Severe Malaria in an Adult Patient from Low-Endemic Area in Flores Island, East Nusa Tenggara

Malaria is an infection caused by protozoa of the genus Plasmodium, commonly found in tropical and subtropical regions worldwide. Plasmodium falciparum causes the most severe form of the disease and may progress to life-threatening manifestations. This case describes a 26-year-old man who suffered cerebral malaria with multiple organ dysfunction and successfully recovered despite poor initial prognosis. Negligent and late diagnosis of malaria leads to severe complications and a worse prognosis. This case emphasizes despite living in a low-endemic malaria area, physicians should remain meticulous and consider malaria as differential diagnosis even after initially presenting with nonspecific symptoms. Consequently, malarial screening should be performed to modify the risk of mortality. Furthermore, close monitoring and early administration of intravenous artesunate are also particularly critical.


Introduction
Malaria is a mosquito-borne disease commonly found in tropical and subtropical regions worldwide. Plasmodium falciparum causes the most severe form of the disease and contributes to the highest incidence of malaria infection. Infection from this parasite can be fatal without promptly recognizing the disease and its complications [1]. Cerebral malaria is one of the most advanced clinical courses of severe malaria, leading to life-threatening complications [2]. Herein, we present a case of a young adult who sufered severe cerebral malaria with multiple organ dysfunction and successfully recovered despite poor initial prognosis.

Case Presentation
A 26-year-old male patient was referred to the General Public Hospital in Sikka Regency, East Nusa Tenggara, Indonesia, with presentations of loss of consciousness and jaundice. Te patient initially developed fever, headache, and abdominal pain since 14 days before being admitted to our hospital. Several days before, he was treated for dyspepsia in another primary health center, which did not get better, and he was treated for the same diagnosis in a private clinic. As his symptoms were persistent, he was transferred to the regional public hospital in his area. At that moment, peripheral blood smear revealed Plasmodium falciparum and parasitemia with a density of 176,000 parasites/μL (3.52%) ( Figure 1). His past medical and travelling history was insignifcant. He worked as a farmer and never used a mosquito repellent before. First dose of intravenous antimalarial artesunate (168 mg) was commenced, and repeated dose was followed at 12 hours afterwards. As he had an episode of seizure and acute kidney injury, after which his consciousness declined progressively, the patient was transferred to our hospital.
On clinical presentation, the patient was stupor, Glasgow coma scale 6, with profound jaundice, blood pressure was 142/75 mmHg, heart rate was 105 bpm, respiratory rate was 30 bpm, oxygen saturation was 96% using a nonrebreathing mask on 12 l/min oxygen, and the temperature was 38.5 C. Physical examination was signifcant for icteric sclera, copious hematemesis, hepatomegaly, splenomegaly, and black colored urine. Baseline and follow-up laboratory fndings during hospitalization are shown in Table 1. Initial laboratory tests were notable for acute kidney injury (creatinine 12.8 mg/dL, urea 529 mg/dL, and blood urea nitrogen 246.87 mg/dL), elevated transaminases (aspartate aminotransferase 214 U/L and alanine aminotransferase 409 U/L), anemia (9.8 g/dL), and thrombocytopenia (61,000/μL). He tested negative for HBsAg, negative for anti-HCV, and negative for anti-HIV. Chest X-ray demonstrated normal lung presentation.
Te patient was diagnosed with severe malaria caused by Plasmodium falciparum with multiple organ dysfunction: acute symptomatic seizure, acute kidney injury, jaundice, anemia, and copious hematemesis. Te patient underwent emergent hemodialysis and intravenous artesunate was given at 24 hours and continued daily. Other symptomatic and supportive treatments such as parenteral feeding, broadspectrum antibiotic, and anticonvulsant were also given. On the second day, his clinical condition did not improve, although we observed initial downtrend in urea, serum creatinine, and liver enzymes levels. He remained feverish and agitated.
Te second hemodialysis was performed in the following days, and he received 250 cc of packed red cell blood transfusion. A repeated malarial blood smear was negative for malarial parasite on the fourth day of hospitalization ( Figure 1). Subsequently, on the seventh day, the patient's condition stabilized. He was alert, obeyed the command, and began enteral feeding. Intravenous artesunate was switched to oral dihydroartemisinin-piperaquine (160 mg/1,280 mg) and primaquine (15 mg). Physical examination revealed no icteric sclera and improved urine color ( Figure 2).
Eventually, the patient underwent an uneventful fourteen days of care in our hospital. His hospitalization concluded with six doses of intravenous artesunate, three sessions of hemodialysis, three doses of dihydroartemisininpiperaquine (DHP), and a single dose of primaquine. Te patient's condition improved signifcantly without any sequelae, and he was discharged and evaluated in the outpatient clinic.

