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Challenges of diagnosing severe malaria with complications in adult patients: a case report | Tropical Diseases, Travel Medicine and Vaccines

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In this case report, the authors report a case of severe malaria in an adult with no history of travel to an endemic area and was RDT/smear negative during acute presentation which found later to be positive on the twelfth day of treatment. More than 10,000 cases of entry of malaria from endemic to nonendemic countries are reported annually; however, cases of introduced malaria in malaria-free urban areas in malaria-endemic countries are less well known [7]. Local transmission causes malaria cases in nonendemic areas to occur in several conditions, including through 1) “airports”, 2) “harbors”, 3) “baggage” malaria, 4) nosocomial transmission, and 5) local transmission by malaria vectors. In addition, cases of mild malaria outbreaks due to local transmission were reported in northern Germany and Berlin until 1947 [8] and in the United States [9].

Transmission of the malaria parasite near airports can occur through infected Anopheles mosquitoes carried by aircraft, which can survive long-distance flights and adapt long enough to new environments [10]. Locally acquired malaria, where cases are mainly concentrated around international airports, is known as airport malaria [11]. The risk factor for this patient may be related to his work as a motorcycle taxi driver. Driving a vehicle in the area around the airport to pick up passengers can increase the patient’s risk of being bitten by Anopheles mosquitoes around the airport. There is ample evidence that airport malaria is on the rise in malaria-free countries. Between 2010 and 2020, the number of infected people in Europe increased 7.4 times compared to the decade of 2000-2009 [11]. This increase may be related to climate change, increased international trade, decreased aircraft disinfection, and delays in diagnosing and treating cases. More importantly, current interventions at preventing this spread are undermined by biological and operational challenges such as malaria parasite drug resistance and vector resistance to insecticides, as well as logistical limitations for instance due to the pandemic the delivery of antimalaria and RDT was hindered between and within countries further causing a lack of local stocks [11]. Therefore, there is a need to strengthen malaria prevention and treatment of people at risk of malaria at airports and to implement strict and regular entomological and epidemiological surveillance in and around airports.

Global warming has become undeniable, and its magnitude and impact on malaria transmission are increasing. For instance, the number of days with average temperatures above 25 °C in summer is increasing. On the other hand, airport malaria cases observed in the last decade were mainly associated with favorable climatic conditions for mosquito survival (mean temperature 23 °C, range: 17–31 °C) [12]. One of the key factors in mosquito development, both in water and on land, and in mosquito parasite development is temperature. Indeed, the duration of sporulation, life expectancy of mosquitoes, and duration of larval development are strongly influenced by temperature [13].

The decision to repeat laboratory testing for malaria was based on the following findings: 1) clinical deterioration continued even with intensive medical treatment, 2) indications of respiratory failure, 3) persistently elevated liver enzymes, 4) elevated levels of urea and creatinine, and 5) thrombocytopenia. Previous studies reported that respiratory failure occurs in 10-25% of cases of severe malaria caused by P. falciparum [14, 15]. According to CDC, patient can be diagnosed with severe malaria if fulfilled at least one of criteria including high percent parasitemia (> 5%), severe anemia (Hb < 7 g/dL), or metabolic abnormalities such as impaired consciousness, seizures, circulatory collapse/shock, acute respiratory distress syndrome (ARDS) or pulmonary edema, acidosis, acute kidney injury, disseminated intravascular coagulation (DIC) or abnormal bleeding, and jaundice [16]. Thus, despite the initial negative RDT and smear, the severe malaria diagnosis are still suspected with elevated serum aspartate and alanine aminotransferase levels, as the infection can cause liver dysfunction. The patient also showed a decrease in the number of platelets as well as an increase in the level of bilirubin which implicates liver dysfunction found in malaria cases [16].

Our center follows standardized laboratory and protocols within WHO standards. Malaria smear examination is being employed to identify the presence of malaria parasites in a patient’s blood. The process involves obtaining a small blood sample from the patient, usually from a fingertip, and creating two types of blood smears on microscope slides which are a thin smear and a thick smear. The thin smear is generated by spreading a small amount of blood across one slide and air-drying it, while the thick smear is produced on a second slide with a larger, thicker distribution of blood. The thin smear is often fixed using heat or methanol. Both smears are then stained, typically with Giemsa stain, following specific staining protocols. Subsequently, the stained thin smear is examined under oil immersion on a microscope, allowing for the identification of malaria parasites and determination of the species present. The results, detailing the type of malaria parasite and the level of infection, are recorded, and reported [17].

