jauréguiberry S, Hansmann Y, Argemi X, Landier J, Caumes E, et al. Comment on “A. annua and A. afra infusions vs. Artesunate-amodiaquine (ASAQ) in treating Plasmodium falciparum malaria in a large scale, double blind, randomized clinical trial” Munyangi et al., 2019. Phytomedicine. 2022;96:152981. encouraged this practice by bringing data that showed the efficacy of the infusion. This article gave power to the critics of Western medicine before it was retracted for data reliability and methodological reasons. In the same “natural medicine” movement, a curative effect of A. annua herbal tea for schistosomiasis and SARS-CoV2 was also evoked without proof1212. Argemi X, Hansmann Y, Gaudart J, Gillibert A, Caumes E, Jaureguiberry S, et al. Comment on “Effect of Artemisia annua and Artemisia afra tea infusions on schistosomiasis in a large clinical trial”. Phytomedicine. 2018;62:152804.,1313. Kapepula PM, Kabengele JK, Kingombe M, Van Bambeke F, Tulkens PM, Sadiki Kishabongo A, et al. Artemisia Spp. derivatives for COVID-19 treatment: anecdotal use, political hype, treatment potential, challenges, and road map to randomized clinical trials. Am J Trop Med Hyg. 2020;103:960-4..

The dose of artemisinin actually present in the herbal tea is inconsistent because artemisinin varies greatly in A. annua cultivars. In the same batch of seeds, one can find plants with a dosage of 0.3% all the way up to 1.9%1414. Ferreira JFS, Benedito VA, Sandhu D, Marchese JA, Liu S. Seasonal and differential sesquiterpene accumulation in Artemisia annua suggest selection based on both artemisinin and dihydroartemisinic acid may increase Artemisinin in planta. Front Plant Sci. 2018;9:1096.. There are also great variations in the percentage extracted when making the tea. It’s often a sub-therapeutic dose which doesn’t protect travelers from getting infected. However, it still exposes them to potential serious side effects, such as developing acute cholestatic hepatitis1515. Ruperti-Repilado FJ, Haefliger S, Rehm S, Zweier M, Rentsch KM, Blum J, et al. Danger of herbal tea: a case of acute cholestatic hepatitis due to Artemisia annua tea. Front Med (Lausanne). 2019;6:221., as addressed in the case report from Switzerland. In addition, the spread of its consumption could probably lead to resistance selection in the long term, so it should be discouraged55. Pays JF. Menaces sur l’efficacité du traitement contre le paludisme. Bull Soc Pathol Exot. 2018;111:195-6..

In this case report, the patient traveled from one malaria-endemic area to another, with only A. annua tea as prophylaxis. He was most likely infected in Cameroon as the symptoms started in Paris; the lag time (24 h) between his arrival in French Guiana and the first diagnosis of malaria is too short to be attributed to the South American journey. Also, P. falciparum cases have greatly decreased in French Guiana and are currently very low compared to P. vivax cases1616. de Thoisy B, Duron O, Epelboin L, Musset L, Quénel P, Roche B, et al. Ecology, evolution, and epidemiology of zoonotic and vector-borne infectious diseases in French Guiana: transdisciplinarity does matter to tackle new emerging threats. Infect Genet Evol. 2021;93:104916.,1717. Scully J, Mosnier E, Carbunar A, Roux E, Djossou F, Garçeran N, et al. Spatio-temporal dynamics of Plasmodium falciparum and Plasmodium vivax in French Guiana: 2005-2019. Int J Environ Res Public Health. 2021;18:1077..

Such behavior may facilitate the transfer of resistant mutant strains from Africa to the Amazon, threatening the proposal to eradicate P. falciparum infections in this area. The burden and consequences of imported malaria cases may be greater than presumed in this region, where Anopheles spp. mosquitoes are endemic.

CONCLUSION

In this case report, the use of A. annua herbal tea as putative prophylaxis could not prevent the occurrence of a severe P. falciparum case imported from Cameroon and diagnosed in the Amazon. Artemisinin is currently the best tool we have against this deadly disease; unusual forms of A. annua products should not be used due to lack of proven efficacy and potential risk to public health.

