case study of malaria patient

Clinical Case Study 1: Fever 6 months after a visit to Pakistan

A 44-year-old man is seen at a physician’s office in the United States, during a week-end, for suspected malaria.

The patient was born in Pakistan but has lived in the United States for the past 12 years. He travels frequently back to Pakistan to visit friends and relatives. His last visit there was for two months, returning 11 months before the current episode. He did not take malaria prophylaxis then.

Five weeks ago, he was diagnosed with malaria and treated at a local hospital. The blood smear at that time was reported by the hospital as positive for malaria, species undetermined. He was then treated with 2 days of IV fluids (nature unknown) and tablets (nature unknown), and recovered.

The patient now presents with a history of low grade fever for the past few days, with no other symptoms. A blood smear is taken and examined at a hospital laboratory by the technician (no pathologist is available on this week-end). Through a telephone discussion, the technician states that she sees 4 parasites per 1000 red blood cells, with rings, “other forms with up to four nuclei,” and that some of the infected red blood cells are enlarged and deformed.

Question 1: What is your most probable diagnosis?

Not Malaria

That is incorrect. Please, try another answer.

Plasmodium falciparum

Plasmodium vivax

That is correct.

This is the most probable diagnosis. The reported microscopic findings are compatible with P. vivax: some infected red cells are enlarged and deformed, and the “other forms with four nuclei” are compatible with the presence of schizonts. Plasmodium vivax does occur in Pakistan, where it is found in slightly more than 50% of malaria cases.

The history suggests a relapse of P. vivax malaria, following an earlier episode five weeks ago. The earlier treatment apparently did not include primaquine, thus allowing the persistence of hypnozoites which caused this relapse.

An alternate explanation would be that the earlier infection was caused by chloroquine-resistant P. vivax (which has been reported in Pakistan), with recrudescence of blood-stage parasites occurring after an unsuccessful earlier treatment (if indeed the earlier treatment included chloroquine). However, recrudescences usually occur within 28 days of the intial episode, rather than at five weeks as described here.

The other species are less likely:

• While P. falciparum does occur in Pakistan (slightly less than 50% of malaria cases), this patient reportedly did not develop symptoms until 10 months after departure from the exposure area: most cases of P. falciparum would have become symptomatic earlier.
• P. ovale occurs mainly in Africa and has been found only occasionally in Asia (in the western Pacific).
• P. malariae occurs worldwide, but its distribution is spotty, and its frequency in Pakistan is low to negligible.
• Babesia would not fit with the microscopic description; in addition, babesiosis has not been reported in Pakistan, although admittedly the disease might have escaped detection.

Plasmodium ovale

Plasmodium malariae

Question 2: What treatment approach would you recommend, based on this clinical history and on the fact that the microscopy findings will not be confirmed by a pathologist for at least 24 hours?

Do not start treatment until a formal microscopic diagnosis is made (in 12-24 hours)

Treat as if chloroquine-sensitive Plasmodium falciparum malaria

A reasonable option, signifying that in the absence of definitive microscopic diagnosis, you prefer to play it safe and treat the patient for the most dangerous and rapidly progressing infection possible.

The safest course of action is to initially admit all cases of proven or suspected P. falciparum to the hospital until one can begin treatment and ensure that they are improving clinically and parasitologically.

However in this case, if the patient is only minimally symptomatic, one might elect against hospitalization and instead treat as an outpatient provided that close follow-up can be arranged. Once the definitive microscopic diagnosis is made the following day, you can always switch treatment.

Treat as if chloroquine-resistant Plasmodium falciparum malaria

Treat as if Plasmodium vivax malaria

P. Vivax schizont

The diagnosis of P. vivax malaria is later confirmed by review of a blood smear available from the first episode (Figure), and by a PCR positive for P. vivax on blood collected during the current episode.

The microscopic diagnosis  of P. vivax is based on the following:

• The infected red cells are enlarged and deformed;
• The schizont shown contains 20 merozoites (schizonts of P. malariae and P. ovale have fewer merozoites; and in P. falciparum , schizonts are not usually seen in the peripheral blood);
• The round gametocyte shown, contained in an enlarged red cell. (In this case, the typical Schüffner’s dots were not visible, probably due to staining problems.)

Question 3. To prevent further relapses from dormant liver stages, what would you recommend?

No further measures needed

A lab test to determine if the patient has dormant liver stages

Treatment immediately with a drug that kills dormant liver stages

A lab test, followed by treatment with a drug that kills dormant liver stages

You should exclude G6PD deficiency first, then give the patient primaquine, 30 mg per day for 14 days.

In case of G6PD deficiency, consultation with an expert in infectious diseases or tropical medicine is advised to discuss options for relapse prevention. For some patients with partial G6PD deficiency, an alternative regimen of primaquine 45 mg weekly for 8 weeks can sometime be used. Alternatively, weekly chloroquine prophylaxis may also be considered. Treatment with primaquine is justified because this patient probably has already had a relapse, and is at risk for further relapses. No test exists to detect the presence of liver stage parasites.

Question 4. Should this patient have taken preventive measures against malaria for his visit to Pakistan, considering that he was born there?

Even to visit friends and relatives, preventive measures must be taken. Chloroquine-resistant Plasmodium falciparum occurs in Pakistan, and thus the drugs recommended would be atovaquone-proguanil (Malarone®), doxycycline or mefloquine. Other preventive measures against mosquito bites also apply. Even though the patient was born in Pakistan, whatever acquired immunity he has developed would most likely have waned; negligence of preventive measures often occurs in individuals visiting friends and relatives , a situation that needs to be remedied.

Main Points

Travelers to Pakistan (including those visiting friends and relatives) need to take prophylaxis (atovaquone-proguanil [Malarone®], doxycycline or mefloquine).

Clinical history and travel history, and careful microscopic examination, probably would have directed the diagnosis toward P. vivax during the earlier episode, so that the relapse could have been prevented.

P. vivax malaria should be treated with chloroquine, except when acquired in Papua New Guinea and Indonesia, areas with high prevalence of chloroquine-resistant P. vivax . After a normal G6PD test, patients should get a radical cure with primaquine (30 mg per day for 14 days).

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Malaria: diagnosis, treatment and management of a critically ill patient

Affiliations.

• 1 Nurse Tutor, Defence School of Healthcare Education, Department of Healthcare Education, Birmingham City University, and Intensive Care Nursing Officer, Queen Alexandra's Royal Army Nursing Corps.
• 2 Principal Nursing Education Officer, Lusaka School of Nursing and Midwifery, Lusaka, Zambia.
• PMID: 28704089
• DOI: 10.12968/bjon.2017.26.13.762

Malaria is a significant cause of mortality in many countries and remains the most prevalent parasitic tropical infection. The World Health Organization estimates that 50% of the world's population is at risk of malaria, with most deaths occurring in sub-Saharan Africa. This case study explores the management of a malaria patient admitted to a critical care unit in Zambia, a lower-middle-income country in sub-Saharan Africa. While malaria is prevalent in Zambia and other countries, in the UK all malaria is imported and less frequently seen by health professionals. This case study will raise the profile of malaria, including its recognition, diagnosis and treatment. This information will assist nurses in both low- and high-income countries to translate theory into practice and improve nurses' understanding of a condition rarely seen in UK critical care practice.

Keywords: Critical care nursing; Developing countries; Disease prevention; International nursing; Malaria; Zambia.

Publication types

• Case Reports
• Antimalarials / therapeutic use
• Artemisinins / therapeutic use
• Critical Care Nursing
• Critical Illness
• Fatal Outcome
• Malaria, Cerebral / diagnosis
• Malaria, Cerebral / drug therapy
• Malaria, Cerebral / etiology
• Malaria, Falciparum / complications
• Malaria, Falciparum / diagnosis*
• Malaria, Falciparum / drug therapy*
• Antimalarials
• Artemisinins

• Case report
• Open access
• Published: 06 May 2022

Case series of three malaria patients from Thailand infected with the simian parasite, Plasmodium cynomolgi

• Piyaporn Sai-ngam 1   na1 ,
• Kingkan Pidtana 1   na1 ,
• Preeyaporn Suida 2 ,
• Kamonporn Poramathikul 1 ,
• Paphavee Lertsethtakarn 1 ,
• Worachet Kuntawunginn 1 ,
• Sarayut Tadsaichol 3 ,
• Montri Arsanok 1 ,
• Siriporn Sornsakrin 1 ,
• Chaiyaporn Chaisatit 1 ,
• Chaiyawat Mathavarat 1 ,
• Sasikanya Thaloengsok 1 ,
• Parat Boonyarangka 1 ,
• Chadin Thongpiam 1 ,
• Samandra Demons 1 ,
• Brian Vesely 1 ,
• Norman C. Waters 4 ,
• Aungkana Saejeng 5 ,
• Mariusz Wojnarski 1 ,
• Sutchana Tabprasit 6 ,
• Chokchai Kwanpichit 7 ,
• John S. Griesenbeck 1 &
• Michele Spring   ORCID: orcid.org/0000-0002-2921-9677 1 , 8  

Malaria Journal volume  21 , Article number:  142 ( 2022 ) Cite this article

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While human cases of Plasmodium knowlesi are now regularly recognized in Southeast Asia, infections with other simian malaria species, such as Plasmodium cynomolgi , are still rare. There has been a handful of clinical cases described, all from Malaysia, and retrospective studies of archived blood samples in Thailand and Cambodia have discovered the presence P. cynomolgi in isolates using polymerase chain reaction (PCR) assays.

Case presentation

In Thailand, an ongoing malaria surveillance study enrolled two patients from Yala Province diagnosed with Plasmodium vivax by blood smear, but who were subsequently found to be negative by PCR. Expanded PCR testing of these isolates detected mono-infection with P. cynomolgi , the first time this has been reported in Thailand. Upon re-testing of 60 isolates collected from Yala, one other case was identified, a co-infection of P. cynomolgi and P. vivax . The clinical course for all three was relatively mild, with symptoms commonly seen in malaria: fever, chills and headaches. All infections were cured with a course of chloroquine and primaquine.

In malaria-endemic areas with macaque populations, cases of simian malaria in humans are being reported at an increasing rate, although still comprise a very small percentage of total cases. Plasmodium cynomolgi and P. vivax are challenging to distinguish by blood smear; therefore, PCR can be employed when infections are suspected or as part of systematic malaria surveillance. As Thai MoPH policy schedules regular follow-up visits after each malaria infection, identifying those with P. cynomolgi will allow for monitoring of treatment efficacy, although at this time P. cynomolgi appears to have an uncomplicated clinical course and good response to commonly used anti-malarials.

The first naturally-acquired human infection of the simian malaria parasite, Plasmodium cynomolgi , was reported from Malaysia in 2014 [ 1 ]. Clinical cases have continued to be reported from Malaysia, and P. cynomolgi has been retrospectively detected in stored isolates from Malaysia, Cambodia and Thailand [ 2 , 3 , 4 , 5 , 6 , 7 , 8 ]. An ongoing malaria surveillance study in Thailand has been enrolling malaria patients to monitor transmission in border provinces and determine resistance patterns in order to better manage and predict effectiveness of anti-malarial treatments. As malaria cases continue to decrease in Thailand, it will become important for such surveillance studies to more actively monitor for human infections by simian malaria parasites.

Malaria case presentations

This minimal risk malaria surveillance study in Thailand has been enrolling individuals diagnosed with malaria by rapid diagnostic test (RDT) and/or microscopy since March 2019. The study operates in several border provinces: Yala (by Malaysia), Sisaket and Ubon Ratchathani (by Cambodia), and Ratchaburi (by Myanmar). After consent, a single venous blood sample is drawn, with a complete blood count (CBC), glucose 6-phosphate dehydrogenase (G6PD) CareStart™ RDT (Access Bio, Inc., USA) and fluorescent spot testing (R&D Diagnostics Ltd., Greece) performed by local Ministry of Public Health (MoPH) or Royal Thai Army (RTA) staff. The remaining blood sample shipped to US Armed Forces Research Institute of Medical Sciences (AFRIMS) in Bangkok, Thailand. There, speciation is verified by blood smears that are made and read by AFRIMS staff, and by conducting multiplex real time polymerase chain reaction (RT-PCR) on isolated parasite DNA. In addition, quantitative G6PD testing (Pointe Scientific, USA), PCR for molecular markers of resistance and submicroscopic gametocytaemia as well as ex-vivo and in-vitro drug susceptibility assays are performed. At the time of writing, 149 malaria patients have been enrolled: 128 Plasmodium vivax cases, 14 Plasmodium falciparum and four Plasmodium knowlesi cases . Three infections with P. cynomolgi were also detected. A short description of these, and the locations within Yala Province, Thailand (Fig.  1 ), follows.

Location of human P. cynomolgi cases in Thailand. Map of Yala Province, Thailand with location of detected human P. cynomolgi cases (yellow dots). The royal blue dotted line indicates the border between Thailand and Malaysia. Provinces in light yellow and red are located in Thailand, and those that are brown and light blue are in Malaysia, with the two states of Perak and Kelantan being two areas with previously reported human P. cynomolgi cases [ 7 ]

A 53-year-old woman presented at a malaria clinic in Ban Nang Sata District, in March 2021 with 38 °C fever, headache, and chills for five days. The haematological assessment showed white blood count (WBC) at 4,200/mm 3 , haemoglobin at 10.9 g/dL, and platelets at 191,000/mm 3 . She reported working at a rubber plantation, and that her husband had recently been diagnosed and treated for P. vivax infection.

A 55-year-old female rubber plantation worker was part of a malaria active case detection investigation by malaria clinic staff from Ka Bang District, in February 2021. The patient reported a history of headache and fever for eight days, although on the day of examination, the subject’s tympanic temperature was 37 °C. Laboratory examination revealed WBC at 4800/mm 3 , haemoglobin at 11.7 g/dL, and platelet count at 330,000/mm 3 .

In June 2021, a 25-year-old male on active duty in the Royal Thai Army presented at a malaria clinic in Yala District, with a complaint of five days of fever and nighttime chills. His temperature was 37.8 °C. Haematology findings showed slight thrombocytopenia at 123,000/mm 3 , WBC at 6900/mm 3 , and haemoglobin at 12.5 g/dL. The patient stated he had been stationed in Yala District for at least 20 months, going out on daily patrols and sleeping overnight in the forest. He reported using mosquito repellent and mosquito coils for personal protection.

Using microscopy, all three subjects were diagnosed with P. vivax ; all presented with uncomplicated illness, had normal G6PD activity and reported no prior history of malaria. Each patient was treated by local health care staff with three days of chloroquine and a 2-week radical cure course of primaquine, as per Thai national treatment guidelines. All were found to be clinically well within 5 days of initiating the anti-malarials, with no recurrences at subsequent follow-up visits required by the Thai MoPH scheduled at 14-, 28-, 60- and 90-days post-treatment.

Laboratory investigations

Blood smears were prepared and read by two World Health Organization (WHO)-certified microscopists at the AFRIMS labs in Bangkok, Thailand. In brief, thick and thin smears were prepared on the same glass slide and air-dried and fixed in methanol, stained for 45 min (min) in 3% diluted Giemsa stain, and examined at an oil immersion magnification of × 100. Parasite counting was done per 500 white blood cells (WBC) in thick films, and percent parasitaemia was calculated based on the actual WBC count. Parasites resembling P. vivax were detected, with densities of 25, 10, and 2718 parasites/µL blood for Case A, B, and C, respectively. Only Case C had gametocytaemia, with four gametocytes per 200 WBCs, or 138 gametocytes/µL. Malaria parasite morphologies in Giemsa-stained thick blood smears are shown in Fig.  2 A–H, demonstrating growing trophozoite stages with amoeboid-shaped cytoplasm (red arrows). No ring forms were detected in any slide. Single (Panels A–D, F), double (blue arrow, Panel E), and triple (Panel H) chromatin dots were seen on examination. There was yellowish-brown pigment dispersed within the cytoplasm in some infected cells. In thin films, parasites were found only in Case C (Fig.  2 I), the individual with mixed infection and higher parasite count. The erythrocytes were not clearly enlarged or distorted, and Schüffner's stippling was prominently visible.

Parasite morphology in Giemsa-stained blood smears from the three malaria patients. Shown are malaria parasites detected in Giemsa-stained films at a magnification of 100x. A - E Case A (thick film) showing growing trophozoite stages with amoeboid-shaped cytoplasm (red arrows). Yellowish-brown pigments were visible ( A - D ) with double chromatin dots in E (blue arrow). F Case B (thick film) with growing trophozoite stages. G and H Case C (thick film). Parasites resembling P. vivax were found in the field of view ( G , red arrow). Early schizont with merozoites was also seen in G (black arrow) and triple chromatin dots in H . I Case C (thin film) with dominant Schüffner’s stippling (pink, scattered dots) and yellowish-brown pigments in a trophozoite. Erythrocytes did not appear enlarged. Scale bar indicates 5 µm

The PCR testing performed at AFRIMS is designed to detect five Plasmodium species: P. falciparum , P. vivax , Plasmodium malariae , Plasmodium ovale and P. knowlesi . Briefly, parasite genomic DNA is extracted from whole blood collected in ethylenediaminetetraacetic acid (EDTA) using EZ1 DNA blood kit with automated EZ1 Advanced XL purification system (QIAGEN, Valencia, CA, USA), and Plasmodium speciation confirmed by multiplex RT- PCR, using species-specific primers and probes [ 9 , 10 ]. Two of the study patients (A and B) were found to be negative by multiplex RT-PCR, with P. vivax reported for Case C.

Since asexual parasites had been observed on blood smear for Cases A and B, further investigations were undertaken to identify the species. The 5-species multiplex RT- PCR was re-run as well as a singleplex RT-PCR testing for P. cynomolgi. Primers and probes specific to small subunit rRNA, S-type (Genbank accession number L08242.1 were selected, with sequences as follows: Forward: 5′-ATTGCGGTCGCAAATAATGAAG-3′, Reverse: 5′-GGTATGATAAGCCAGGGAAGTG-3′ and Probe: 5′-FAM-TACTCGCTCCTTCTGTTCCCTGGA-BHQ1′). The reaction was carried out in a 25 µl reaction using Rotor-Gene Multiplex PCR kit (QIAGEN, Hilden, Germany) with cycling conditions consisting of an initial activation step at 95 °C for 5 min, followed by 45 cycles of denaturation at 95 °C for 15 s and annealing /extension at 60 °C for 15 s. Blood from a macaque infected with P. cynomolgi was used as a positive control. Mono-infection with P. cynomolgi was confirmed by PCR in Cases A and B, with Case C having co-infection with P. vivax . All remaining Yala samples (n = 60) were then tested for P. cynomolgi by singleplex RT-PCR and were negative.