Discussion
Malaria continues to be a major global health problem, an epidemic in tropical and subtropical regions of Asia, America, and Africa [3]. Indonesia is one of the malariaendemic countries, and the majority of malaria cases are concentrated in Eastern Indonesia. Te following provinces have the high prevalence of malaria: Papua, West Papua, East Nusa Tenggara, North Maluku, and Maluku [4]. As the Indonesian Ministry of Health has a target to eliminate malaria transmission completely by 2030, in recent years, the malaria elimination program in Indonesia has shown particularly positive progress. Between 2007 and 2017, the annual parasite incidence (API) in Indonesia fell by three times, from 2.89 per 1000 to 0.9 per 1000. [5] According to a local provincial report, in 2022, East Nusa Tenggara province has declared major reduction in malarial cases with an API value of 2,2 per 1000 population. Of 22 districts, there are 12 districts categorized as low-endemic areas (API <1 per 1000), and 7 districts have reached zero transmission [6]. Within East Nusa Tenggara province, the highest prevalence of malaria is in Sumba Island, while more than half of the districts in Flores Island have ofcially been reported malaria-free. Tis achievement marked that East Nusa Tenggara province has gradually approached its malaria elimination goal (Figure 3). In this case, the patient came from East Flores district in Flores Island, categorized as a low-endemic area.
Severe malaria is most commonly caused by infection with Plasmodium falciparum. Te World Health Organization defnes specifc clinical fndings and laboratory results for severe malaria [1]. Cerebral malaria had the highest case fatality rate ranging from 16% to 35%, whereas respiratory distress had a case fatality rate of 20.9% [7]. Another study revealed that the mortality of severe malaria was higher in patients with impaired consciousness (26.5%), severe anemia (11.5%), and acute kidney injury (10%) [8]. Severe manifestations in this case report were impaired consciousness with convulsion, acute kidney injury, jaundice, anemia, and copious hematemesis.
Cerebral malaria is a fatal neurological complication that mostly occurs in children and pregnant women, while the mortality rate of cerebral malaria is higher in adults [9]. In our case, severe malaria likely occurred due to a delay in the diagnosis. In a systematic review and meta-analysis, Mousa et al. showed that a prolonged treatment delay (3-≥4 days) was at a 2.4-fold risk of developing cerebral malaria versus treatment ≤24 hours [10]. Te neurological damage induced by cerebral malaria may be lethal when treatment is delayed or in the setting of limited resources [11]. Our patient is a young immunocompetent adult, and he had a Plasmodium falciparum parasite density of 3.5%. Tis parasitemia could have potentially induced endothelial lesions of the blood-brain barrier, resulting in brain ischemia and neurological damage. Fortunately, after intravenous artesunate and supportive treatment were initiated periodically, his consciousness gradually improved, and he was discharged without any neurological defcit.  According to the WHO criteria for severe malaria, AKI is defned as a serum creatinine >3 mg/dL [1]. It is associated with a mortality as high as 75% when renal replacement therapy (RRT) is not started in time [12]. Te incidence of AKI in severe malaria patients varies across studies, with the AKI incidence rate reached as high as 52.5% in malarial patients [13][14][15]. Prompt dialysis has been associated with a 25% mortality reduction and a 30% improvement in renal function among malarial patients with AKI [16]. On admission, our patient showed elevated urea and serum creatinine levels with signifcant uremic manifestations. Tus, he underwent emergent hemodialysis. During hospitalization, laboratory results showed gradual renal function improvement after three hemodialysis sessions.