REFERENCES

  • 1
    World Health Organization. World malaria report 2021. [cited 2022 Oct 5]. Available from: https://www.who.int/teams/global-malaria-programme/reports/world-malaria-report-2021
    » https://www.who.int/teams/global-malaria-programme/reports/world-malaria-report-2021
  • 2
    World Health Organization. Consolidated guidelines for malaria. [cited 2022 Oct 5]. Available from: https://www.who.int/teams/global-malaria-programme/guidelines-for-malaria
    » https://www.who.int/teams/global-malaria-programme/guidelines-for-malaria
  • 3
    Lagarce L, Lerolle N, Asfar P, Le Govic Y, Lainé-Cessac P, de Gentile L. A non-pharmaceutical form of Artemisia annua is not effective in preventing Plasmodium falciparum malaria. J Travel Med. 2016;23:taw049.
  • 4
    Argemi X, Houze S, Noel H, Broca O, Chidiac C, Rapp C. Imported Plasmodium falciparum malaria following non-pharmaceutical forms of Artemisia annua prophylaxis. J Travel Med. 2019;26:taz073.
  • 5
    Pays JF. Menaces sur l’efficacité du traitement contre le paludisme. Bull Soc Pathol Exot. 2018;111:195-6.
  • 6
    Epelboin L, Rapp C, Faucher JF, Méchaï F, Bottieau E, Matheron S, et al. Management and treatment of uncomplicated imported malaria in adults: update of the French malaria clinical guidelines. Med Mal Infect. 2020;50:194-212.
  • 7
    Bruneel F, Raffetin A, Corne P, Llitjos JF, Mourvillier B, Argaud L, et al. Management of severe imported malaria in adults. Med Mal Infect. 2020;50:213‐25.
  • 8
    Lima RB, Rocha e Silva LF, Melo MR, Costa JS, Picanço NS, Lima ES, et al. In vitro and in vivo anti-malarial activity of plants from the Brazilian Amazon. Malar J. 2015;14:508.
  • 9
    Silva LF, Magalhães PM, Costa MR, Alecrim M, Chaves FC, Hidalgo AF, et al. In vitro susceptibility of Plasmodium falciparum Welch field isolates to infusions prepared from Artemisia annua L. cultivated in the Brazilian Amazon. Mem Inst Oswaldo Cruz. 2012;107:859-66
  • 10
    Fairhurst RM, Dondorp AM. Artemisinin-resistant Plasmodium falciparum malaria. Microbiol Spectr. 2016;4.
  • 11
    Gillibert A, Jauréguiberry S, Hansmann Y, Argemi X, Landier J, Caumes E, et al. Comment on “A. annua and A. afra infusions vs. Artesunate-amodiaquine (ASAQ) in treating Plasmodium falciparum malaria in a large scale, double blind, randomized clinical trial” Munyangi et al., 2019. Phytomedicine. 2022;96:152981.
  • 12
    Argemi X, Hansmann Y, Gaudart J, Gillibert A, Caumes E, Jaureguiberry S, et al. Comment on “Effect of Artemisia annua and Artemisia afra tea infusions on schistosomiasis in a large clinical trial”. Phytomedicine. 2018;62:152804.
  • 13
    Kapepula PM, Kabengele JK, Kingombe M, Van Bambeke F, Tulkens PM, Sadiki Kishabongo A, et al. Artemisia Spp. derivatives for COVID-19 treatment: anecdotal use, political hype, treatment potential, challenges, and road map to randomized clinical trials. Am J Trop Med Hyg. 2020;103:960-4.
  • 14
    Ferreira JFS, Benedito VA, Sandhu D, Marchese JA, Liu S. Seasonal and differential sesquiterpene accumulation in Artemisia annua suggest selection based on both artemisinin and dihydroartemisinic acid may increase Artemisinin in planta. Front Plant Sci. 2018;9:1096.
  • 15
    Ruperti-Repilado FJ, Haefliger S, Rehm S, Zweier M, Rentsch KM, Blum J, et al. Danger of herbal tea: a case of acute cholestatic hepatitis due to Artemisia annua tea. Front Med (Lausanne). 2019;6:221.
  • 16
    de Thoisy B, Duron O, Epelboin L, Musset L, Quénel P, Roche B, et al. Ecology, evolution, and epidemiology of zoonotic and vector-borne infectious diseases in French Guiana: transdisciplinarity does matter to tackle new emerging threats. Infect Genet Evol. 2021;93:104916.
  • 17
    Scully J, Mosnier E, Carbunar A, Roux E, Djossou F, Garçeran N, et al. Spatio-temporal dynamics of Plasmodium falciparum and Plasmodium vivax in French Guiana: 2005-2019. Int J Environ Res Public Health. 2021;18:1077.

Publication Dates

  • Publication in this collection
    16 Jan 2023
  • Date of issue
    2023

History

  • Received
    30 July 2022
  • Accepted
    4 Oct 2022
Instituto de Medicina Tropical de São Paulo Av. Dr. Enéas de Carvalho Aguiar, 470, 05403-000 - São Paulo - SP - Brazil, Tel. +55 11 3061-7005 - São Paulo - SP - Brazil
E-mail: revimtsp@usp.br