Plasmodium cynomolgi is a malaria species with Southeast Asian macaques as a natural host, transmitted through the bites of the forest-dwelling, Leucosphyrus Group of Anopheles mosquitoes, which exhibits relapses upon activation of hypnozoites similar to P. vivax [ 4 , 7 , 11 , 12 ]. This report describes three individuals enrolled in a malaria surveillance study in Thailand who were found to have P. cynomolgi infection, although after an initial microscopic diagnosis of and treatment for P. vivax . The morphologic characteristics shown on the blood films in Fig.  2 are present in both species, with similarities also evident at the structural level as described by Kosaisavee et al. [ 13 ]. For Case C, who harboured co-infection with P. cynomolgi and P. vivax , it was not possible to identify individual parasite species accurately, even in the thin film, and the parasitaemias in Cases A and B were too low to confidently locate parasites and characterize morphology. Malaria RDTs currently in use are not adequate diagnostic tools for P. cynomolgi . Test antigens are either pan- Plasmodium (e.g., aldolase or lactate dehydrogenase (LDH)) or P. falciparum or P. vivax specific, and the sensitivity in pan- Plasmodium RDTs detecting non-falciparum or non-vivax species of malaria is quite variable [ 14 ]. Cross- reactivity between P. vivax and P. cynomolgi LDH in laboratory setting has recently been demonstrated [ 15 ], but it is not clear this would translate to accuracy in a field-deployed RDT. In addition, the low parasitaemias seen in P. cynomolgi may further reduce RDT sensitivity. With the difficulties in diagnosis by blood smear even for qualified/experienced microscopists, and the lack of utility for RDTs, diagnostic testing by PCR or other molecular methods is likely to be required.

The only other publication on P. cynomolgi prevalence in Thailand conducted PCR assays on 1152 archived samples from malaria patients in Tak, Ubon Ratchathani, Chanthaburi, Yala, and Narathiwat Provinces during the period of 2007 to 2017 [ 8 ]. There were nine P. cynomolgi infections detected, all co-infections: P. cynomolgi with P. vivax (n = 7), with P. falciparum (n = 1), or with both P. vivax and P. knowlesi (n = 1). Cases were distributed across various years, diagnosed between April and December (rainy season is May–October), and found in all provinces, although Yala had five of the nine cases (55%). In these P. cynomolgi clinical cases from 2021, two of the three were mono-infections, which is the first time this has been reported in Thailand. There is one case report of P. cynomolgi mono-infection from a European tourist traveling through Thailand (Surat Thani Province) and Malaysia [ 3 ]. However, the origin of infection could not be confirmed.

With an initial microscopic diagnosis of P. vivax , the patients were not questioned for a history of contact with macaques. At the follow-up visits by the Yala study team, Case A and B did report the presence of macaques near their homes. In Thailand, the main hosts of P. cynomolgi , P. knowlesi , Plasmodium inui , and Plasmodium coatneyi are Macaca fascicularis and Macaca nemestrina , with recent reports in stump-tailed macaques, Macaca arctoides [ 16 ]. Co-infections of simian malaria are not uncommon in macaques, with the presence of two or three species simultaneously detected in 18% to 40% of monkeys [ 16 , 17 ], which may explain why some human studies report co-infections more than mono-infections [ 2 , 5 ]. Plasmodium cynomolgi was first reported as a mono-infection in a Malaysian woman in 2014 [ 1 ], and up to now, cases have been shown to exist in both peninsular Malaysia and Borneo Malaysia, the latter where P. knowlesi , another simian malaria is endemic [ 5 , 7 ]. There have been six other studies reporting the prevalence of P. cynomolgi in humans in Southeast Asia, shown in Table 1 .

To date, most of the publications reporting on human P. cynomolgi infections are retrospective testing of blood samples. In the two clinical case reports of mono-infection, and past experimental infections in humans [ 1 , 2 , 18 ], undifferentiated flu-like symptoms have been present, with symptoms occurring at very low parasitaemias and not progressing in severity. In humans, the anti-malarial treatment required for P. cynomolgi is not well studied, but macaques in P. cynomolgi drug and vaccine studies respond well to chloroquine and primaquine, the regimen for P. vivax in Thailand [ 19 ] . All the patients from Yala recovered rapidly, and there were no recurrences over three months of active follow-up. The low prevalence of simian malarias infecting humans means the parasites are not under frequent anti-malarial drug selection pressure and should remain susceptible to treatment [ 6 ]. In the study by Imwong et al. [ 6 ], two Cambodian individuals were found to have P. cynomolgi again three months after the initial diagnosis, but it was not possible to conclude whether it was a relapse, new infection, or persistent blood-stage infection.

The P. cynomolgi survey by Putaporntip et al. [ 8 ] demonstrated that P. cynomolgi has been infecting humans in Thailand for the last 15 years and is likely underdiagnosed. However among the published studies reviewed here, the prevalence of P. cynomolgi has been less than 1.5% in samples tested. In Thailand, the first clinical case P. knowlesi was reported in 2004, and by 2017, cases began to be regularly reported by the Thailand MoPH, peaking at 53 cases in 2021 [ 20 , 21 ]. It is not yet understood if the increases in human simian malaria infections are due to better detection methods, the result of human encroachment into macaque habitats, or both. The three Yala patients were diagnosed separately in time and space, although Yala province borders with Perak and Kelantan States in Malaysia where P. cynomolgi has been documented [ 7 , Fig.  1 ]. Whole-genome sequencing of the isolates is planned, which will allow lineage comparisons among these three cases as well as with data available from cases in the neighboring Malaysian states [ 7 ]. To mitigate the potential spread of P. cynomolgi and P. knowlesi and remain on track for malaria elimination, increased vigilance will be required for any signs of increased transmission in Yala and other areas in Thailand where exposure to macaques is possible.

Conclusions

This cases series is the second time human P. cynomolgi infections have been documented in Thailand and the first report of mono-infections, along with a description of the clinical course of each. P. cynomolgi is quite challenging to distinguish from P. vivax microscopically, and while this may lead to underdiagnosis, the disease course is usually mild and should be adequately and rapidly treated using antimalarial regimens for P. vivax . Molecular characterization is the most accurate way to detect these rare infections, but the capabilities may not reach the areas that need it most. Going forward, for all samples collected during this malaria surveillance study, primers for P. cynomolgi will be included for 6-species real time PCR verification. Although the diagnoses may not be available before treatment is administered, the results will allow for a more accurate estimation of infection prevalence in Thailand and evaluation of treatment efficacy during the 90-day Thai MoPH follow-up period.

Availability of data and materials

The majority of the data generated is presented in this article, but requests may be made to the corresponding author. Permission from Thai MoPH and Royal Thai Army will also be required.

Abbreviations

Armed Forces Research Institute of Medical Sciences

Deoxyribonucleic acid

Ethylenediaminetetraacetic acid

Glucose 6-phosphate dehydrogenase

Ministry of Public Health

Polymerase chain reaction

Ribosomal ribonucleic acid

Royal Thai Army

White blood cell

World Health Organization

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Thailand Malaria Elimination Programme, Ministry of Public Health, Thailand. http://malaria.ddc/ma.moph.go.th/malariar10/index_newversion.php . Accessed 17 December 2021.

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Acknowledgements

We would like to thank all the malaria patients who have joined this study as well as the members Yala malaria study team who help recruit, diagnose, transport, translate, and follow-up volunteers: Chalermpol Osodpromma (Director of The Office of Disease Prevention and Control 12 Songkhla), Pathomporn Prikchoo, Suwich Thammapalo, Wanwisa Chunkaew, Sub Lieutenant Wijai Sakoolkaew, Salida Yama. We also would like AFRIMS staff and former staff who supported the surveillance project: Krisada Jongsakul, Nicholas Martin, Mark Fukuda, Kittijarankon Phontham, Saowaluk Wongarunkochakorn, Ladaporn Bodhidatta and Phimphan Pisutsan, as well those from the Ministry of Public Health Office of Disease Control and Prevention, Ubon Ratchathani: Danai Jaerakul and Chatree Raseebut, and our colleagues from the Royal Thai Army: Nithinart Chaitaveep and Darunee Utennam.

Material has been reviewed by the Walter Reed Army Institute of Research. There is no objection to its presentation and/or publication. The opinions or assertions contained herein are the private views of the author, and are not to be construed as official, or as reflecting true views of the Department of the Army or the Department of Defense. The investigators have adhered to the policies for protection of human subjects as prescribed in AR 70–25.

The malaria surveillance study is supported by funding obtained through US Department of Defense Global Emerging Infections Surveillance (PROMIS ID P0055_22_AF) and Defense Malaria Assistance Programs.

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Piyaporn Sai-ngam and Kingkan Pidtana Co-authors; both contributed equally to this work

Authors and Affiliations

US Army Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand

Piyaporn Sai-ngam, Kingkan Pidtana, Kamonporn Poramathikul, Paphavee Lertsethtakarn, Worachet Kuntawunginn, Montri Arsanok, Siriporn Sornsakrin, Chaiyaporn Chaisatit, Chaiyawat Mathavarat, Sasikanya Thaloengsok, Parat Boonyarangka, Chadin Thongpiam, Samandra Demons, Brian Vesely, Mariusz Wojnarski, John S. Griesenbeck & Michele Spring

Ministry of Public Health (MoPH), Vector Borne Disease Control Center 12.1, Yala, Thailand

Preeyaporn Suida

Southern Border Provinces Medical Center, Yala, Thailand

Sarayut Tadsaichol

US Army Medical Materiel Development Activity, Fort Detrick, MD, USA

Norman C. Waters

Ministry of Public Health, Division of Vector Borne Diseases, Nonthaburi, Thailand

Aungkana Saejeng

Royal Thai Army-Army Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand

Sutchana Tabprasit

Royal Thai Army-Forward Internal Security Operation Command Region 4, Yala, Thailand

Chokchai Kwanpichit

The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, Bethesda, MD, USA

Michele Spring

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Study concept, design and support: MS, JSG, MW, NW, BV, SD, WK, PL, BV, ST, AS Study execution and collection of samples/data: PS, KP, KP, MS, WK, PL, SS, PS, CK, SS, CC, MA, PB, CM, CT, ST Performed assays and interpreted data: PS, KP, KP, WK, PL, SS, PS, SS, CC, MA, PB, CM, CT, ST Drafting of the manuscript: PS, KP, KP, MS, PL, WK, CC, MW. All authors read and approved the final manuscript.

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Ethical approval for the conduct of this malaria study was obtained from the Walter Reed Army Institute of Research Institutional Review Board (WRAIR IRB) #00000794 in Silver Spring, Maryland, US on 12 September 2018 and Institute for Development of Human Research Protection (IHRP) IRB #00006539 in Bangkok, Thailand on 22 October 2018. Signed informed consent was obtained from all individuals prior to participation.

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Sai-ngam, P., Pidtana, K., Suida, P. et al. Case series of three malaria patients from Thailand infected with the simian parasite, Plasmodium cynomolgi . Malar J 21 , 142 (2022). https://doi.org/10.1186/s12936-022-04167-w

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Malaria Journal

ISSN: 1475-2875

• Submission enquiries: [email protected]

This nursing study guide provides an overview of malaria including the five species of the malaria parasite, treatment, preventive options, nursing interventions, and nursing care planning, nursing diagnosis , and management.

Malaria is one of the most common infectious diseases known to mankind and is among the leading causes of morbidity and mortality in the world. It predominantly occurs in tropical and subtropical areas such as in sub-Saharan Africa, Asia, and Latin America where the mosquitos that carry the parasite live.

Table of Contents

What is malaria, pathophysiology, statistics and incidences, clinical manifestations, assessment and diagnostic findings, pharmacologic management, nursing assessment, nursing diagnosis, nursing care planning and goals, nursing interventions, documentation guidelines, practice quiz: malaria.

Malaria , is a potentially life-threatening disease caused by infection with Plasmodium protozoa transmitted by an infective female Anopheles mosquito vector.

• Malaria is a serious and sometimes fatal disease caused by a parasite that commonly infects a certain type of mosquito which feeds on humans.
• People who get malaria are typically very sick with high fevers, shaking chills, and flu -like illness.
• The 5 Plasmodium species known to cause malaria in humans are P falciparum , P vivax , P ovale , P malariae , and P knowlesi .
• Timely identification of the infecting species is extremely important, as P falciparum infection can be fatal and is often resistant to standard chloroquine treatment.
• Plasmodium falciparum is distinguished from the rest of the plasmodia by its high level of parasitemia and the banana shape of its gametocytes.

The types (species) of Anopheles present in an area at a given time will influence the intensity of malaria transmission.

• Plasmodium falciparum. The most malignant form of malaria is caused by this species; P falciparum is able to infect RBCs of all ages, resulting in high levels of parasitemia; sequestration is a specific property of P falciparum; as it develops through its 48-hour life cycle, the organism demonstrates adherence properties, which result in the sequestration of the parasite in small postcapillary vessels.
• Plasmodium vivax. If this kind of infection goes untreated, it usually lasts for 2-3 months with diminishing frequency and intensity of paroxysms; of patients infected with P vivax, 50% experience a relapse within a few weeks to 5 years after the initial illness;P vivax infects only immature RBCs, leading to limited parasitemia.
• Plasmodium ovale. These infections are similar to P vivax infections, although they are usually less severe; P ovale infection often resolves without treatment; similar to P vivax, P ovale infects only immature RBCs, and parasitemia is usually less than that seen in P falciparum.
• Plasmodium malariae. Persons infected with this species of Plasmodium remain asymptomatic for a much longer period of time than do those infected with P vivax or P ovale; recrudescence is common in persons infected with P malariae. 
• Plasmodium knowlesi. Autochthonous cases have been documented in Malaysian Borneo, Thailand, Myanmar, Singapore, the Philippines, and other neighboring countries; it is thought that simian malaria cases probably also occur in Central America and South America; patients infected with this, or other simian species, should be treated as aggressively as those infected with falciparum malaria, as P knowlesi may cause fatal disease. 

The natural history of malaria involves cyclical infection of humans and female Anopheles mosquitoes.

• In humans, the parasites grow and multiply first in the liver cells and then in the red cells of the blood .
• In the blood, successive broods of parasites grow inside the red cells and destroy them, releasing daughter parasites (“merozoites”) that continue the cycle by invading other red cells.
• The blood-stage parasites are those that cause the symptoms of malaria; when certain forms of blood stage parasites (gametocytes, which occur in male and female forms) are ingested during blood feeding by a female Anopheles mosquito, they mate in the gut of the mosquito and begin a cycle of growth and multiplication in the mosquito.
• After 10-18 days, a form of the parasite called a sporozoite migrates to the mosquito’s salivary glands .
• When the Anopheles mosquito takes a blood meal on another human, anticoagulant saliva is injected together with the sporozoites, which migrate to the liver, thereby beginning a new cycle.
• Thus the infected mosquito carries the disease from one human to another (acting as a “vector”), while infected humans transmit the parasite to the mosquito.
• In contrast to the human host, the mosquito vector does not suffer from the presence of the parasites.

Malaria is one of the most severe public health problems worldwide

• Almost all US cases of malaria are imported from patients traveling from endemic areas.
• Outbreaks of locally transmitted cases of malaria in the United States have been small and relatively isolated, but the potential risk for the disease to re-emerge is present due to the abundance of competent vectors, especially in the southern states.
• In 2016, an estimated 445,000 people died of malaria—most were young children in sub-Saharan Africa.
• Within the last decade, increasing numbers of partners and resources have rapidly increased malaria control efforts.
• his scale-up of interventions has saved millions of lives globally and cut malaria mortality by 25% from 2010 to 2016, leading to hopes and plans for elimination and ultimately eradication.
• In areas with high transmission, the most vulnerable groups are young children, who have not developed immunity to malaria yet, and pregnant women, whose immunity has been decreased by pregnancy.
• Nearly half the world’s population lives in areas at risk of malaria transmission in 91 countries and territories.
• In 2016, malaria caused an estimated 216 million clinical episodes, and 445,000 deaths; an estimated 90% of deaths in 2016 were in the WHO African Region.

Causes of malaria may include the following:

• Endemic areas. Individuals with malaria typically acquired the infection in an endemic area following a mosquito bite. 
• Transfusion. Cases of infection secondary to transfusion of infected blood are extremely rare.
• Poor immunity. The outcome of infection depends on host immunity; individuals with immunity can spontaneously clear the parasites; in those without immunity, the parasites continue to expand the infection. 
• Climate. Climate is a key determinant of both the geographic distribution and the seasonality of malaria; without sufficient rainfall, mosquitoes cannot survive, and if not sufficiently warm, parasites cannot survive in the mosquito.

The classical malaria attack lasts 6–10 hours. It consists of: 

• Cold stage. A sensation of cold and shivering.
• Hot stage. There is fever , headaches, vomiting ; and seizures in young children.
• Sweating stage. Patient experiences sweat, return to normal temperature, and tiredness . 

Rapid and accurate diagnosis of malaria is integral to the appropriate treatment of affected individuals and in preventing the further spread of infection in the community.

• Blood smears. A diagnosis of malaria should be supported by the identification of the parasites on a thin or thick blood smear; thick smears are 20 times more sensitive than thin smears, but speciation may be more difficult; thin smears are less sensitive than thick smears, but they allow identification of the different species. 
• Rapid diagnostic tests. Immunochromatographic tests based on antibody to histidine-rich protein-2 (PfHRP2), parasite LDH (pLDH), or Plasmodium aldolase appear to be very sensitive and specific; some RDTs may be able to detect P falciparum in parasitemias that are below the threshold of reliable microscopic species identification; only one RDT (BinaxNOW) has been approved to date for the diagnosis of malaria in the United State
• Other tests. In addition to the RDT listed above, new molecular techniques, such as PCR assay testing and nucleic acid sequence-based amplification (NASBA), are also available for diagnosis; they are more sensitive than thick smears but are expensive and unavailable in most developing countries.

Medical Management

Treatment of malaria depends on many factors including disease severity, the species of malaria parasite causing the infection, and the part of the world in which the infection was acquired.