Te presence of jaundice in malaria indicates a more severe illness with a higher incidence of complications and mortality. Jaundice developed in our patient was caused by hepatic dysfunction and damaged red blood cells during acute malaria illness, resulting in anemia and black water fever [17]. Black water fever is hemoglobinuria from massive intravascular hemolysis, characterized by the black-tea color of urine, as seen in our patient. Black water fever also occurs in G6PD defciency patients who take particular drugs. However, we cannot perform G6PD examination as it is unavailable in our hospital. Subsequently, after days of treatment, our patient showed improved transaminases and bilirubin levels, and urine color progressively switched from blacktea to yellowish color ( Figure 2). Te presence of rapidly progressing anemia in malaria needs prompt treatment [18]. During the acute phase of the illness, our patient showed progressive anemia; thus, he received packed red cell blood transfusion. Interestingly, our patient also showed massive hematemesis when admitted to our hospital. Even though complicated falciparum malaria may develop bleeding manifestations, they rarely present with overt bleeding in adults [19]. Te pathogenesis of bleeding in malaria is believed to result from platelet dysfunction and coagulopathy which leads to thrombocytopenia [20]. Albeit gastrointestinal endoscopy was not performed, we suggested that the stress-related gastric erosions in severely ill conditions were the sources and that thrombocytopenia with dysfunctional platelets could have been the etiology of hematemesis in our patient. In studies evaluating gastric-related symptoms in malarial patients, mucosal edema and congestion (gastritis) were the majority endoscopic fndings; thus, gastritis should be considered in malaria infection [21,22].
Te risk of mortality is increased if treatment of uncomplicated malaria is delayed. Te possibility of mortality increased by almost four times in patients who delayed consultation by a day compared to those who came in very early [23]. Recognizing and prompt treatment is, therefore, of vital importance. Te highly variable presentation of malaria may mimic that of many other diseases creating misdiagnosis [1]. Tis case was initially suspected as dyspepsia syndrome before being referred to our hospital. After two weeks since the initial symptoms appeared, the patient was diagnosed with Plasmodium falciparum malaria and developed severe complications. He was treated in the intensive care unit because of multiorgan dysfunction due to the delayed malaria diagnosis. We thought that the delayed diagnosis is due to lack of consideration of malaria as differential diagnosis, even in low-endemic areas, causing severe complications similar to our case. Recent local data showed that East Nusa Tenggara province has declared major reduction of malaria cases and most of the districts have been downgraded to low transmission area [6]. Tis important achievement, however, may cause inadvertence and reluctance of physician to perform malarial screening. Te patient came from a low malaria-endemic district (East Flores) in Flores Island; hence, severe and life-threatening complications should not have occurred if diagnosis and surveillance of malaria had been performed properly. Fortunately, prompt treatment with intravenous artesunate and other appropriate treatment prevented the patient from deteriorating. Terefore, to modify the mortality risk, even in lowendemic malaria areas, physicians should remain meticulous and have high suspicion of malaria in patients presenting with nonspecifc manifestation. Additionally, lack of experience in malaria diagnosis and misdiagnosis of diseases in primary health care lead to delayed diagnosis and lifethreatening complications, ultimately increasing the mortality risk among patients [24].

Conclusion
Negligence and late diagnosis of malaria infection lead to severe complications and a worse prognosis. While several factors may infuence a patient's prognosis, intravenous artesunate must be initiated as early as possible to maximize the chance of recovery. Close monitoring and other supportive medical care are also critical. Despite major reduction of malaria cases in endemic areas, physicians should remain meticulous and eager to perform malarial screening even without specifc manifestations.

Data Availability
Te data used to support the fndings this case are included within the article.

Consent
Informed consent was obtained from the patient for his anonymized information and accompanying images to be published in this article.

Conflicts of Interest
Te authors declare that they have no conficts of interest.