The Rapid Diagnostic Tool that was being used was the Right Sign Malaria Pf test (Biotest, Hangzhou Biotest Biotech Co, China). For the RDT that we used the sensitivity and specificity reached> 99.9% which shows the most likely cause of false negative results was due to sample error including how the sample was stored and delivered. As with the limitation of diagnostic tests in general, the result should be interpreted together with other clinical information that has been required by the physician. Further, if negative results are accompanied by clinical symptoms, additional testing with alternative clinical methods is recommended. This RDT has several limitations in which it can only be used for in vitro diagnostic use only, is used for the detection of Plasmodium falciparum (P.f), Plasmodium vivax (P.v), Plasmodium ovale (P.o), and Plasmodium malariae (P.m.) specimens only which can be used for qualitative not quantitative purpose. Also, the result of RDT cannot be used as the sole criterion in diagnosing of malaria [18].

Regarding how the RDT works, firstly whole blood (10 μL) sample from the patient was added into a specific tube and then mixed with three drops of buffer. After that, the test strip was vertically inserted into the previous tube and then we were able to see results within 10 min. The interpretation of the result depended on the band’s appearance. The appearance of two-colored bands which refer to control line ‘C’ along with test line ‘T’) can be inferred as a P. falciparum-positive result. On the other hand, if only a single-colored line on the control line ‘C’ is interpreted as negative results. Results were deemed invalid if any color could not be found on the control line [19].

False-negative (FN) examination findings can result from the procurement and use of poor-quality RDTs, issue with the microscope’s quality, or varied capability between lab worker in reading and interpret smears [20]. Another possibility is that poor storage procedures for RDTs, as well as prolonged exposure to high temperatures, could affect their diagnostic efficacy. Although rare, operator error in checking and/or interpreting the RDT can lead to false negative results [21]. One of the causes of FN-RDT results that has received recent attention is deletion of the pfhrp2/3 genes [22]. These deletions have been reported initially in South America and now in several locations in Asia and Africa [23]. Parasites with these gene deletions are not recognized by PfHRP2-based RDTs, leading to the prediction that RDTs expressing only PfHRP2 recognize select parasites [24].

Based on the study conducted by Ditombi et al. which compare four malaria RDT, more than 95% of positive blood smear were confirmed positive based on the RDT test. In addition, the number of false-positive results were ranging between 14.1 -17.5% depending on the specific RDTs. Further the number of false-negative results were less than 5% of febrile cases of total population [19]. For the RDT that we used the sensitivity and specificity was reaching > 99.9% which shows the most likely cause of false negative results was due to sample error including how the sample was stored and delivered.

Chest X-ray examination showed bilateral pleural effusion and pulmonary infiltrates. Therefore, early ventilator intervention was carried out in these patients. Adults with severe P. falciparum malaria are at risk of developing noncardiogenic pulmonary edema and acute respiratory distress syndrome (ARDS), which have a high mortality rate. This is very common in patients infected with P. falciparum. ARDS can occur in 5-25% of people with severe falciparum malaria [25]. Although rare, severe malaria must be differentiated from fulminant liver failure due to viral infection. This can have implications in determining treatment and patient outcomes. In patients with severe malaria, the liver can be affected to varying degrees from liver dysfunction to heme abnormalities such as anemia. Also, in patients with severe malaria infection, the incidence of jaundice was 2.58%. The presence of jaundice in falciparum malaria indicates a severe condition of the disease with a higher incidence of complications [26]. Another differential diagnosis in this case was Weil’s disease due to pathognomonic signs of gastrocnemius muscle pain. In addition, pulmonary involvement can occur (20-70%). However, the symptoms are often mild without complications. The incidence of ARDS in malaria requiring mechanical ventilation is rare, but when it occurs, the mortality rate from ARDS can reach 50%. Such conditions are often associated with pulmonary hemorrhage due to disruption of the vascular endothelium and impaired coagulation [27].

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