• Inpatient. Patients with elevated parasitemia (>5% of RBCs infected), CNS infection, or otherwise severe symptoms and those with P falciparum infection should be considered for inpatient treatment to ensure that medicines are tolerated; obtain blood smears every day to demonstrate a response to treatment. 
• Prevention. Avoid mosquitoes by limiting exposure during times of typical blood meals (ie, dawn, dusk); wearing long-sleeved clothing and using insect repellants may also prevent infection; avoid wearing perfumes and colognes.
• Consultations. Consider consulting an infectious disease specialist for assistance with malaria diagnosis, treatment, and disease management.

The 4 major drug classes currently used to treat malaria include quinoline-related compounds, antifolates, artemisinin derivatives, and antimicrobials; no single drug that can eradicate all forms of the parasite’s life cycle has been discovered or manufactured yet.

• Antimalarials. These agents inhibit growth by concentrating within acid vesicles of the parasite, increasing the internal pH of the organism; they also inhibit hemoglobin utilization and parasite metabolism.

Nursing Management

The nursing management of a patient with malaria may include the following:

Assessment of a patient with malaria include:

• History. In patients with suspected malaria, obtaining a history of recent or remote travel to an endemic area is critical; asking explicitly if they traveled to a tropical area at anytime in their life may enhance recall; maintain a high index of suspicion for malaria in any patient exhibiting any malarial symptoms and having a history of travel to endemic areas.
• Demographic data. Also determine the patient’s immune status, age, and pregnancy status; allergies or other medical conditions that he or she may have; and medications that he or she may be using.

Based on the assessment data, the major nursing diagnosis for a patient with malaria may include:

• Risk for infection related to weakened immune system.
• Hyperthermia related to increased metabolic rate and dehydration .
• Impaired tissue perfusion related to a decrease in the cellular components needed for the delivery of oxygen and nutrients in the body.
• Fluid volume deficit related to excessive sweating and dehydration .
• Knowledge deficit related to lack of exposure and information about the disease process, its treatment, and prognosis.

The nursing care plan goals for a patient with malaria are:

• Prevent infection.
• Reduce increase in and regain normal body temperature.
• Improve tissue perfusion.
• Improve fluid volume of the body.
• Gain information on malarial disease process, treatment, and prognosis.

Nursing interventions for a patient with malaria include the following:

• Improve body temperature. Warm water compress on forehead and both axilla (not more than 15 minutes each time); maintain warm environment by using warm blankets, adequate clothing); patient may sweat excessively, make sure to avoid exposing patient to wet clothes and linens; administration of antipyretic drugs as ordered.
• Improve tissue perfusion. Patient may need supplemental oxygen if condition is severe; maintain a well-ventilated room; head of the bed at 30º.; lessen activities that require moderate to high exertion.
• Improve fluid volume. Expect loss of fluid through sweat; provide information about fluid balance and guideline for fluid replacement; encourage increase in oral fluid intake; administer parenteral fluids as ordered.
• Educate the patient and family. Review the disease process and therapy, focusing on patient’s concerns; discuss importance of adhering to therapy; go over medication, purpose, frequency, dosage , and side effects; have a family member or trusted individual listen to and understand guideline of treatment as the patient chooses.

Nursing evaluation of patients with malaria includes meeting the following goals:

• Prevention of infection.
• Reduced increase in body temperature.
• Improved tissue perfusion.
• Improved fluid volume of the body.
• Gained and retained information on malarial disease process, treatment, and prognosis.

Nursing documentation in a patient with malaria include:

• Individual findings, including factors affecting, interactions, nature of social exchanges, specifics of individual behavior.
• Cultural and religious beliefs, and expectations.
• Plan of care.
• Teaching plan.
• Responses to interventions, teaching, and actions performed.
• Attainment or progress toward the desired outcome.

Nursing practice questions for Malaria. For more practice questions, visit our NCLEX practice questions page .

1. The infectious agent that causes malaria is known as which of the following?

A. Protozoan parasite B. Bacterial parasite C. Viral parasite D. Fungal parasite

1. Answer: A: Protozoan parasite

• Option A: Malaria is caused by members of the protozoan genus Plasmodium.

2. The malaria parasite is spread by which of the following?

A. Male mosquitoes B. Female mosquitoes C. Both male and female mosquitoes

2. Answer: B. Female mosquitoes

• Option B: The malaria parasite is spread by the bite of the female mosquito only.

3. Which mosquito genus is associated with spreading the human malaria parasite?

A. Culex B. Anopheles C. Aedes D. Lutzia

3. Answer: B. Anopheles

• Option B: Members of the Anopheles genus are responsible for spreading the malaria parasite to humans (also known as vectors).

4. Which one of the following are NOT antimalarial compounds?

A. Quinine B. Artemisinin C. Chloroquine D. Mefloquine E. Penicillin

4. Answer: E. Penicillin

• Option E: Penicillin is an antibiotic that targets bacteria. The others are all antimalarial compounds.

5. Which of these statements is correct?

A. Malaria is a neglected tropical disease B. If you get malaria once, you won’t get it again C. Malaria is quite often endemic in poorer regions of the world

5. Answer: C. Malaria is quite often endemic in poorer regions of the world

• Option C: Whilst malaria is not caused by poverty itself, the ability to control and eliminate the disease is affected by socio-economic factors. A study by Xia Zhao and colleagues from the University of Oxford found that increased socio-economic improvements such as wealth, life expectancy and urbanization were the key drivers in eliminating malaria in Europe in the early 20th century.

Sources and references for malaria nursing study guide:

• Black, J. M., & Hawks, J. H. (2005).  Medical- surgical nursing . Elsevier Saunders,. [ Link ]
• Kimberlin, D. W. (2018).  Red Book: 2018-2021 report of the committee on infectious diseases  (No. Ed. 31). American academy of pediatrics.
• Oshinsky, D. M. (2005).  Polio : an American story . Oxford University Press. [ Link ]
• Willis, L. (2019).  Professional guide to diseases . Lippincott Williams & Wilkins. [ Link ]
• WHO Expert Committee on Malaria, & World Health Organization. (2000).  WHO expert committee on malaria: twentieth report  (No. 892). World Health Organization. [ Link ]

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Hi Cynthia, Thanks for the feedback! It’s great to hear that the malaria study guide was clear and easy to grasp. If there’s more you’d like to learn about malaria or any other topic, just give a shout. Always here to make learning as straightforward as possible!

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• Published: 08 April 2024

Malaria risk mapping among children under five in Togo

• Gountante Kombate 1 , 2 ,
• Issouf Kone 3 ,
• Bili Douti 4 ,
• Kamba André-Marie Soubeiga 5 ,
• Diederick E. Grobbee 6 &
• Marianne A. B. van der Sande 6 , 7  

Scientific Reports volume  14 , Article number:  8213 ( 2024 ) Cite this article

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• Epidemiology
• Infectious diseases

Malaria is a major health threat in sub-Sahara Africa, especially for children under five. However, there is considerable heterogeneity between areas in malaria risk reported, associated with environmental and climatic. We used data from Togo to explore spatial patterns of malaria incidence. Geospatial covariate datasets, including climatic and environmental variables from the 2017 Malaria Indicator Survey in Togo, were used for this study. The association between malaria incidence and ecological predictors was assessed using three regression techniques, namely the Ordinary Least Squares (OLS), spatial lag model (SLM), and spatial error model (SEM). A total of 171 clusters were included in the survey and provided data on environmental and climate variables. Spatial autocorrelation showed that the distribution of malaria incidence was not random and revealed significant spatial clustering. Mean temperature, precipitation, aridity and proximity to water bodies showed a significant and direct association with malaria incidence rate in the SLM model, which best fitted the data according to AIC. Five malaria incidence hotspots were identified. Malaria incidence is spatially clustered in Togo associated with climatic and environmental factors. The results can contribute to the development of specific malaria control plans taking geographical variation into consideration and targeting transmission hotspots.

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Introduction

Malaria in children under the age of five is a major cause of morbidity and mortality worldwide. Despite efforts to combat the disease, the number of cases is rising, and has been estimated at around 232 million in 2019, 245 million in 2020 and 247 million in 2021. Sub-Saharan African countries have the highest rates of infection, with children under the age of five most affected 1 .

For example, in Togo, 2,136,877 confirmed cases and 1275 deaths were recorded in 2020 on a population of about 8 million inhabitants. Children under five years of age represented 31.6% of cases 2 , 3 . According to the distribution of cases reported in the country by the National Malaria Control Program (PNLP), malaria infection is regionally heterogeneous: in 2019, malaria prevalence was 18% in the Lomé commune region, 39% in the Plateaux region and 42% in the Kara region 4 . A recent study in Togo on spatio-temporal analysis used district-level health system data (2008–2017) to analyze the trend and change in malaria incidence 5 . Other studies have explored the burden of malaria in children under five 6 , 7 , 8 , 9 at the regional level 4 using individual and household level factors, but contextual factors such as the climate and environmental may play an important role in malaria transmission also 10 . Thus, the spatial variation observed may be related to different ecological conditions, variations in health care systems, and socioeconomic differences or intervention coverage 11 . Effective interventions and prevention efforts could be improved by deepening our understanding of the spatial variation and related ecological factors underlying malaria transmission and risk of disease 12 .

Several environmental and ecological factors are known to influence malaria transmission; of which the main ones are precipitation and temperature 12 , 13 . Precipitation is directly related to rainfall and influences the biological dynamics of the Anopheles mosquito vectors of malaria parasites. Rainfall, especially when it is heavy, washes away much of the breeding sites of these mosquitoes, while temperature determines during how much time mosquito larvae can develop in the environment and parasites in the vector. Environmental change caused by the construction of dams and irrigation systems can influence the type and distribution of mosquitoes 13 , 14 . Environmental and ecological factors can lead to local transmission hotspots, defined as geographical areas within a larger transmission zone in which the intensity incidence is significantly higher than the average level in the surrounding area. In contrast, there are cold spots of malaria, defined as a location of cases where the intensity of transmission incidence is significantly lower than expected 15 .

Hotspots are the main reservoirs of persistent malaria transmission and are associated with higher vector density, sporozoite prevalence, and malaria incidence than in neighboring areas 16 . Malaria hotspots occur mostly in poor, tropical and subtropical areas of the world, with Africa being the most affected. The main risk factors of malaria hotspots are associated with local climatic and environmental conditions, such as proximity to vector breeding sites, precipitation 15 , vegetation cover, temperatures, housing conditions 17 , 18 , net use and household occupancy 19 . Nevertheless, the exact role of these factors in the formation of malaria hotspots is still under debate 20 , 21 , 22 . Several African countries have observed the persistence of malaria hotspots after an overall reduction in malaria transmission 21 , 22 . Lack of knowledge about malaria hotspots can therefore undermine the effectiveness of intervention programs. Identifying these hotspots is crucial to achieving the sustainable development goal of zero malaria incidence in a given area by 2030 23 , 24 particularly in Togo.

The aim of this study was to use geospatial techniques to identify malaria hotspots on the basis of environmental and climatic factors in a Togolese context, as availability of national data from the 2017 Malaria Indicators Survey provided a unique opportunity to assess spatial and temporal patterns of malaria transmission.

Study areas

Togo is a country located in West Africa, on the coast of the Gulf of Guinea. It is bordered to the north by Burkina Faso, to the south by the Atlantic Ocean, to the east by Benin and to the west by Ghana (Fig.  1 ). In 2022, Togo had a population about 8 million inhabitants with a density of 152 inhabitants/km2. It covers an area of 56,785 km 2 with 95.8% land and 4.2% water. It stretches over a length of 600 km and a width varying between 50 and 150 km. The highest altitude is at 986 m.

Source: Region level country shapefiles obtained from spatial reference; https://spatialreference.org/ .

Study clusters (n = 171) of the 2017 Togo MIS.

Study design and data source

Cross-sectional data were collected as part of the Togo Malaria Indicator Survey (MIS) 2017–2018, which is a national representative survey. The main objective of this MIS was to obtain population-based estimates for malaria indicators such as prevalence and risk factors. Standardized household cluster sampling methods were applied. Figure  1 presents the map of the 171 study clusters where data were collected.

The distribution of study clusters reflected a higher concentration in more densely populated areas as sampling was proportional to population size. The data collected included geospatial covariates such as temperature, aridity, rainfall, precipitation, proximity to water and vegetation derived from various sources, at different levels of national coverage 25 .

Malaria incidence data were calculated as the mean number of people per year with fever, in the 2 km (urban) or 10 km (rural) buffer zone surrounding the survey cluster location. Cases obtained from each country surveillance system are reported by the National Malaria Control Program (NMCP). This includes among others information on the number of suspected cases, number of tested cases, Number of positive cases by method of detection and by species as well as number of health facilities that report those cases. This information is summarized in a District Health Information Software (DHIS2) application 25 , 26 . The DHS experts made a link between DHS data with routine health data, health facility locations, local infrastructure such as roads and rivers, and environmental conditions. Aside from this, data on malaria incidence was obtained from all 171 MIS clusters in the country with a 5 year interval (2000, 2005, 2010 and 2015). The Table 1 below presents the descriptions of the different variables included in the study.

Statistical analysis

Analyses of malaria incidence and climatic and environmental factors was performed through the computation of mean difference, frequency counts, percentages, independent t-test, and one-factor analysis of variance (ANOVA). Geospatial modelling exploring malaria incidence in relation to environmental and climatic variables, including temperature, rainfall, precipitation, distance to water bodies, aridity and population density were performed using the Ordinary Least Squares (OLS), the Spatial Lag Model (SLM), and the Spatial Error Model (SEM). The non-spatial OLS model provides a global model of the variable or process one is trying to understand or predict 27 ; it describes the relationship between one or more quantitative variables and a dependent variable provides the covariate adjustment and prediction of mean risk of malaria in an area 28 . The spatial SLM model can accommodate a spatial dependency between the dependent variable and explanatory variables by incorporating a “spatially-lagged dependent variable” in the regression model. This model accounts for autocorrelation in the model with the weight matrix. The spatial SEM model is a model that considers corrective measures for residual spatial autocorrelation. For this model, the residuals were not assumed to be independent; instead, they exhibited a moving average map pattern 27 , 29 . The aim of using both spatial and non-spatial models is to compare the best-fitting models for predicting malaria incidence in children, using Akaike Information Criterion (AIC) to decide, and also to produce the most plausible risk maps 19 , 27 , 29 . The AIC allows us to select the model that minimizes the loss of information. We chose these models since we it to provide unbiased point estimates of the parameters. They offer the possibility to estimate spatial overlap coefficients, thus informing about correlation or spatial influence processes 30 .

Overall spatial autocorrelation between an ecological predictor and the incidence of malaria was assessed with Moran’s I statistical test 27 . The Moran scatter plot was used to quickly obtain an overview of the global spatial autocorrelation of malaria incidences, and a Local Indicators of Spatial Association (LISA) analysis was used to identify hot and cold spots of cluster location 27 , 28 . The analyses were performed using R software.

Ethics approval and consent to participate

For this study, ethics approval was not sought since our analysis was based on publicly available data. However, DHS reports that informed consent, both written and verbal, was obtained from all participants by the Institutional Review Board of ICF International and the Bioethics Committee for Health Research (BCRS) of Togo. Prior to the start of the investigation, all ethical guidelines governing the use of human subjects were strictly adhered to and the methods were applied in accordance with the relevant guidelines and regulations of the Declaration of Helsinki. The data set and permission to conduct secondary data analysis were granted by the DHS program.

Spatial and temporal distribution of the mean malaria incidence (per 1000 population at risk)

The spatial distribution of the mean malaria incidence in Togo in 2000, 2005, 2010 and 2015 is presented in Fig.  2 below. Overall, between 2000 and 2015, the mean malaria incidence decreased, although an increase in the average malaria incidence was observed in the Savanes region until 2010. The Savanes and Central health regions had a higher average malaria incidence than the Plateaux and Kara regions in 2000. The evolution of the incidence of malaria in 2010 shows an aggravation in the Savannah and Kara regions. The Lomé commune region recorded the lowest average malaria incidence rates in 2000, 2005, 2010 and 2015.

(Source: Region level country shapefiles obtained from spatial reference; https://spatialreference.org/ ) .

Spatio-temporal variation of malaria incidence in children under 5 years old in Togo: ( a ) Malaria incidence in 2000, ( b ) Malaria incidence in 2005, ( c ) Malaria incidence in 2010, ( d ) Malaria incidence in 2015.

Spatial autocorrelation analysis of malaria incidence

The effects of the most important environmental and climate factors as described in the methods are presented in Table 2 . Both climatic and environmental factors, in particular temperature, aridity, precipitation and proximity to water, were related to the mean malaria incidence in each of the three analysis models.

The SLM model with the lowest AIC (− 65.906) was the best model with the best fit. For mean temperature, there was a positive significant association with malaria incidence in children under five. Each additional one-degree Celsius increase in mean temperature (26–29 °C) being associated with an increase in incidence of about 0.55%. For precipitation, with every millimeter of additional water precipitated, there was an associated increase in malaria incidence of the order of 0.392% in Togo. Malaria incidence also increased with an increase in aridity index and with proximity to water. In contrast, annual rainfall and population density might bean inversely associated with mean malaria incidence.

Spatial autocorrelation: global moran’s I

The global Moran's I test (Moran I = 0.469, p < 0.05) showed significant spatial dependence in the observed malaria incidences. Figure  3 depicts a scatter plot of mean malaria incidence.

Mean Moran’s I values for local spatial autocorrelation for malaria incidence at varying spatial lags.

Spatial autocorrelation: local indicators of spatial association (lisa)

The LISA results are shown in Fig.  4 below.

( a ) LISA map ( b ) and LISA significance map of Local Moran’s I test show the hot and cold malaria spot locations in Togo using GeoDa software.

The areas shown in red in Fig.  4 a are the locations of clusters representing hot spots. The areas shown in blue are the locations of clusters representing cold spots. Figure  4 b shows the significance levels, with different colors representing different p-value ranges. Dark green represents areas with significant (p-value less than 0.001) local spatial autocorrelation in malaria incidence; simple green represents areas with significant (p-value less than 0.01) local spatial autocorrelation in malaria incidence; and bright green represents areas with significant (p-value < 0.05) local spatial autocorrelation in malaria incidence.

Malaria remains a serious threat in sub-Saharan Africa, including Togo, even if incidence has decreased overall, with significant differences in incidence between regions over the years. This study used spatial and non-spatial regression models to identify hotspots of malaria infection transmission in Togo through ecological analysis. Spatial heterogeneity could be explained by the precipitation seasonality, mean temperature, aridity index and proximity to water which were all positively correlated with malaria incidence in our analyses. All these factors are predominant environmental factors that characterized the Plateaux region where the highest incidence was observed and favour malaria transmission in the region 10 .

For all the ecological predictors, some, as mentioned above (the mean temperature, aridity, precipitation seasonality and proximity to water), showed positive correlations and significant associations with malaria incidence. The daily survival rate of mosquitoes is optimal at about 90% with temperatures between 16°C and 36°C (Craig 1999). Increasing temperature reduces the blood meal-seeking behaviour of female Anopheles mosquitoes, resulting in a corresponding decrease in ovulation and juvenile mosquito production, and consequently a decrease in the number of new malaria cases. Increased precipitation was also positively associated with malaria incidence and can have both a direct and indirect effect, particularly where dams are located. Precipitation increases reservoir water levels and creates potential breeding grounds for mosquitoes along the banks of the reservoir 12 , 31 . The southern regions (Lomé commune, Maritime, Plateaux and Central) benefit from a longer duration of rainfall than the northern regions (Kara and Savanes) in Togo 10 . Concerning aridity, this very strong positive correlation with malaria incidence may be related to the fact that increased aridity influences malaria transmission by reducing the mosquito biting rate and adult life span as well as the extrinsic incubation period of the malaria parasite 18 , 31 . Thus, the ability of adult vectors to survive long enough and contribute to the spread of parasites, and the ability of pre-adult stages to sustain a minimum population, depends on aridity levels and species-specific resilience to arid conditions 32 . In contrast, a study in northeastern Benin 33 georeferencing all mosquito breeding sites in two rural sites showed that aridity had a negative influence on malaria transmission. According to the authors, this could be due to the fact that classic anopheles breeding sites have dried up due to the very high aridity in these regions, leading gravid females to lay their eggs in unusual habitats already hosting larvae of other general species. As for proximity to water bodies, our results corroborate with studies in Nigeria 19 and The Gambia 34 . Using respectively logistic regression methods and post-hoc analyses on mosquitoes catches, these studies observed a positive relationship with distance to water bodies up to 4 km before decreasing.

Other ecological predictors showed inverse but non-significant relationships, such as rainfall and population density. The inverse correlation with rainfall observed in the three analysis models suggests a negative impact of continuous heavy rainfall on malaria parasite vectors and eventual transmission of the disease. Similar previous studies conducted in Burkina Faso 10 , 31 , 32 also showed a negative correlation of rainfall on malaria incidence. Another study in Sri Lanka 35 observed seasonal variation in malaria infection in the country. The varying seasonal effects of rainfall on the number of malaria cases was reflected in the weak correlations observed, in which situation rainfall may be of limited use in predicting malaria. An observed linear relationship between rainfall and malaria could hide non-linear effects. An important aspect would be to investigate the relationship between rainfall and mosquito reproduction and survival. Variables influenced by rainfall, such as soil water saturation and river flow, could be more directly linked to the specific breeding conditions of malaria vectors. However, these variables are more costly to measure and are therefore often estimated from rainfall 17 .

Prevention measures are also likely to have a significant temporal effect on the time series of malaria cases. E.g. a study in urban and peri-urban areas in Africa (Mozambique and Senegal) and in the Indian Ocean (republic of Mauritius) 36 found a negative association between malaria infection and vector abundance. They attributed this to the willingness of people to use mosquito nets or to the stimulated development of immunity during early childhood in high-risk areas 37 . This variable has not been considered. Moreover, control methods and insecticides have changed over time, making it a complex variable 35 .

A limitation of spatial statistical models is that disease data can show a great deal of intra-and inter-annual variability, while a regression analysis assumes that the association between exposure and outcome is stationary over time 29 . Generalized linear mixed models (GLMM) could be used to capture transmission dynamics over time while controlling for temporal autocorrelations 38 .

Nevertheless, the data illustrate the opportunity to identify hotspots for malaria control. With regard to seasonal climate forecasts, environmental monitoring and the evolution of malaria morbidity in the country, these results can help design an early warning system for the National Malaria Control Program, which will help identify areas at risk of epidemic outbreak.

We evaluated the spatial and temporal association in Togo between malaria transmission hotspots and environmental and climatic risk factors. Malaria incidence was more related to incidence in nearby clusters than to those far away. Mean temperature, precipitation, aridity and proximity to water bodies showed a significant and positive association with malaria incidence. These results may help to channel available resources to disease hotspots and sustain prevention efforts for better control of malaria infection in children under 5 years of age in Togo and in similar sub-Saharan context.

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Acknowledgements

Thanks to the ICF International and DHS (Demographic and Health Surveys) Program for providing and granting permission for the use of the data in this study and to the Ministry of health, public hygiene and universal access to care, Togo for their support and advise.

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USF Health researchers are working to advance the understanding of how malaria becomes resistant to the most popular drug used to treat the disease. 

To fight malaria parasite, researchers try tricking it with a time-travel strategy

• Dave Scheiber
• March 25, 2024

College of Public Health , Research

It has the sound of a Hollywood movie – including mutants and deadly parasites that develop an alarming resistance to traditional means of containment, threatening to overtake populations on two continents.

But this is no summer popcorn flick. It’s how malaria is actually spreading in Africa and many parts of Southeast Asia. The mosquito-driven disease has grown increasingly tolerant to traditional drug treatment, with potentially devastating consequences, particularly to children.

Enter two USF Health researchers: distinguished USF professor John Adams, PhD, director of the USF Genomics Program and co-director of the Center for Global Health and Inter-Disciplinary Research; and a member of his lab, clinical scientist Caroline Simmons, PhD – newly anointed with her medical sciences doctorate in the areas of genomics, drug resistance and infectious diseases.

She served as lead author and Dr. Adams as senior author, along with nine other USF Health researchers, in a recently published study analyzing novel factors that can alter a malaria parasite’s response to drugs – particularly significant given the parasite’s increasing drug resistance, leading to treatment failure.

The importance of their work is even more clear now, following the diagnosis this summer of seven Florida residents infected with malaria that was transmitted by mosquitoes in Florida, as well as another case in Texas. These are the first locally transmitted cases of malaria infection in the U.S. in 20 years.

Dr. Simmons was a fifth-grader when Dr. Adams published his first study on a new tool for forward genetics research in malaria in 2005 – two years prior to joining the USF College of Public Health’s Infectious Research Program. He had worked the previous 16 years at the University of Notre Dame, building on his training in basic parasitology and molecular approaches to malaria at the National Institutes of Health.

“I joined the Morsani College of Medicine PhD program and had the chance to rotate between three labs,” said Dr. Simmons, who earned her undergraduate degree in Microbiology and masters in Medical Sciences from USF as well. “And Dr. Adams was one of the labs I decided to join – he was doing amazing work on malaria. I’ve always found drug-related issues interesting, and I love working on things that have an impact on people. I started out just rotating in his lab, and then I decided to join.”

Now they have teamed up to create a major advance in the understanding of malaria’s resistance to artemisinin or artemisinin-based combination therapies, known as ACTs – the drug used to cure and treat the malaria-infected parasite.

And they’ve done it with what you might liken to a different Hollywood approach – Back to the Future. Essentially, through a study she conducted, Simmons found a way to go back to an earlier time point in a parasite’s normal development, disrupting it in a manner that makes it less effective in tolerating artemisinin or ACTS – but more on that in a moment.

First, some important background in the progression of events: In 2015, the Nobel Prize in Physiology or Medicine was awarded to Chinese scientist Youyou Tu for her key contributions in the discovery of artemisinin as the active ingredient in a traditional herbal medicine.

“It was such a great discovery, but it has some limitations,” said Dr. Adams. “It’s a fast-acting drug but it also disappears very quickly.  There are various older drugs it’s partnered with, and what happens when the artemisinin portion disappears, there’s a resistance to the partner drug. At the same time, the parasite has slowly evolved. It just has to hang around long enough not to get killed by artemisinin, which disappears so fast. And if the parasite is in the early phase of its development, it has a natural resistance to the drug.”

That is what has led to the unfolding, new crisis in Africa and Southeast Asia, where malaria has begun to take hold once again, raising fears of a new global health emergency.

What happens to the body when a person contracts malaria? Dr. Adams explained that the parasite enters the red blood cells, where it finds a “food” source in the form of hemoglobin, which carries oxygen through the bloodstream.

“It’s a protein, but in the center of the protein is an iron molecule, which carries oxygen,” Dr. Adams said. “The protein is there to hold the iron in place, and not allow it to interact with anything else. But when the parasite eats the protein part, it releases the iron, which is very toxic. The release of this iron activates the artemisinin. But the parasite now has an increased resistance to the drug, basically resulting from a slowed-down ingestion of the hemoglobin. By slowing down, the parasite is better equipped to deal with the effects of the fast-disappearing drug. All the parasites in Southeast Asia now carry this mutation.”

The outward manifestation of malaria often portrayed in the movies, said Dr. Adams, is of a person shaking and sweating in some subtropical bed. “That’s what is known as malaria fever, which happens every 48 hours,” he said. “The parasite is synchronized in its growth, so all the stages in the blood are maturing at the same time. When they finish, they rush out of the cell, so there’s all this garbage released into the circulatory system, and that induces a shock response. The person feels cold, but they have an intense fever that can last four or five hours.”

The fact that the parasite could survive the intense fever when it enters the cell intrigued Dr. Adams and Dr. Simmons.  

“We were curious why it was not dying under these extreme temperatures,” he said. “We discovered that these are the same genes people are seeing with drug-resistant parasites. And they’re the same genes we’ve already started to identify in these other screening methods. So the parasite has evolved over the years to survive fever – and now artemisinin.”

Dr. Simmons’ work with Dr. Adams was recently featured in Johns Hopkins University’s  “Malaria Minute Extended” podcast, explaining how she has gained a greater understanding of which genes are responsible for artemisinin resistance. She did that by creating mutants of the malaria parasite, with certain genetic elements inserted into the genome – known as “transposons.”

“We’re pretty familiar [with the idea] that genes play an important role in how organisms respond to different stimuli,” she told the host. “So with transposeons, these are mobile genetic elements – essentially chunks of genes that can be inserted at different points through the genome.” These gene-disrupting insertions often cause a loss of function of the affected gene.

For her study specifically, and in many of the mutants analyzed in the lab, Dr. Simmons called these clusters “single insertion piggyBac transposon mutants.” And they provided a key to unlocking the mystery of the parasite’s increased drug resistance. She was able to take these mutant genes and screen them against artemisinin, and observe how the parasites respond to drugs.

Through that process, Dr. Simmons learned that seven genes have increased drug sensitivity – one of which is called KIC5. When she researched the gene for her dissertation, the gene’s function was considered unknown. But a research group in Germany later found a connection between KIC5 and a Kelch 13 protein, also linked to artemisinin resistance. That was a step forward. And Dr. Simmons soon began a deeper dive with the KIC5 gene, on the verge of a breakthrough.

While other parasites showed a tolerance to artemisinin, the KIC5 mutant parasite did not. Here’s where a bit of “time travel” came into play. The KIC5 gene she inserted in a mutant parasite altered the time point of that parasite’s development. That essentially made it impossible for the parasite to have a normal metabolism, delaying its ability to recover and adapt to the stress induced by artemisinin.

“It’s unable to have a normal response when it encounters artemisinin,” she said. “In fact, it’s an abnormal response, causing the parasite to be more sensitive to artemisinin.”

Dr. Adams likened the parasite’s response to throwing a pebble in a pond, and watching the ripples that result.

“We look at where the ripples occur through the parasite development,” he said. “The parasite development is very rhythmic, with a cascade of genes that are turned off and on in a predictable manner. A lot of genes are expressed just in time for when they’re needed, and then they’re gone. So if they are made at the wrong time, they will not have the same function as they did. In the case of KIC5, the parasite survived, but it was enough to make it different than its normal type.”

Much research remains to be done. But with the KIC5, USF Health has moved the study of malaria-infected parasites forward – by turning back their internal clock.

- Photos by Allison Long, USF Health News 

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• Published: 10 April 2024

Who was the first to visualize the malaria parasite?

• Emmanuel Drouin 1 ,
• Patrick Hautecoeur 1 &
• Miles Markus 2 , 3  

Parasites & Vectors volume  17 , Article number:  184 ( 2024 ) Cite this article

Metrics details

Human malaria, an ancient tropical disease, is caused by infection with protozoan parasites belonging to the genus Plasmodium and is transmitted by female mosquitoes of the genus Anopheles . Our understanding of human malaria parasites began officially in 1880 with their discovery in the blood of malaria patients by Charles Louis Alphonse Lavéran (1845–1922), a French army officer working in Algeria. A claim for priority was made by Philipp Friedrich Hermann Klencke (1813–1881) in 1843, who wrote a chapter entitled: “ Marvellous parallelism between the manifestations of vertigo and the presence of animalcule vacuoles in living blood .” We should not lose sight of this old controversy, which is rarely mentioned in historical reviews on malaria.

Graphical Abstract

Human malaria is caused by infection with protozoan parasites belonging to the genus Plasmodium and is transmitted by female Anopheles spp. mosquitoes. The whole of the transmission cycle in culicine mosquitoes and birds infected with Plasmodium relictum was elucidated by Ronald Ross (1857–1932), a British army surgeon, in 1897. Malaria remains a leading cause of morbidity and mortality in humans worldwide. Our understanding of human malaria began officially in 1880, 144 years ago, with the discovery of the causative parasites in the blood of malaria patients by Alphonse Lavéran (1845–1922).

In 1882, he was able to convince Louis Pasteur (1822–1895) and Emile Roux (1853–1933), pre-eminent scientists of the time, of the protozoal etiology of malaria by demonstrating the parasite in a case of malignant malaria. In his important 1884 publication, “Traité des fièvres palustres,” Lavéran described his experience of a total of 480 cases.

On 23 November and then again on 28 December 1880, Alphonse Lavéran, a French military doctor and parasitologist, made the National Academy of Medicine in Paris aware of the existence of a specific parasite in the blood of some patients affected with fevers, thus demonstrating the parasitic etiology of malaria [ 1 ]. While serving as a surgeon in the French army in Algiers (Constantine), Lavéran discovered, on 6 November 1880, organisms in the blood of a soldier suffering from malaria. He noticed "moveable filaments or flagella, whose extremely rapid and varied movements left no doubt as to their nature." According to him, these elements had nothing in common with elements normally found in the blood, and he concluded that he was seeing organisms specific to malaria. Lavéran used fresh blood and dry objectives giving a maximum magnification of ×400 [ 2 ]. He found that the “flagella” detach easily and swim in the plasma. A full account of his studies was reported to the Académie des Sciences on 24 October 1881 [ 3 ] and was also presented before the Society of Medical Hospitals of Paris [ 4 ]. On 12 November 1881, the work was published in The Lancet [ 5 ]. E. Richard, a colleague of Lavéran stationed at Philippeville, Algeria, soon confirmed Lavéran's observations. The latter received the 1907 Nobel Prize in Physiology or Medicine. Lavéran named the infective organism Oscilliaria malariae ; the genus name was subsequently changed to Plasmodium . Camillo Golgi (1843–1926) confirmed that malaria was caused by a protozoon and not a bacterium [ 6 ]. Excellent histories of malaria include [ 7 ].

At the time, there was protest against attribution of the discovery to Lavéran. Some detractors said that the intra-globular, so-called “spherical bodies" were not organized parasites but simply vacuoles, which are frequently encountered in the corpuscles on bad preparations. Scientists then wanted to invoke globular degeneration as an explanation for what was being seen. What becomes of the elements? How are they introduced into the host? How do they cause the disease? There were, as yet, no answers. It was natural that Lavéran's early observations on the hematozoon of malaria should be received with skepticism. Following controversies, Lavéran eventually had the satisfaction of seeing his discovery go unchallenged.

However, Lavéran was not in fact the first investigator to visualize the malaria parasite. It had already been observed before but without stimulating the interest the observations were deserved.

Already in the middle of the nineteenth century, many morbid anatomists including, among the first, Johann Friedrich Meckel (1821–1856) in 1847, had noted the presence of brown pigment in the organs of people who had died of pernicious fever. Meckel pointed out that the dark color of the spleen, liver, brain, or kidneys on autopsy of these cases was often associated with the accumulation of pigment in the blood. This was confirmed by Rudolf Virchow (1821–1902) in Germany. It is this pigment that formed the starting point for Alphonse Lavéran’s work. Meckel was probably observing malaria parasites without realising it because he did not mention malaria, thinking that the pigment was melanin.

A claim for priority was made by Philipp Friedrich Hermann Klencke (1813–1881) in 1843 [ 8 ]. Indeed, in his book he wrote a chapter entitled: “Marvellous parallelism between the manifestations of vertigo and the presence of animalcule vacuoles in living blood” (pp. 163–172), accompanied by his ambiguous Fig. 25 (Fig.  1 ). It is not clear that the structures illustrated by Klencke are Lavéran’s “flagella,” which are the microgametes of malaria parasites (see “ Conclusions ” below). Klencke portrayed red globules filled with black pigment and stated that such red globules are found in the blood of patients affected by vertigo (attacked by febrile fevers). As for the “growing body” and the “spherical body,” they were observed and illustrated as showing what might or might not have been the microgametes under development. Klencke clearly indicated that “animalcule vacuoles” arise on the surface of red blood cells.

Klencke's Fig. 25 included in “Neue physiologische Abhandlungen auf selbständige Beobachtungen gegründet; für Aerzte und Naturforscher.” Leipzig; 1843. a Stacked red cells; b front view of red cells; c red blood cell stretched into the shape of a violin; d described by Klencke as small enterozoa adhering to red blood cells [ 8 ]; e fibrinous coagulum trapping red blood cells; f described by Klencke as larger, caterpillar-shaped, crawling enterozoa [ 8 ]; k group of eight crenate red blood cells; x described by Klencke as a caterpillar-shaped animal [ 8 ]. It is perhaps vaguely reminiscent of a free (extracellular) gametocyte of Plasmodium falciparum ; y described by Klencke [ 8 ] as an enlargement of a smaller enterozoon, with the supposed head thereof at “ m ” in the representation. Drawings a–k at ×410 magnification, drawings x and y at ×800 magnification

Thus, affected by fever, Klencke would observe his own blood under a microscope and stated that “The entozoa usually surrounded a specific globule and did not detach themselves, so that I never saw the animalcules move from one globule to another. This is true of the smallest animalcules, while the largest were not connected to any globule.” The small animalcules “curved in rapid movement around the globule, attacking it at one point by an extremity corresponding to the head or detaching to reattach a little further away.” Klencke specified that every day when he was affected by the fever, he observed a large number of animalcules in his blood, 5 to 8 per 1000 globules, and they were extremely agile. “The parallelism of the appearance of entozoa and the attack of fever is truly astonishing,” he wrote. Klencke found that parallelism in five other patients who, like himself, were affected by fever.

Conclusions

From a purely historical point of view, priority regarding the discovery may have been in Klencke's favor, but his description of what might have been exflagellation (formation of microgametes) is not clearly compatible with what he illustrated by drawings (Fig.  1 ). The morphology of microgametes in photomicrographs [ 9 , 10 ] differs from that in the drawings in Fig.  1 .

Klencke made the great parallelism between the presumed presence of organisms and the importance of vertigo, but without understanding its full significance as Lavéran had been able to do. It is very likely that Lavéran did not know about Klencke's observations, like the Germans themselves. Lavéran was probably not the first investigator to visualize the malaria parasite. We do not talk about Maxime Cornu (1843–1901) in 1871. Observations by Cornu have never been taken into consideration because they have remained unpublished. Camillo Golgi, a recipient of the Nobel prize for Medicine, was convinced of the value of Lavéran’s observations. Lavéran had the merit of understanding and indicating the general scope of his discovery [ 11 ].

Availability of data and materials

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Emmanuel Drouin & Patrick Hautecoeur

Wits Research Institute for Malaria, Faculty of Health Sciences, University of Witwatersrand, Johannesburg, South Africa

Miles Markus

School of Animal, Plant and Environmental Sciences, Faculty of Science, University of Witwatersrand, Johannesburg, South Africa

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Drouin, E., Hautecoeur, P. & Markus, M. Who was the first to visualize the malaria parasite?. Parasites Vectors 17 , 184 (2024). https://doi.org/10.1186/s13071-024-06145-4

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Study shows effect of socio-economic factors that predict diabetic patients' risk of heart failure

by Case Western Reserve University

A recent study by Case Western Reserve University used national data from U.S. military veterans with diabetes to validate and modify a widely accepted model used to predict the risk of heart failure in diabetic patients.

The model, called the WATCH-DM score, is used to predict the likelihood of heart failure in diabetes patients within five years.

But because it overlooks the influence of social determinants of health' such as housing, food and a patient's neighborhood, the researchers used a social deprivation index (SDI), a multi-component summary score, to adjust the WATCH-DM score.

The SDI, introduced by the Robert Graham Center, a group of clinical researchers, can quantify the level of disadvantage in particular areas using food, housing, transportation and community conditions. Prior research demonstrated this score is directly proportional to the level of health disparities observed in communities.

The study identified about 1 million U.S. veterans with type 2 diabetes without heart failure treated as outpatients at Veterans Affairs medical sites nationally in 2010.

Researchers used patient zip codes to obtain their SDI, which was then entered into the risk calculator to determine how likely they would be hospitalized for heart failure within five years.

While the hospitalization rate for heart failure for the whole cohort of more than 1 million patients was 5.39%, this incidence varied from 3% (in the least socially deprived) to 11% (in the most deprived).

Researchers found that, depending on the patients' other clinical information, adding the SDI into the risk-prediction model could even double the probability of that patient developing heart failure in the next five years.

The team of investigators then optimized the WATCH-DM score for each SDI group using a statistical correction factor and improved its predictive accuracy across the whole range of the social determinants of health.

"We found that adding the SDI enhanced the WATCH-DM score's ability to forecast risk," said Salil Deo, an associate professor in the Department of Surgery at the Case Western Reserve School of Medicine, who led the study. "These results highlight the necessity of including social determinants of health in any future clinical risk prediction algorithms. This will increase their accuracy, which will benefit patients by improving their health outcomes."

This calculator is available to the public from their device for free here .

"We hope our study encourages health care providers to adopt a wholistic approach when treating patients in the future," Deo said. "Understanding and quantifying social inequity is likely the first step we can take toward trying to ensure that it does not affect the health of our patients."

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CASE REPORT article

Hydroxychloroquine-induced hyperpigmentation of the skin and bull’s-eye maculopathy in rheumatic patients: a case report and literature review.

• 1 Guizhou University of Traditional Chinese Medicine, Guiyang, China
• 2 Department of Rheumatology and Immunology, Second Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, China

Hydroxychloroquine (HCQ) is used as a traditional disease-modifying antirheumatic drugs (DMARDs), for the treatment of autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). However, it can cause serious adverse reactions, including hyperpigmentation of the skin and bull’s-eye macular lesions. Here, we present a case of HCQ-induced hyperpigmentation of the skin and bull’s-eye macular lesions in a patient who received HCQ for RA. A 65-year-old female patient developed blurred vision and hyperpigmentation of multiple areas of skin over the body for one month after 3 years of HCQ treatment for RA. Based on clinical presentation, ophthalmological examination and dermatopathological biopsy, a diagnosis of drug-induced cutaneous hyperpigmentation and bullous maculopathy of the right eye was made. After discontinuation of HCQ and treatment with iguratimod tablets, the hyperpigmentation of the patient ‘s skin was gradually reduced, and the symptoms of blurred vision were not significantly improved. We also reviewed the available literature on HCQ-induced cutaneous hyperpigmentation and bull’s-eye macular lesions and described the clinical features of HCQ-induced cutaneous hyperpigmentation and bull’s-eye macular lesions. In conclusion, clinicians should be aware of early cutaneous symptoms and HCQ-associated ophthalmotoxicity in patients with rheumatic diseases on HCQ sulphate and should actively monitor patients, have them undergo regular ophthalmological examinations and give appropriate treatment to prevent exacerbation of symptoms.

Introduction

Hydroxychloroquine (HCQ) is a 4-aminoquinoline antimalarial drug. It is commonly used as a sulfate, namely HCQ sulfate. Its antimalarial effect is the same as that of chloroquine, but its toxicity is only half that of chloroquine. In addition, HCQ sulfate also has anti-inflammatory, immunomodulatory and anticoagulant effects ( 1 – 4 ), so it is widely used in clinical treatment of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjögren’s syndrome, skin diseases, etc., and the adverse reactions are gradually increasing ( 5 , 6 ). There are fewer reports on HCQ-induced hyperpigmentation of the skin and macular lesions in the bull’s eye. This article analyses the literature related to HCQ sulfate-induced hyperpigmentation of the skin and macular lesions in the bull’s eye in conjunction with the literature review by taking a case of HCQ sulfate-induced hyperpigmentation and macular lesions in the bull’s eye as an example in order to warn the clinic to fully understand the adverse effects of HCQ.

Case report

We assessed a 65-year-old female patient with RA in December 2023 who had been diagnosed with RA 10 years earlier and was now feeling pain in both shoulders, wrists, and finger joints of both hands with mild limitation of movement. The patient was treated with HCQ (400mg/d) and low-dose prednisolone (5 mg/d) for 3 years. The patient had no other comorbidities or medications, and for the past month felt blurred vision and noticed a darkening of the skin color. Our physical examination revealed excessive skin pigmentation in many parts of the body, especially in the head and face, neck, upper limbs and lower limbs ( Figure 1 ). The patient attributed this to chronic ultraviolet light exposure.

Figure 1 Hyperpigmentation of head, face, neck, upper limbs and lower limbs.

We performed relevant laboratory tests on the patient, which showed an elevated erythrocyte sedimentation rate of 61.00 mm/h (normal, 0-20 mm/L), an elevated rheumatoid factor of 43.15 IL/ml (normal, 0-20 IL/ml), and an elevated anti-cyclic citrullinated peptide antibody of > 500.00 U/mL (normal, 0-20 U/mL). We performed an ophthalmological examination of the patient because he had symptoms of blurred vision and because studies have shown that HCQ can cause retinopathy ( 7 , 8 ). The visual field examination results showed that the visual field of the right eye showed a visual field defect outside the range of 45° above and 25° on the nasal side, and the light sensitivity of the remaining visual field decreased significantly. Compared with the dark spots around the physiological blind spots of the left eye, the photosensitivity decreased widely outside the range of 40°, and the photosensitivity decreased scattered within the range of 40°. Therefore, we performed optical coherence tomography (OCT) ( Figure 2 ) and fundus screening ( Figures 3A-D ) on the patient. The results of OCT examination showed that the retinal pigment epithelium (RPE) layer in the macular area of the right eye was disordered and uneven, and irregular mass uplift was seen. The reflection of the ellipsoid zone and the IS/OS layer was interrupted and discontinuous. The RPE layer on the temporal side of the macular showed localized choroidal depression. The macular morphology was irregular, and the thickness of the macular fovea was significantly thinner ( Figure 2A ). However, the results of OCT of the left eye did not show any significant abnormality ( Figure 2B ). The results of fundus screening showed that the right eye had a round-like lesion in the macular area, about 2.5*3PD in size. The lesion was uneven yellow-white, and the center was dark brown. In conjunction with the OCT findings, a bull’s eye macular lesion was considered.

Figure 2 (A) OCT results of the right eye; (B) OCT results of the left eye.

Figure 3 (A) Right anterior segment findings; (B) Right eye fundus screening results; (C) Left anterior segment findings; (D) Left eye fundus screening results.

From the results of the ophthalmologic examination, our patient was not considered for the diagnosis of age-related macular degeneration (AMD), which is characterized by the accumulation of extracellular deposits and the progressive degeneration of photoreceptors and adjacent tissues ( 9 – 12 ). The prevalence increases gradually with age and usually affects vision for a short period of time, even leading to blindness ( 13 , 14 ). In AMD, the damage is concentrated in the central portion of the retina, known as the macula. One of the features of AMD is the scattered or confluent areas of degeneration of RPE cells and overlying photoreceptors in the photoreceptors of the photoreceptors, which depend on the RPE for trophic support. Although our patient’s OCT results showed disturbed and uneven RPE reflection seen in the retina of the macular area of the right eye. However, there was no significant abnormality in the left eye OCT results. Another feature of AMD is the formation of choroidal neovascularization, in which immature blood vessels grow from the choroid below toward the outer retina. These immature blood vessels leak fluid below or inside the retina ( 10 ). In contrast, our patient’s funduscopic findings showed no vasculopathy. So we consider that this macular lesion is not so much related to aging as it is to the use of HCQ.

In addition, we performed a skin biopsy on the patient. HE staining ( Figure 4A ) showed excessive keratinization of the epidermal mesh basket, a significant increase in melanin in the basal layer, sparse lymphocyte and tissue cell infiltration around the blood vessels in the superficial dermis, and a few melanocytes and melanin granules were seen locally, considering drug-induced pigmentation. Therefore, it can be differentiated from skin pigmentation caused by exposure to ultraviolet light ( 15 ). Fontana-Masson staining ( Figure 4B ) showed a significant increase in melanin in the basal layer of the epidermis and a few melanin granules in the superficial dermis. Prussian blue staining and silver hexamine staining were negative ( Figures 4C, D ). Five items of direct immunofluorescence ( Figure 5 ) C3, IgG, IgM, IgA and Fib were all negative.

Figure 4 (A) HE staining; (B) Fontana-Masson staining; (C) Prussian blue staining; (D) silver hexamine staining.

Figure 5 Direct immunofluorescence staining.

According to the patient ‘s medical history and examination results, we believe that the patient ‘s long-term use of HCQ in the treatment of RA, resulting in hyperpigmentation of the skin and bull’s-eye maculopathy. Therefore, we decided to discontinue HCQ and replace it with iguratimod tablets (50mg/d) and prednisone acetate tablets (5mg/d) to control the disease. It is important to note that iguratimod is only used in China and Japan for the treatment of RA and has been shown to be effective ( 16 – 18 ). Since then, we followed up the patient for three months. After discontinuation of HCQ and treatment with iguratimod tablets, the hyperpigmentation of the patient ‘s skin was gradually reduced, and the symptoms of blurred vision were not significantly improved.

Literature retrieval

Based on the patient’s clinical presentation and ophthalmologic findings, we reviewed similar cases reported in PubMed, Embase, Web of Science and other databases from the establishment of the database to December 2023. We used “hydroxychloroquine”, “plaquenil”, “case study”, “case report”, “bull’s-eye maculopathy” and “hyperpigmentation” as the search terms to filter out the eligible literature and extract the relevant information of the cases. From the results of our literature search, a total of 181 articles were retrieved from the literature related to hyperpigmentation of the skin. After screening, 18 articles were obtained, the total number of cases was 20, female patients were more than male patients, distributed in different countries or regions, the primary disease was mainly RA or SLE, the color of skin pigmentation was mainly blue/gray, and the site of skin pigmentation was mainly on the face, the upper limbs or the lower limbs, and the daily dosage of HCQ was mainly 400mg, and the skin pigmentation of the over-pigmented skin of the majority of the patients could be gradually subsided after stopping the HCQ. Table 1 shows the detailed clinical features of these cases. A total of 46 articles were retrieved from the literature related to macular degeneration of the bull’s eye. After screening 11 valid literature were obtained, the total number of cases was 13, all were female patients, the daily dose of HCQ was 200-1200mg and the approximate cumulative dose was 438-2920g, and most of the patients’ solution was to stop HCQ therapy. Table 2 shows the detailed clinical features of these cases.

Table 1 Reported cases of hyperpigmentation of HCQ.

Table 2 Reported Adverse Ocular Region Effects of HCQ.

Hyperpigmentation of skin induced by HCQ

Hyperpigmentation of the skin caused by antimalarial treatment has been reported since the Second World War ( 48 ). However, the associated skin hyperpigmentation due to HCQ seems to be uncommon compared to other antimalarials such as chloroquine ( 28 , 49 ). One study showed that the onset of HCQ-associated skin hyperpigmentation ranged from 3 months to 22 years after the start of treatment, with a median of 6.1 years ( 50 ). In our reported case, the patient developed hyperpigmentation of the skin about 3 years after the start of treatment, and the treatment was to discontinue HCQs and to control the RA with iguratimod tablets, which led to a gradual reduction of the patient’s skin hyperpigmentation over several months ( 22 , 25 ). Although there is evidence that both melanin and iron deposition can be present in the dermis in HCQ-induced hyperpigmented skin lesions ( 50 ), the exact mechanism is unknown ( 30 ). Our patients completed the relevant pathological examination. Fontana-Masson staining ( Figure 4B ) showed a significant increase in melanin in the basal layer of the epidermis and a few melanin granules in the superficial layer of the dermis. Prussian blue staining was negative ( Figure 4C ). Therefore, we describe the pathological features of some cases ( Table 3 ). In terms of treatment, most of the investigators took the approach of discontinuing HCQ treatment to prevent further exacerbation of HCQ-induced hyperpigmentation of the skin. Most patients were able to reduce their hyperpigmentation after discontinuing HCQ treatment.

Table 3 Pathological features of some cases.

Retinal toxicity due to HCQ

Long-term treatment with HCQ can lead to retinal toxicity ( 51 ). This retinal change is typically characterized by a thinning of the photoreceptor layer, starting with a paracentral sulcus ring and progressing over time to a “bull’s-eye” maculopathy, caused by pericentral atrophy and retention of the central sulcus ( 52 ). Some researchers have suggested that HCQ may be associated with bilateral retinopathy involving not only the macula but also the peripheral retina ( 39 ). The relationship between HCQ-related skin pigmentation and ocular toxicity is currently unknown ( 28 ); However, there is a need for regular ophthalmological follow-ups so that the patient’s eye condition can be understood ( 30 ). Our patient developed vision loss after 36 months of HCQ treatment, with a cumulative dose of about 438 g. Ophthalmological examination revealed macular lesions in the right eye. Table 2 describes some of the published information on similar cases, and the case we reported is similar to those reported in the literature. In terms of treatment, most of the investigators took to discontinuing HCQ treatment to prevent further worsening of the ocular adverse effects caused by HCQ. However, patients who have developed bull’s-eye macular degeneration are difficult to rehabilitate ( 41 ). In terms of ophthalmic examination, Fung et al. ( 40 ) suggest that OCT may be a useful, non-invasive clinical assessment if a patient presents with new visual changes associated with HCQ. In addition, OCT findings of diffuse retinal atrophy or increased reflectivity around the macular central pucker can support the port suspected diagnosis of HCQ-associated retinal toxicity.

In conclusion, HCQ can cause adverse reactions such as hyperpigmentation of the skin and macular degeneration of the bull’s eye, clinicians should be aware of early cutaneous symptoms and HCQ-associated ophthalmotoxicity in patients with rheumatic diseases on HCQ sulphate and should actively monitor patients, have them undergo regular ophthalmological examinations and give appropriate treatment to prevent exacerbation of symptoms.

Data availability statement

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

Ethics statement

The studies involving humans were approved by Ethics Committee of the Second Affiliated Hospital of Guizhou University of Traditional Chinese Medicine. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

Author contributions

J-PP: Writing – original draft, Writing – review & editing. X-YY: Writing – original draft. FL: Writing – original draft. X-MY: Writing – original draft. HX: Writing – original draft. W-KM: Writing – original draft. X-MY: Writing – original draft, Writing – review & editing.

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. The study was funded by the National Natural Science Foundation of China, 82160869, 82374494; Guizhou Provincial Key Technology R&D Program, Qiankehe Support [2021] General 006; Guizhou Provincial Basic Research Program(Natural Science) Qiankehe Basic-ZK[2023] General 412; Guizhou Kehe Academic New Seedling[2023-36]; Guizhou University of Traditional Chinese Medicine National and Provincial Scientific and Technological Innovation Talent Teams Cultivation Project, Guizhou University of Traditional Chinese Medicine TD He Zi [2022]004.

Acknowledgments

We appreciate Yuzheng Yang (Organization: Guizhou University of Traditional Chinese Medicine, Guiyang, China) for organizing the data, Yuheng Shi and Shasha Du (Organization: Ophthalmology Department, Second Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, China) for performing the ophthalmologic examinations, and all authors for their cooperation.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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Keywords: hydroxychloroquine, adverse drug reaction, hyperpigmentation of the skin, bull’s-eye maculopathy, literature review, autoimmune disease

Citation: Peng J-p, Yang X-y, Luo F, Yuan X-m, Xiong H, Ma W-k and Yao X-m (2024) Hydroxychloroquine-induced hyperpigmentation of the skin and bull’s-eye maculopathy in rheumatic patients: a case report and literature review. Front. Immunol. 15:1383343. doi: 10.3389/fimmu.2024.1383343

Received: 07 February 2024; Accepted: 27 March 2024; Published: 10 April 2024.

Reviewed by:

Copyright © 2024 Peng, Yang, Luo, Yuan, Xiong, Ma and Yao. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Xue-ming Yao, [email protected]

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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Imported malaria in adults: about a case of cerebral malaria

Sarra ben abderrahim.

1 Ibn El Jazzar Faculty of Medicine, the University of Sousse, Mohamed Karoui street, 4002 Sousse, Tunisia

2 Department of Forensic Medicine, Farhat Hached University Hospital, Ibn El Jazzar street, 4000 Sousse, Tunisia

Sarra Gharsallaoui

Amal ben daly, amal mosbahi, selma chaieb.

3 Department of Pathological Anatomy and Cytology, Farhat Hached University Hospital, Ibn El Jazzar street, 4000 Sousse, Tunisia

Zeineb Nfikha

Samar ismaïl.

4 Parasitology-Mycology Laboratory, Farhat Hached University Hospital, Ibn El Jazzar street, 4000 Sousse, Tunisia

Chahnez Makni

Moncef mokni, akila fathallah-mili, maher jedidi, mohamed ben dhiab, associated data.

Not applicable.

Malaria is the first parasitic infection endemic in the world caused by parasites species of Plasmodium . Cerebral malaria (CM) is a rapidly progressive and severe form of Plasmodium falciparum infection, characterized by a greater accumulation of red blood cells parasitized by Plasmodium falciparum in the brain. The diagnosis of malaria is usually made in living patients from a blood sample taken in the course of a fever on return from an endemic country, whereas CM, often associated with fatal outcomes even in treated subjects, is usually diagnosed at autopsy.

Case presentation

We present the case of a 36-year-old man who died a few days after returning from a business trip to the Ivory Coast. As a result of an unclear cause of death, a medicolegal autopsy was ordered. Autopsy findings revealed massive congestion and edema of the brain with no other macroscopic abnormalities at organ gross examination. Histology and laboratory tests were conducted revealing a Plasmodium falciparum infection, with numerous parasitized erythrocytes containing dots of hemozoin pigment (malaria pigment) in all examined brain sections and all other organs. Death was attributed to cerebral malaria with multiple organ failure.

Conclusions

This report summarizes several features for the diagnosis of malaria and how postmortem investigations, as well as histology and laboratory diagnosis, may lead to a retrospective diagnosis of a fatal complicated form with cerebral involvement.

Imported malaria in adults is an infection caused by parasites species of Plasmodium (single-celled parasites) that occurs in a person returning from a stay in a malaria-endemic area (Bruneel et al. 2012 ). Since its eradication in 1979 (Chahed et al. 2001 ), Tunisia has stopped the chain of indigenous malaria transmission. All cases reported in Tunisia since that date are imported cases (Ayadi et al. 2000 ; Belhadj et al. 2008 ; Aoun et al. 2010 ; Mtibaa et al. 2018 ). This is mainly due to the increasing number of African students who come to Tunisia for their studies and the growing international commercial and professional exchanges with malaria-affected African countries (Belhadj et al. 2008 ). The vast majority of severe malaria attacks are related to Plasmodium falciparum (among the four pathogenic agents of human malaria), due to its neurological damage, known as “cerebral malaria (CM)” or “neuromalaria” (Pongponratn et al. 2003 ). In adults, CM is often part of a picture of multi-visceral failure. This condition is associated with a large number of sequestered parasites throughout the organs of the body (especially the brain), and disseminated intravascular coagulation, rapidly leading to death (Milner et al. 2015 ). Convulsions are though less frequent than in children (Milner et al. 2015 ). The diagnosis of malaria is usually made in living patients from a blood sample taken in the course of a fever on return from an endemic country. Our observation constitutes one of the rare cases where the diagnosis was made only postmortem, emphasizing the need for cross-disciplinary collaboration in the diagnosis of CM after death.

The case involves Mr. N., a 36-year-old man with no previous medical history, who had returned from a long stay in Ivory Coast for professional activities (about 0–6 months). Since his return to Tunisia, he presented a symptomatology associating fever, headache, asthenia, and diarrhea. A polymerase chain reaction (PCR) test for Covid-19 had previously been performed (before traveling), which was negative. Mr. N. did not seek medical advice and resorted to self-medication including antipyretic and analgesics. On the 5th day, Mr. N.’s condition worsened as he presented a generalized tonic-clonic convulsive seizure, after which he did not regain consciousness. His family members called for medical assistance, but Mr. N. died before the arrival of the emergency units. As a result of an unclear cause of death, a medicolegal autopsy was ordered by the prosecutor, and the body was thus transferred to our department for autopsy. Malaria infection was already suspected at this point upon investigating the death circumstances with his relatives. A postmortem blood sample, on ethylenediamine tetraacetic acid (EDTA) preserved blood sample, was hence referred to the Parasitology Laboratory in order to confirm our assumptions before autopsy. Malaria rapid diagnostic test (RDT) (i.e., rapid diagnostic test for malaria which detects malaria antigens in a person’s blood) was positive. In both thick and thin Giemsa-stained blood smears (Fig. ​ (Fig.1), 1 ), numerous Plasmodium falciparum (trophozoites) were found, showing high parasitemia. The percentage of parasitemia was though difficult to assess due to the hemolysis state of the postmortem samples. External examination revealed cyanosis with frank mucocutaneous icterus. Autopsy findings revealed massive congestion and edema of the brain, weighing 1550 g (Fig. ​ (Fig.2), 2 ), lungs (weighing 745 g on the right and 640 g on the left), and inner organs. Hepatomegaly was noted (liver weighing 2905 g) with heterogeneous parenchyma on section. The spleen (weighing 385 g) was enlarged with a tense, smooth capsule, and congested parenchyma of brown-black color. Histology showed cerebral gray and white matter with congested capillaries (Fig. ​ (Fig.3) 3 ) containing numerous parasitized erythrocytes (trophozoites) in each examined brain section. Each cell contained dots of hemozoin pigment (malaria pigment). The same findings were also observed in the histology of the remaining thoracic and abdominal organs (Fig. ​ (Fig.4). 4 ). Toxicological analyses did not reveal the presence of any toxic substance that might have been involved in the death.

Thick blood smear showing numerous Plasmodium falciparum . Giemsa, ×100

Representative image of the brain at autopsy showing congestion and edema

Histology findings showing congested brain capillary containing numerous parasitized erythrocytes (trophozoites), with intraerythrocytic malaria pigment appearing as small black dots (enlarged image with arrow). Hematoxylin and eosin, ×400

Histology findings showing numerous parasitized erythrocytes (trophozoites) of the organs, 400× original magnification. a – f Hematoxylin and eosin-stained sections of the heart ( a ), lung ( b ), liver ( c ), spleen ( d ), pancreas ( e ), and kidney ( f )

Based on histology, autopsy findings, as well as parasitology expertise, the case was considered to have died of fulminant cerebral malaria with multiple organ failure.

In the present case, a postmortem diagnosis of cerebral malaria with multiple organ failure due to malaria infection was observed. Similar autopsy diagnoses of undiagnosed or misdiagnosed malaria cases with cerebral involvement were described in the literature (Kain et al. 2001 ; Muehlethaler et al. 2005 ; Alunni-Perret et al. 2010 ; Checkley et al. 2012 ; Ajili et al. 2013 ; Yağmur et al. 2015 ; Féron et al. 2017 ) . To the best of our knowledge, the reported case is one of the rarest autopsy discoveries of CM in Tunisia. As the term implies, imported neuromalaria corresponds to imported cases of acquired exposure to Plasmodium parasites in endemic regions, to non-endemic countries (Mischlinger et al. 2020 ). There are many reasons which can lead to this importation. The main sources include traditional cross-border migration in search of work, tourists coming back from endemic countries, displacement due to demographic changes (Odolini et al. 2012 ; Sriwichai et al. 2017 ), and even in military personnel returning from an external operation (Ajili et al. 2013 ). Our case corresponded to imported malaria during travel undertaken for professional reasons.

Cerebral malaria, renal malaria, and pulmonary malaria are the three most common causes of sudden death in adults with a severe form of Plasmodium falciparum (Peoc’h et al. 2000 ; Yapo Ette et al. 2002 ; Muehlethaler et al. 2005 ; Alunni-Perret et al. 2010 ; Prat et al. 2013 ; Yağmur et al. 2015 ). Many factors play specific but interlinked roles in the pathophysiology of CM, characterized by the sequestration of parasitized erythrocytes in the brain microvessels and the resulting metabolic and immune disorders. CM is considered to be a syndrome that includes the presence of asexual forms of Plasmodium falciparum in the blood smear, with no other etiology of encephalopathy (Idro et al. 2010 ). The criteria of malaria severity were first defined in 1990 by the World Health Organization (WHO), essentially concerning malaria in tropical areas, and then revised in 2000 (World Health Organisation (WHO) 2000 ), in 2010 (Word Health Organization (WHO) 2010 ), and again in 2015 (Word Health Organization (WHO) 2015 ). CM is considered a severe form of malaria infection with fatal outcomes.

Imported malaria is an infection that should be considered in the presence of any suggestive symptom (fever, chills, myalgias, asthenia, digestive problems, headaches, respiratory signs, and especially signs of severity) after returning from a stay in a malaria-endemic area (Bruneel et al. 2012 ). This was the case of the deceased who presented flu-like symptoms. Given the pandemic context and a negative PCR, he did not consider his symptoms to be important, although he came from an endemic malaria country (the transmission in Ivory Coast occurs throughout the year, with a peak incidence in April to July). It would appear that the deceased was not properly informed about prophylaxis nor was he aware of the warning signs of malaria. He did not seek pretravel health advice either. Neuromalaria occurs when infected red blood cells induce microvascular thrombosis in the cerebral vessels. It is fatal in almost 100% of cases in the absence of treatment, especially in nonimmune subjects (Alunni-Perret et al. 2010 ). Death may occur without prodrome, which gives this type of death a suspicious character requiring a forensic autopsy.

In our case, the external examination found mucocutaneous jaundice as was the case in an autopsy series of 18 sudden deaths due to severe malaria-discovered postmortem (Djodjo et al. 2015 ). Its incidence is reported to range from 11.5 to 62% (Djodjo et al. 2015 ). Its occurrence during severe malaria is either related to massive hemolysis or hepatocellular failure. Brain congestion and swelling were also reported in other case reports (Muehlethaler et al. 2005 ; Prat et al. 2013 ; Sevestre et al. 2021 ). This swelling is not associated with vasogenic edema, although cytotoxic edema is seen in some patients. The brain swelling is rather attributable to increased blood volume that occurs as a result of sequestration of the infected erythrocytes and/or an increase in cerebral blood flow, particularly in response to anemia, fever, and seizures (Mishra and Newton 2009 ). Hepatomegaly and splenomegaly are common in neuromalaria, due to the obstruction of the lobular veins of the liver and hyperplasia of the adenoid tissue (white pulp of the spleen) (Prat et al. 2013 ). Pulmonary edema, which causes adult respiratory distress syndrome during severe malaria, is most often associated with high plasmodial parasitemia (direct effect of sequestered parasites in the lungs) (Bhutani et al. 2020 ).

Histology is the main means of diagnosing malaria postmortem (Burel-Vandenbos et al. 2008 ; Alunni-Perret et al. 2010 ). The diagnosis is based on the observation of sequestrated parasitized red blood cells in the brain vessels. They may obstruct the lumen of small capillaries or be margined against the endothelium of larger vessels (Djodjo et al. 2015 ). These histological aspects reflect the properties of the parasitized red blood cells to adhere to the endothelial cells of capillaries and venules (Milner et al. 2015 ). Red blood cells acquire these cytoadherence properties when parasitized by mature forms of Plasmodium falciparum (Djodjo et al. 2015 ). The presence of malaria pigment is another important element of the histological diagnosis, as well as other histological findings (although inconsistent) such as ring hemorrhages around necrotic vessels and microthrombi (Milner et al. 2015 ). In our case, the diagnosis was based on the histological examination, by the demonstration of parasitized red blood cells obstructing the lumen of the cerebral capillaries and by the presence of malarial pigments in most of the organs sampled. Similar observations have been reported by other authors (Yapo Ette et al. 2002 ; Menezes et al. 2012 ).

Analysis of malaria case reports in the literature reveals the great scientific contribution of autopsies, as most of the data related to CM have been drawn from autopsy observations. Pathogenic mechanisms leading to cerebral malaria were at the beginning poorly defined as studies have been hampered by limited access to human tissues. This is also because limited studies can be performed in humans, and common models conducted on mouses do not reproduce all aspects of CM. The first attempts to discover the pathogenesis of this syndrome relied significantly on the histopathology of brain tissue from deceased CM patients (Rénia et al. 2012 ). According to Milner D., the diagnosis of CM can only be determined after death through postmortem examination of the brain and other organs (Milner 2020 ). Other malarial causes of death, such as severe malaria anemia, respiratory failure, acute respiratory distress syndrome, and acute renal failure, might be confirmed with laboratory testing without the need for an autopsy (Milner 2020 ). Indeed, macro- and microscopic examination of the human body after death allows the pathologist to catalog anatomic findings and determine an immediate cause of death, which allows malaria mortality to be averted (Milner 2020 ). This case also highlights the importance of malaria as the leading cause of unexplained death in the context of travel to endemic areas. There is no limit to the diagnosis of malaria in alive as well as dead people in endemic areas and among travelers visiting these areas.

This article reports a case of CM-discovered postmortem. This case report illustrates the fact that travelers, often through the lack of advice, fail to take preventive treatment when making frequent trips to endemic malaria areas. It also confirms the importance of informing these travelers of the rapid fatal outcome and hence of the need for early treatment and follow-up. This report summarizes several features for the diagnosis of malaria and how postmortem investigations may lead to a retrospective diagnosis of a fatal complicated form, with cerebral involvement. The proper diagnosis was made possible, thanks to close collaboration between the different pathologists.

Acknowledgements

We thank the Department of Pathological Anatomy and Cytology as well as the Parasitology-Mycology Laboratory for their expertise.

Abbreviations

Authors’ contributions.

SBA and SG performed the autopsy and wrote the manuscript. ABD, AM, and CM helped in editing the manuscript. SC, ZN, and MM performed the histology expertise. SI and AFM performed the parasitology expertise. MJ and MBD were in charge of conceptualization, original draft preparation, and final editing. All authors read and approved the final manuscript

No financial support has been received for this manuscript.

Availability of data and materials

Declarations.

An oral consent was taken from the deceased’s descendant after informing him of the purpose of the case report. No private details of no scientific relevance were mentioned within the case report; thus, we did not need to take written consent.

The authors declare that they have no competing interests.

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• Case report
• Open access
• Published: 06 April 2024

Patients' perspectives on buprenorphine subcutaneous implant: a case series

• Claudio Pierlorenzi 1 ,
• Marco Nunzi 1 ,
• Sabino Cirulli 1 ,
• Giovanni Francesco Maria Direnzo 2 ,
• Lucia Curatella 1 ,
• Sandra Liberatori 2 ,
• Annalisa Pascucci 2 ,
• Edoardo Petrone 3 ,
• Generoso Ventre 2 ,
• Concettina Varango 4 ,
• Maria Luisa Pulito 4 ,
• Antonella Varango 4 ,
• Cosimo Dandolo 4 ,
• Brunella Occupati 5 ,
• Roberta Marenzi 6 &
• Claudio Leonardi 7  

Journal of Medical Case Reports volume  18 , Article number:  202 ( 2024 ) Cite this article

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Considering the enormous burden represented by the opioid use disorder (OUD), it is important to always consider, when implementing opioid agonist therapy (OAT), the potential impact on patient’s adherence, quality of life, and detoxification. Thus, the purpose of the study is to evaluate how the introduction of a novel OAT approach influences these key factors in the management of OUD.

Case presentation

This article marks the pioneering use of OAT through buprenorphine implant in Europe and delves into the experience of six patients diagnosed with OUD at a relatively young age. The patients, comprising both males and a female, are of Caucasian Italian and African Italian ancestry (case 4) and exhibit an age range from 23 to 63, with an average drug abuse history of 19 ± 12 years. All patients were on stable traditional OAT before transitioning to buprenorphine implants. Despite the heterogeneity in social and educational backgrounds, health status, and drug abuse initiation histories, the case series reveals consistent positive treatment outcomes such as detoxification, absence of withdrawal symptoms and of side effects. Notably, all patients reported experiencing a newfound sense of freedom and improved quality of life.

Conclusions

These results emphasise the promising impact of OAT via buprenorphine implants in enhancing the well-being and quality of life in the context of OUD.

Peer Review reports

Introduction

Opioid use disorder (OUD) is a chronic, relapsing condition accounting for over 16 million people worldwide [ 1 , 2 ]. International guidelines recommend opioid agonist therapy (OAT) with sublingual buprenorphine or methadone as first-line treatments of opioid dependence [ 3 ]. However, the rates of oral OAT misuse, abuse, and diversion are of public concern due to their social, sanitary, and economic repercussions [ 4 , 5 ]. Additionally, patient adherence to oral OAT remains a challenge nowadays.

Little research has been carried out about strategies to support long-term remission from opioid dependence [ 6 , 7 ]. An implantable formulation of buprenorphine has been developed to address problems with adherence, diversion, and non-medical use [ 6 ]. The rod-shaped implant consists of a mixture of a polymeric ethylene vinyl acetate matrix and buprenorphine that, following an initial pulse release, delivers a constant and stable medication level over 6 months after a single procedure [ 8 ].

Buprenorphine implant has shown its effectiveness in placebo-controlled studies [ 6 , 8 , 9 ] displaying a significant reduction of the opioid abuse (percentage of opioid-negative urine samples: 36% in implant group vs. 14.4% in placebo) and percentage of participants who completed the study [ 8 ]. As compared with standard sublingual buprenorphine or buprenorphine/naloxone tablets, the implant showed comparable efficacy and adverse event rate [ 6 , 8 ]. A systematic benefit-risk assessment, based on a semiquantitative analysis of the available data, found a favourable profile for buprenorphine implant in comparison to sublingual buprenorphine [ 10 ]. The main benefits identified for buprenorphine implant included: improved compliance and convenience, reduced risk of illicit opioid abuse, quality of life, and risk of misuse/diversion. On the other hand, risks were mostly associated with the insertion and removal procedure. The benefits mentioned so far outweighed the risks [ 10 ]and long-acting buprenorphine implants appears to sustain the long-term remission of patients suffering from OUD [ 10 ].

This article describes a series of patients with OUD who received OAT through buprenorphine implant, marking the pioneering cases at the European level. Each case report provides a comprehensive narrative, encompassing the patients' history and clinical progression, starting from the initiation of drug abuse to the subsequent outcomes (in terms of detoxification, absence of withdrawal symptoms, side effects and improved quality of life) achieved with buprenorphine implant.

Case report 1

Clinical case description.

The patient is a 54-year-old male of Caucasian Italian ancestry with lower secondary education. The patient, the youngest child of 5, experienced the tragic loss of a brother at the age of 17 due to an accident, and the father passed away 38 years ago from gastric haemorrhage. The mother, who is still alive and in fair health, works from home as a seamstress. The patient lives with his mother, but often sleeps away from home because of work. He engaged in a romantic relationship, including cohabitation, which lasted for a few years. Ultimately, at the conclusion of this period, he returned to live with his mother and stated: “ I was not in the right state of mind… Who wants to be with me? I'm never at home… and then I'm fine like this ”. He worked as a welder for a brief period. At the age of 18, he started working as a courier and then as a truck driver for third parties, constantly moving around Italy. Currently, he continues to work as a truck driver, but on his own account.

Medical history

The patient reports having contracted common childhood exanthems and undergoing a splenectomy due to a car accident in his 20s, followed by hemotransfusions. In 1986, he was diagnosed with chronic HCV hepatitis (it is unclear whether it was related to drug addiction), classified as G4, F2-related, and was treated with glecaprevir/pibrentasvir.

Toxicological history

At the age of 23, the patient began his journey with drugs by abusing intravenous heroin, cocaine, and alcohol (in the latter case, moderately). He was referred in April 1991, based on Article 75, to the Addiction Service of Lodi by the Prefecture of Piacenza. Two months later, the patient started OAT with a daily dose of 50 mg of methadone. From the age of 23 to 27, the patient exhibited very oppositional behaviour: he was lying, provocative, sometimes aggressive and threatening. During that period, the patient began and interrupted several therapeutic programmes.

Traditional opioid agonist therapy

In July 2004, the first contact with our Addiction Service occurred. The patient began therapy with sublingual buprenorphine at 8 mg/day in increments, but he never completed the scaling. In this regard, in 2013, we read in the clinical diary: “He is not able to disengage from buprenorphine despite remaining abstinent from drugs for some months” . The patient continued with sublingual buprenorphine 2 mg/day until May 2018, at which point he transitioned to a dosage of 2 mg every other day. The patient maintained this regimen until June 2022.

• Buprenorphine implant

In May 2022 we proposed the subcutaneous buprenorphine implant treatment to the patient, as he appeared to align with the characteristics of the ideal patient. He showed immediate interest and accepted. The selection was based on his consistent use of 2 mg sublingual buprenorphine every other day over the years, prolonged negative drug tests, frequent business-related travel as a lorry driver, and the logistical challenge of attending the Addiction Service every weekend (which also involved transfers to various Services). Furthermore, the patient expressed a desire to avoid encounters with other users at the Addiction Service with whom he no longer wished to share experiences.

In August 2022, the implant surgery was conducted for the patient.

Follow up visits

Throughout the six months of treatment, the patient underwent several visits, including monthly and sometimes fortnightly follow-ups. A urine toxicology check was performed every two weeks, consistently yielding negative results. The patient did not encounter any issues with the implanted arm site, finding it easy to use. He reported a notable absence of the fluctuations ("spikes") experienced with tablet intake, a diminished taste for cigarettes, and a complete lack of cravings for drugs. He expressed satisfaction with his choice but recommended the buprenorphine implant primarily for individuals aiming to cease the use of drugs of abuse. In his perspective, the implant may seem "a bit light" and more suitable for those seeking complete abstinence rather than those intending to remain on agonist therapy. The patient did not have interviews with the psychologist due to work-related commitments.

The organisation and management of the patient’s surgery proceeded smoothly. The patient was consistently monitored through visits, urine tests, and phone calls, especially during his business travels. The psychophysical condition of the patient has always been good, and the patient also observed a stabilisation in his nightly rest. In February 2023, the patient removed the device after the 6-month period, expressing great satisfaction with the experience. Subsequently, the patient did not encounter any issues and did not require buprenorphine/naloxone. In fact, the patient conveyed the intention to abstain from a second implant and forgo further OAT because he felt well. During the months with the implant, he successfully distanced himself from addiction after many years.

Case report 2

The patient is a 63-year-old man of Caucasian Italian ancestry who underwent treatment at the Medical Toxicology Department in Florence. He is a former addict, having maintained abstinence for over 30 years from heroin and methadone. After an extended period of traditional OAT with sublingual buprenorphine, he consistently expressed his desire to discontinue this treatment. Subsequently, the patient was presented with the option of a buprenorphine implant, which he accepted with the goal of achieving detoxification as the dosage in the subcutaneous implant is depleted by the end of the 6th month.

The patient's family history includes a hypertensive mother who died in 2010at the age of 86, a father who died at the age of 89, and an older sister in apparent good health. Throughout his life, the patient has experienced chronic hypoxia, maintained a low body mass index (BMI), and displayed regular diuresis and bowel function. Employed as an office worker, he grapples with insomnia and smokes approximately 15 cigarettes daily. Since the 1990s, the patient has tested positive for Hepatitis C (HCV). In 2008, he was diagnosed with renal heteroplasia on the right side, necessitating surgical exeresis. In 2010, a fracture of the right distal condyle of the femur occurred, prompting surgical intervention. From 2017 onward, the patient has been under the surveillance of the Systemic Manifestations of Hepatitis Virus Centre (MASVE), where he was diagnosed with cryoglobulinemia. Successful HCV eradication measures were undertaken.

The patient began illicit drug abuse in 1978 at the age of 19, with heroin being the primary substance of abuse. Of note, around the age of 30, the patient underwent a period of community day care. Concomitantly, he has consistently used and continues to use cannabinoids. Currently, the patient has been abstinent from heroin use for about 30 years.

From 1982 to 2007, the patient received treatment at the Medical Toxicology Department of the regional reference centre with methadone for heroin use disorder. Subsequently, he underwent OAT with sublingual buprenorphine until October 2022 (Table  1 ), at which point he transitioned to buprenorphine implant therapy.

Psychological aspects prior to buprenorphine implant

The patient exhibits compensated histrionic traits without psychosocial relapse. He is also characterised by an anxious temperament but maintains an on-axis mood [ 8 ]. The acceptance of this treatment stems from the desire for increased freedom, as it eliminates the need for frequent visits to the facility for sublingual buprenorphine, with the ultimate goal of achieving definitive detoxification.

At the time of implantation, the patient was on 8 mg sublingual buprenorphine agonist therapy. The patient underwent subcutaneous implant surgery in October 2022. The implantation was performed at the Vascular Access Centre Unit, Department of Anaesthesia and Resuscitation AOUC (for a comprehensive outline of the procedure, please refer to Additional file 1 : Appendix SI). Except for the initial days when the patient experienced mild withdrawal symptoms and a minor infection at the implant site, promptly addressed with antibiotics, the patient expressed overall satisfaction and happiness with the decision made.

Follow-up visits

The patient engaged in numerous follow-up visits, during which evaluations were performed to assess both physical and psychological outcomes. The Clinical Opiate Withdrawal Scale (COWS) score was employed throughout these visits to monitor the patient's withdrawal symptoms and general well-being (Table  2 ). The COWS categorical score ranges are defined as follows: no withdrawal (0–4), mild (5–12), moderate (13–24), moderately severe (25–36), and severe withdrawal (> 36) [ 11 , 12 ].

The removal of the implant, initially planned at the latest after 7 months from insertion, was delayed by a few months at the patient's request. The patient underwent monitoring of buprenorphine blood levels, which showed a slow decline in values, maintaining excellent toxicological compensation. The removal procedure was scheduled for the July 17, 2023, at the Vascular Access Centre Unit of the AOUC, but it was unsuccessful. After 2 h, the removal intervention was interrupted, and the patient was directed to ultrasound and MRI examination, which allowed visualization of the implants in the subfascial space in the brachial biceps muscle of the left arm instead of subcutaneous space. Following a thorough orthopaedic consultation, it was decided to forgo surgical intervention due to the patient's asymptomatic clinical presentation. Instead, the plan is to monitor the progress through semi-annual follow-ups. As of now, no complications have been identified.

The patient consistently reported minimal withdrawal symptoms and no significant cravings throughout the follow-up period with an excellent toxicological compensation. Furthermore, the patient expressed overall satisfaction with the subcutaneous implant, emphasizing its positive impact on mood, anxiety levels, and sleep patterns. Despite the initial challenges in the removal procedure, the patient's clinical presentation remains asymptomatic, contributing to the overall success of the buprenorphine implant treatment.

Case report 3

The patient, a 55-year-old woman of Caucasian Italian ancestry, was admitted to a psychiatric clinic in 2012 with a diagnosis of “depressive syndrome in a patient suffering from bipolar disorder, diffuse polyarthralgias and resumption of alcoholism”. She has been consistently under the care of a trusted psychiatrist since then.

Her primary substance of abuse was heroin until the late 1990s, followed by the development of alcohol use disorder. Alcohol consumption persisted over the years with long periods of remission and brief relapses mainly in a binge-like manner. Due to her history, the patient had been actively engaging with the Alcohol Centre and participating in self-help groups. She has been abstinent from alcohol consumption since 2021 and from heroin for over 20 years.

Since 2004, the patient has been undergoing OAT with buprenorphine (Table  3 ), and during this period, she has also been consistently receiving stable and concurrent psychopharmacological therapy. The patient had repeatedly expressed interest in discontinuing OAT, thus at the end of 2022 she was offered the option of using a buprenorphine implant. The proposed plan involved utilizing the implant for a duration of either 6 or 12 months, contingent on the patient's decision to pursue or decline a second implant at the conclusion of the initial period. This approach aimed to facilitate the detoxification process. At the time of the decision, the patient was in good compensation from a psychiatric and toxicological point of view.

The patient underwent subcutaneous implant surgery in February 2023. For the detailed procedure, please refer to Additional file 1 : Appendix SII. The patient did not show any signs of withdrawal or overdose in the days following implantation.

Psychological aspects following the buprenorphine implant

Generally, the patient considers herself satisfied and happy with the choice made. Moreover, the World Health Organization Quality of Life – BREF (WHOQOL-BREF), a self-report questionnaire assessing quality of life [ 13 ], was administered to the patient. Her assessment yielded the following scores: physical health = 21 (scale range: 7–35), psychological health = 23 (scale range: 6–30), social relationships = 10 (scale range: 3–15), and environment = 27 (scale range: 8–40).

During the follow-up visits, the patient’s physical and psychological state were assessed, and the COWS score was employed to evaluate withdrawal symptoms and general well-being (Table  4 ).

Throughout the observation period, the patient displayed overall well-being. However, as the removal procedure approached, she experienced mild anxiety, which was successfully managed with low doses of sublingual buprenorphine. The clinician notes that the patient's overall progress indicates a positive response to the buprenorphine implant treatment, showcasing effective control over withdrawal symptoms and cravings. The patient herself expresses satisfaction with her experience.

Case report 4

The patient, a 53-year-old male of African Italian ancestry, reported that his initial exposure to drugs, particularly THC, occurred around the age of 12. Subsequently, following the dissolution of his marriage, he had encounters with cocaine and later opioids, leading to the development of addiction.

After a period spent abroad, the patient returned to Italy in 2002 and sought treatment from various Addiction Services, where he began treatment with methadone. Approximately four years ago he transitioned to OAT with sublingual buprenorphine. Upon admission to our Service in May 2022, his therapy consisted of sublingual buprenorphine 6 mg + sublingual naloxone 1.5 mg per day.

During the meetings, the patient consistently demonstrated willingness and motivation. While his language was partially fluent, there were occasional interruptions attributed to difficulties in recalling certain phases of his life history. He showed spontaneity and did not need to be triggered to express himself, showing reflexivity and ability to contextualise. Adequate introspection and the absence of emotional blocks related to traumatic experiences were evident. The patient exhibited an internal locus of control and a sense of self-efficacy overall. From the behavioural point of view, within the service and with the clinical staff, we can highlight a good adherence to the indications given and to the scheduled appointments, and a good general compliance.

Due to pharmacological stability for over 5 years and restricted drug use limited to cannabinoids, the patient was deemed eligible for the buprenorphine implant, meeting the psychosocial inclusion criteria. Following the proposal, he exhibited heightened curiosity about the implant, experiencing a sense of "euphoria" in anticipation of this novel experience. His interest increased during the presentation of the implant procedure, which he quickly accepted. The impetus to accept the proposal stemmed from some of the patient's reflections, especially regarding the potential for a lifestyle change and the reclamation of "his time," envisioning more opportunities for hobbies, family, and travel. Moreover, he imagined the recovery and achievement of life goals linked both to everyday life and to the possibility of planning without “personal” constraints of time and organisation. Eventually, some reflections "almost of tiredness" emerged, referencing both to the regular visits to the Addiction Service and to the interactions with other service users. This weariness stemmed from the perceived hindrance of traditional OAT, seen as a substantial impediment to daily freedom due to the commitment required for therapy. Additionally, it extended to the challenges in achieving personal and life goals.

Since this was the first buprenorphine implant carried out at our facility, it was necessary to draw up a procedure, and have it approved by the Health Management. This protocol encompassed the establishment of a dedicated outpatient file and the provision of a specialized room, serving both for the surgical procedure and for consultations with prospective candidates, some of whom were referred from other Addiction Services.

The patient exhibited a comprehensive shift in mood, a heightened inclination toward openness with others, and a rejuvenated approach to life planning. Following the implant procedure, the patient demonstrated improved speech fluency attributed to heightened introspective abilities. He identified the socio-affective dimension as the most significant element in the initiated change, leading to increased stability on the affective level. This translated into a newfound capacity to navigate relationships with more meaningful and secure emotional grounding. Moreover, the initial days following the implant marked a shift in self-perception and how the patient was perceived by others. The awareness of the significant impact of the intervention on his life became apparent, bringing about a rediscovery of energy, an enhanced "esprit de vivre", and a transformation in interpersonal relations with the Addiction Service staff. Overall, a newfound optimism and fortitude was evident.

During the post-implant interviews, the patient was subjected to a patient-reported outcome (PRO) measure using a visual analog scale (VAS) to capture the severity or other aspects of craving. A VAS measure usually requires participants to indicate their response by marking a point on a 100-mm line, with the extremities represented by 0 as "no craving for heroin" and 100 as "absolute craving for heroin" [ 12 , 14 ]. At the follow-up the patient reported a “lack of craving” in terms of intensity and frequency, and he also denied the possibility of starting drug use in the event of experiencing craving. Throughout the course of treatment, the patient underwent weekly visits during the first month, followed by fortnightly visits in the second month, and eventually transitioning to monthly visits. Toxicological tests were conducted during these visits to monitor the patient's progress. No additional sublingual buprenorphine tablets or other drugs were necessary. Out of 11 toxicological tests carried out on urine samples, 2 were negative for all the substances sought. All other tests showed positivity for cannabinoids; this was consistent with the patient’s reported reduced daily use of THC before going to sleep.

From the outset, the patient expressed a reluctance to pursue a second implant, although he did not entirely rule out the possibility. As a result, the decision was made to defer the removal of the implant, allowing for close follow-up to monitor any changes. If needed, oral therapy could be resumed while awaiting a potential second implant to be grafted. In line with the patient's preferences and the agreement with healthcare providers, the implant remained in place beyond the initially planned sixth month. This extension allowed the patient additional time to contemplate the option of a second implant while ongoing urine buprenorphine screening, toxicological monitoring, and regular interviews were conducted. The removal was originally scheduled for the end of the seventh month. However, due to the patient's unavailability, primarily driven by severe personal reasons, the removal was subsequently postponed by two weeks. As of today, the removal procedure has been successfully performed and the patient exhibits a complete absence of craving and no desire to use substances. During the last interview the patient reported: “Every day I feel better!” .

Overall, the patient has experienced significant improvements in mood, interpersonal openness, and life planning. Additionally, there appears to be a reduction in THC use. Remarkably, even after the removal of the implant, the patient has not reported any cravings related to substance use.

Case report 5

The patient, a 40-year-old male of Caucasian Italian ancestry university graduate currently in permanent employment, initiated drug experimentation around the age of 20. In this period, he became fascinated with and started attending rave parties, leading to gradual experimentation (reported as "controlled") with illicit drugs including Afghan opium, eventually resulting in the development of an addiction disorder.

The patient’s toxicological history indicated a pattern of polyaddiction, involving the use of cannabinoids, particularly hashish, since the age of 18. At the age of 21, he began attending rave parties, engaging in simultaneous and occasional consumption of various drugs such as cocaine, MDMA, amphetamines, LSD, and Ketamine. Subsequently, the patient transitioned from regular opium use to heroin after approximately two years.

He continued his substance use until the age of 25, at which point he initiated treatment with sublingual buprenorphine at an Addiction Service. Upon admission, he had a diagnosis of OUD in protracted remission under treatment with partial OAT (buprenorphine in combination with naloxone), and concomitant depression. Throughout the course of treatment, the patient maintained a steady intake of buprenorphine/naloxone sublingual tablets at a fixed dosage of 2 mg/0.5 mg per day. Since his initial admission, he consistently reported challenges in discontinuing OAT. Specifically, he mentioned being able to refrain from the medication for a few days (up to a maximum of 4 days). However, with the onset of anxiety and intensified cravings for buprenorphine, the patient resumed his daily intake of 2 mg. Since initiating OAT, the patient reported abstinence from opium or heroin use. Despite maintaining a stable clinical picture, the presence of recurrent unsuccessful attempts to discontinue OAT prompted consideration for transitioning from sublingual to subcutaneous therapy. In August 2022, during a toxicology interview, the possibility of buprenorphine implant therapy was proposed to the patient.

In conjunction with the pharmacological aspect of the new therapy, the patient concurrently received treatment with specific antidepressants. Additionally, he has actively participated in individual psychotherapy for a duration of two years and is presently engaged in group psychotherapy. The patient promptly made himself available and demonstrated willing adherence to the instructions provided by the medical staff, consistently attending his scheduled appointments. Notably, he exhibited overall good mentalisation and fair self-esteem.

The patient initially exhibited moderate curiosity during the first interview introducing the buprenorphine implant. However, his interest in the proposed treatment escalated swiftly. This interest and curiosity stimulated thoughts about the prospect of embarking on a new lifestyle. Throughout the interviews, he conveyed that he embraced the proposal due to tiredness from the constant mood swings induced by traditional OAT, which required daily visits to the facility. These factors, coupled with other personal considerations, amplified his discomfort with commitment, hindering the overall pursuit of life goals.

After establishing a dedicated room at our facility, the patient was directed to the Addiction Service, where an external doctor from the hospital conducted the implant surgery. Following the surgery, we maintained continuous monitoring through both group psychotherapy and individual therapy sessions.

Throughout the course of treatment, the patient initially underwent weekly visits during the first month, followed by fortnightly visits in the second and third month, and eventually transitioning to monthly visits. During these regular check-ups, the patient underwent toxicological controls, and notably, no additional sublingual buprenorphine tablets were required.

After the implant procedure, the patient experienced mood stabilization, which he described as surprisingly positive. This positive change was openly shared by the patient within the therapy group. He demonstrated introspective ability, albeit stereotyped, aligning with the ideological and social models of his peer group. Following the implant there appeared to be a recognition of subjective aspects that he had not previously explored, potentially serving as a foundation for renewed self-awareness. Moreover, the patient exhibited rich and articulate language, along with good introspective and self-reflective ability, fair insight, and a proficient recall of his life history. Shortly after the implant, he conveyed his sense of liberation in an email, stating: "…I am a free man…" . In a group session, he elaborated on this feeling, expressing that he now perceives himself as "like everyone else," no longer dependent on the daily tablet, and experiencing mood fluctuations akin to any other individual.

The patient has been undergoing treatment for several months and reported only experiencing a headache in the initial days following the implant. Toxicological controls indicate positivity only for THC, as the patient has consistently used cannabinoids by smoking a "joint" in the evening to relax before going to sleep, with no intention of discontinuing this habit.

In post-implant interviews, the patient underwent the VAS test and reported a "lack of craving" both in terms of intensity and frequency. Furthermore, he expressed no inclination to initiate drug use in the event of experiencing cravings.

From the outset, the patient has made it clear that he had no intention of pursuing a second implant. Although he does not rule out the possibility entirely, his hope is to attain complete liberation from OAT and, more broadly, from drugs. This suggests a reasonably sound capacity for judgment on his part. Hence, the decision was made to defer the removal of the initial implant, utilizing the gradual reduction of the drug, and assessing how best to support the patient on his journey towards detoxification.

The patient appears to be progressing well on the detoxification path, as evidenced by his expressed intention to refrain from further OAT after the removal of the implant. The patient's determination is a crucial factor in the success of the detoxification process. The absence of craving after the removal of the implant, along with the noted mood stabilization and positive treatment perception reported by the patient, are significant indicators contributing to the success of the patient's detoxification journey.

Case report 6

Filippo (fictitious name), a 23-year-old male of Caucasian Italian ancestry, reflects on his childhood, describing it as “normal”. His father is portrayed as a diligent worker, while his mother is characterized as a pragmatic and less sentimental woman. As an intelligent child, Filippo sensed the weight of the expectations his mother had placed on him. During the transition to middle school, he experienced a loss in friendships, became apathetic, distracted, and spent most of his time playing video games, rarely venturing outside. However, there was an improvement in his social life and academic performance during high school, which led Filippo to enrol in university, where he also initiated a romantic relationship with a girl.

In the summer of 2018, following his first year of university, Filippo started experiencing anxiety disorders, making it challenging for him to cope with his exams. Simultaneously, he found out that his girlfriend was using heroin and cocaine. In response, he decided to experiment with these substances. Initially, his usage was occasional and seemed "manageable", but Filippo rapidly developed both physical and mental addiction. Furthermore, he began using cocaine to counteract the effects of heroin. His drug abuse progressively escalated from occasional to daily, extending beyond social contexts to solitary moments. Filippo found himself trapped in a vicious cycle, marked by a constant need to soothe himself and promptly reactivate. His academic performance suffered, and financial resources were increasingly diverted towards substance abuse. Recognizing the severity of the situation, Filippo sought help from a psychiatrist-psychotherapist, who advised him to approach an Addiction Service. Although Filippo was not fully convinced, he perceived that seeking help was his only viable option. When he shared his predicament with his family, their initial response was a mix of anger and concern. However, that single conversation remained an isolated instance, and subsequently, they seemed to adopt an approach of denial, choosing not to acknowledge the reality of Filippo's struggles.

Filippo initiated his treatment at the Addiction Service in January 2020 with a dosage of 2 mg of sublingual buprenorphine. This regimen was subsequently increased to 4 mg after a few weeks. Notably, Filippo demonstrated commendable adherence to the treatment regimen, attending interviews regularly and concurrently engaging in private psychotherapy. He ceased his heroin use immediately after commencing OAT, and he also managed to discontinue cocaine, with only a few relapses in October 2020. Subsequently, Filippo experienced improvements in mood, school performance, and social interactions. However, his main concern revolved around the prospect of discontinuing the daily tablet intake.

In January 2022, after Filippo's previous doctor departed from the service, I had a clinical interview with Filippo. During this meeting, I suggested a questionnaire to assess the current state of his therapy and his interest in transitioning to newly available drug formulations. Filippo embraced the idea of transitioning to a subcutaneous buprenorphine implant with enthusiasm. Despite considering the possibility of balancing his personal life with regular visits to the Addiction Service, he expressed a keen interest in the new treatment. At that point, he had been on a 4 mg sublingual buprenorphine tablet regimen for approximately two years, and his toxicological tests consistently showed negative results for illicit drugs.

Filippo's excitement stemmed from several profound considerations: the weariness of identifying himself as an addict, a label that he felt no longer accurately portrayed his current state; the conscious desire to disengage from the daily ritual of medication, which he defined as a "substitute" for his previous heroin use, and thus corresponded to him as if still "getting high" every day; and the wish to regain control over his daily routine without being tethered to the demands of therapy, envisioning a future where he could plan vacations and travel abroad without the constraints of regular visits. Lastly, Filippo held a hopeful anticipation of achieving a definitive conclusion to his therapy, marking a significant milestone in his journey towards recovery. Despite receiving comprehensive information from the data sheet, Filippo's determination to pursue the subcutaneous buprenorphine implant treatment remained unwavering. He maintained a steadfast commitment to this choice, eagerly anticipating further details about the practicality and feasibility of undergoing the implant procedure. The Addiction Service practitioners collaborated closely with the hospital pharmacy and the Palliative Care operating unit to efficiently organize the day of the surgery. On the morning of the surgery, Filippo exhibited no signs of agitation. He adhered to the given directions and refrained from taking the morning sublingual buprenorphine tablet. Without experiencing any withdrawal symptoms, he maintained focus on the day's objective. The surgical procedure proceeded smoothly, lasting approximately an hour, after which Filippo proceeded to attend his university activities.

In the days following the surgery, Filippo reported a sustained, almost heightened sense of well-being, exceptional concentration (especially in his studies), and an energy level he had not experienced before. While there may have been a brief, two-day period resembling a hypomanic phase, Filippo soon returned to a stable and regular state of well-being, seamlessly resuming his daily activities. Despite being aware of the option to supplement the implant with buprenorphine tablets, Filippo never felt the necessity to do so. In agreement with the department director, we limited Filippo's visits to the Ser.D to the bare minimum needed to perform the monitoring required by the implant protocol. These included urine tests at various intervals post-intervention: 1 week, 2 weeks, 1.5 months, 3 months, 4.5 months, 6 months, and 7 months. During these visits, we assessed his overall health, general well-being, reactions at the implantation site, degree of patient satisfaction, and any withdrawal or craving symptoms, along with potential drug abuse.

In our regular phone interviews with Filippo, he would describe positive events that were taking place in his life. Approximately four months post-intervention, during an in-person interview, we delved into the impact of the implant on Filippo's lifestyle. A significant transformation was evident: his self-perception had undergone a complete shift. During the six-month period of the implant, Filippo encountered an emotional reconnection with his mother when he shared his experience with the subcutaneous treatment. Until then, his addiction had only been briefly mentioned within the family context, resulting in a negative outcome. This revelation left his mother surprised, astonished, and moved, but also visibly proud.

On a separate occasion, Filippo attended a party and unexpectedly spent the night away from home. He emphasized that he only realized the next day that such spontaneity would not have been possible without the implant. Without the need for daily tablets, he could participate freely without the fear of experiencing withdrawal symptoms the following morning. He no longer needed the “daily heroin substitute” and he no longer needed heroin. These and other episodes strengthened his conviction to “get rid” of therapy and of the fear of not being able to “walk without that crutch”. His determination grew, accompanied by the belief that the removal of the implant would mark the conclusion of his therapy. Filippo explicitly requested the removal of the implant not at the initially specified deadline but at a later time, and he duly signed a written request expressing this desire.

The implant removal occurred in mid-November 2022, precisely 7 months and 9 days after its initial placement. Despite Filippo was at the time a little tense, the removal proceeded smoothly. The urine test conducted at this time still showed a positive result for buprenorphine. In the subsequent days, Filippo experienced symptoms including chills, tearing, arthralgia, and asthenia. Initially attributing these symptoms to a form of flu without strong conviction, he persevered. After 20 days, despite lingering discomfort, his determination to discontinue oral OAT prevailed. The subsequent urine test confirmed the absence of buprenorphine, marking the achievement of Filippo's goal.

General discussion

The buprenorphine implant represents an innovative formulation for OAT, specifically designed for individuals with OUD who have achieved stabilization through prior oral therapy. Notably, the implant demonstrates equivalent therapeutic effectiveness and similar rates of adverse effects when compared to standard sublingual buprenorphine or buprenorphine/naloxone tablets [ 6 , 8 ]. Nonetheless, a comprehensive risk–benefit evaluation has revealed several advantages associated with the subcutaneous buprenorphine implant in comparison to conventional OAT [ 10 ]. These benefits include enhanced treatment adherence, improved quality of life for patients, decreased likelihood of engaging in illicit opioid abuse, and a reduced risk of misuse or diversion [ 10 ]. These findings have been validated through the experiences of the first six patients in Europe who underwent the buprenorphine implant, as outlined in this case series. The report provides insights into the tangible effects of the buprenorphine implant on patients' quality of life and the achievement of therapeutic objectives, specifically focusing on abstinence from illicit drug abuse and the detoxification process.

Eligible patients were carefully assessed by the medical equipe in terms of clinical, psychological, and pharmacological status. All patients had refrained from using illicit drugs, were receiving low-dose sublingual buprenorphine (≤ 8 mg), demonstrated adherence to OAT and regular visits to the Addiction Service, and exhibited psychological stability. The heterogeneity observed in this group of patients stemmed from variations in sociocultural background, gender, age, duration of substance abuse history, length of the period of drug abstinence, and the specifics of their medical and pharmacological history, including the duration, dosage, and any prior OAT before transitioning to buprenorphine (Table  5 ).

Buprenorphine implant emerges as a viable treatment alternative for diverse patient profiles, contingent upon achieving a certain level of pharmacological stability (≤ 8 mg), psychological well-being, and a documented recent history of drug withdrawal.

The reaction of the patients to the implant proposal ranged from moderate interest in some cases to genuine enthusiasm in others as delineated in Table  6 (Buprenorphine implant proposal). All patients embraced the buprenorphine implant to enhance their quality of life, eliminating the need for regular visits to the Addiction Service for the administration of tablets and moving closer to complete detoxification.

To assess the impact of both traditional OAT and buprenorphine implant, a semi-quantitative narrative analysis was conducted [ 15 , 16 , 17 , 18 ]. Every quote pertaining to patients' experiences with either treatment was considered in the analysis and subsequently categorised into one or more of the following topics: commitment to achieving complete detoxification, disengagement from therapy, smoothness of therapy, emotional impact, and improved quality of life in terms of free-time, finances, work, and interpersonal relationships (Fig.  1 ). Subsequently, the positive or negative valence associated with each statement was recorded. The implant was viewed as a valuable means to achieve abstinence from both drugs and medications, as evidenced by a total of 22 positive statements (Fig.  1 A), compared to 6 for traditional OAT (Fig.  1 B). The regular attendance at the Addiction Service was seen as a “constraint that disrupted daily routines” and “contributed to social stigma”, undermining patients' commitment to therapy and overall quality of life (7 out of 9 negative statements). The desire to break free from the daily tablet intake, perceived as a “substitute for heroin” and a source of mood swings, was a common sentiment. In contrast to the peaks associated with oral intake, the subcutaneous implant offered a stable release of buprenorphine, as evidenced by the 22 positive statements (Fig.  1 A) compared to 7 (Fig.  1 B) associated with traditional oral intake. This consistency helped in mitigating both physical and emotional fluctuations experienced by the patients.

A narrative analysis of patients' reported experiences was conducted for both traditional OAT ( A ) and buprenorphine implant ( B ). The analysis was conducted by categorizing the statements related to each treatment into the five identified topics positioned at the vertices of the pentagon. The number of positive (blue line) and negative (red line) statements per topic were plotted along the direction of the corresponding vertex and connected by a 5-pointed closed line. The distance from the centre indicates the frequency of iterations. Notably, the scale of the pentagon differs between the two graphs

In terms of surgical procedure, the buprenorphine implant insertion was carried out in a specialised facility, by a professional surgeon, and no significant issues were encountered for any of the patients (Table  6 , Surgery outcome). Solely one patient developed a minor infection at the implant site, which was promptly addressed with antibiotics. He also reported a subjective feeling of overdose in the initial days post-insertion, followed by mild withdrawal symptoms, that were stabilised by a 3-day course of 1 mg sublingual buprenorphine. Consistent with findings from a previous study [ 19 ], the buprenorphine implant insertion procedure and the subsequent adaptation to treatment appear to be overall safe and well-tolerated.

During 6 months of follow-up, as outlined in Table  6 (Follow-up visits), the potential onset of withdrawal symptoms was closely monitored through regular assessments for most patients. Psychometric tests were also conducted to evaluate various aspects. Importantly, no patient reported experiencing cravings throughout the course of treatment, and all toxicological tests yielded negative results for the detection of illegal opioid abuse. All the patients expressed satisfaction with the buprenorphine implant treatment, and most of them reported being content with their decision, as indicated in Fig.  1 and Table  6 (End of therapy). On an emotional level, all patients reported a sense of well-being, with 18 positive statements compared to 3 positive statements for traditional OAT (Fig.  1 A, B), and no instances of relapse were noted. Half of the patients experienced increased lucidity, improved introspective ability, and greater stability on the affective level (Table  6 , End of therapy). The majority showed an on-axis mood (4 out of 6), absence of anxiety, hypnic pattern within limits, and restful sleep. Two out of six patients explicitly described a marked improvement in self-perception during the 6-month buprenorphine implant treatment. Overall, buprenorphine implant was perceived as a step closer to complete detoxification with 13 positive statements (Fig.  1 A) vs. 5 positive statements for traditional OAT (Fig.  1 B).

The removal procedure was successful for most of the patients, and none of them opted for a second implant. Solely one patient reintroduced sublingual buprenorphine at low dosages, although this decision was not prompted by any withdrawal symptom. Most importantly, none of the patients experienced craving episodes, indicating the potential for them to continue living without any OAT and ultimately achieve complete detoxification.

In summary, this case series explores the pioneering use of buprenorphine implant as a treatment option for OUD in a small European cohort of eligible patients. The findings suggest positive outcomes, including improved patient satisfaction and quality of life, reduced stigma associated with regular clinic attendance, and perceived advantages in achieving opioid abstinence. However, certain limitations must be acknowledged, including the small sample size, the relatively short follow-up period, and the reliance on self-reported questionnaires to evaluate patients’ perspective and experiences. The relatively small yet heterogenous sample size, while providing valuable insights into how various patient profiles might respond to this treatment approach, could affect the generalizability of the findings to a broader population. Moreover, the variability in the frequency and duration of follow-up visits, while enabling to capture the moderate-to-long term effects of the treatment, limits the ability to assess longer-term outcomes. Furthermore, the study's reliance on self-reported questionnaires while focusing on patients’ perspective, might introduce the possibility of response bias. This could include an inclination to offer responses that align with social expectations or recall biases. Therefore, in future studies the adoption of standardized assessment tools will ensure consistency and facilitate more robust cross-study comparisons. Future research should prioritise larger cohorts, encompassing comparative analyses with traditional OAT, and long-term investigations to assess sustained efficacy and diverse dynamics of patient profiles. Collaborative efforts to standardize assessment protocols across facilities would further strengthen the reproducibility of research findings in this evolving field.

Final conclusions

This case series outlines the therapeutic journey of the first six European patients who underwent buprenorphine implant therapy. The results demonstrate favourable outcomes, including successful opioid abstention, alleviation of withdrawal symptoms, and enhanced quality of life and psychological well-being. Importantly, the treatment exhibited a high level of safety and tolerability, with no significant adverse events reported during the peri-operative period. The smooth insertion procedure and subsequent adaptation highlight the consistent benefits of the implant, with most patients achieving complete abstention, a milestone that might have been challenging with traditional approaches. Overall, the patients' satisfaction with the buprenorphine implant underscores its potential as a viable treatment option for pharmacologically stable individuals seeking to transition from traditional OAT. Nevertheless, further research into patient profiles, craving dynamics, and patient-centred outcomes is essential for optimizing personalized interventions in the field of addiction medicine.

Availability of data and materials

The datasets used during the current study are available from the corresponding author on reasonable request.

Abbreviations

• Opioid use disorder
• Opioid agonist therapy

Hepatitis C Virus

Centro Manifestazioni Sistemiche Virus Epatitici, Systemic Manifestations of Hepatitis Virus Centre

World Health Organization Quality of Life-BREF

Tetrahydrocannabinol

Visual analog scale

Methylenedioxymethamphetamine

Lysergic acid diethylamide

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CV, MLP, AV, and CD collected, analysed, and interpreted the patient data regarding the Case n.1. BO collected, analysed, and interpreted the patient data regarding Case reports 2 and 3. CL, SB, GFMD, LC, SL, MN, AP, EP, CP, and GV collected, analysed, and interpreted the patient data regarding Case reports 4 and 5. RM collected, analysed, and interpreted the patient data regarding the Case report 6. All authors participated in the writing process, reviewed, and approved the final version of the manuscript.

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Supplementary Information

Additional file 1: case report 1..

Buprenorphine implant procedure.

Additional file 2: Case report 2.

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Pierlorenzi, C., Nunzi, M., Cirulli, S. et al. Patients' perspectives on buprenorphine subcutaneous implant: a case series. J Med Case Reports 18 , 202 (2024). https://doi.org/10.1186/s13256-024-04483-6

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DOI : https://doi.org/10.1186/s13256-024-04483-6

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