Afebrile falciparum malaria with severe hemolytic anemia in a returning traveler: a case report

Abstract

Background

Malaria classically presents with fever, however, atypical afebrile presentations can lead to significant diagnostic delays, particularly in non-endemic regions. We report an unusual case of afebrile Plasmodium falciparum malaria presenting primarily as severe hemolytic anemia in a returning traveler.

Case presentation

A 45-year-old Chinese man presented with a 12-day history of persistent dizziness, fatigue, and poor appetite. Upon transfer to our hospital, he developed acute confusion and quadriparesis. Laboratory tests revealed severe hemolytic anemia (hemoglobin 48 g/L), thrombocytopenia, and intravascular hemolysis. The patient remained afebrile throughout his illness. Neuroimaging ruled out acute intracranial pathology. Diagnosis was confirmed by peripheral blood smear showing P. falciparum (0.9% parasitemia, approximately 1746 parasites/µL), supported by HRP-2 antigen testing and PCR. Treatment with intramuscular artesunate followed by oral dihydroartemisinin-piperaquine led to full recovery and parasite clearance.

Conclusion

This report demonstrates that malaria can present as severe hemolytic anemia without fever. In elimination settings, heightened clinical suspicion and routine peripheral blood smear examination are essential for timely diagnosis in at-risk returned travelers. This case reinforces the need to maintain diagnostic vigilance for afebrile malaria, even in non-endemic regions.

Background

Malaria remains a major global health threat, with Plasmodium falciparum responsible for most severe cases and deaths. Although fever is the hallmark symptom, atypical presentations can occur—especially in semi-immune individuals or those with altered immune responses. We report a case of afebrile P. falciparum malaria presenting with severe hemolytic anemia and transient neurological symptoms in a traveler returning from Rwanda, illustrating diagnostic challenges in non-endemic regions.

Case presentation

A 45-year-old Chinese male was admitted to our neurology department following an acute neurological episode. He had worked in Rwanda as a brick kiln worker for three years and returned to China 23 days prior to admission. His symptoms began at a local hospital, where he reported a 12-day history of persistent dizziness, fatigue, poor appetite, and vertigo. Initial labs showed severe anemia (hemoglobin 52 g/L) and thrombocytopenia (52 × 10⁹/L). Despite transfusions of red blood cells and platelets, his anemia persisted—his hemoglobin rose temporarily to 67 g/L but dropped to 51 g/L the next day. Due to the unexplained rapid decline, he was referred to our hematology department for further management.

Upon arrival, while being moved from the vehicle, he experienced a sudden onset of confusion and weakness in all four limbs, manifesting as an inability to lift his extremities. This prompted an urgent neurological consultation. As cerebral infarction could not be ruled out, he was admitted to the neurology department with a preliminary diagnosis of “suspected cerebral infarction.” Notably, the patient regained consciousness spontaneously within a short time.

Past medical history was unremarkable, with no history of trauma, stroke, or seizures. Physical examination on admission revealed pallor, mild jaundice, and normal vital signs (blood pressure 99/60 mmHg, pulse 92/min, temperature 36.5 °C). Neurological examination showed clear consciousness, coherent speech, bilateral pupils equal and round (3.0 mm in diameter) with reactive light reflexes, normal eye movements without nystagmus, symmetrical forehead wrinkles and nasolabial folds, no facial deviation, and a midline tongue protrusion. Sensation to pinprick was symmetrical in all four limbs, with no muscle atrophy. Muscle strength was 5/5 in all limbs, muscle tone was normal, and the Babinski sign was negative. Brain MRI and MRA revealed no acute intracranial or vascular abnormalities. Comprehensive neuroimaging (MRI brain with MRA) showed no acute intracranial pathology or vascular occlusion. Given the normal neuroimaging findings and the resolved neurological symptoms in the context of profound anemia, the acute neurological episode was attributed to severe anemia-induced transient cerebral hypoperfusion.

Laboratory investigations at our hospital confirmed severe anemia (hemoglobin 48 g/L, RBC 1.54 × 10¹²/L) and thrombocytopenia (88 × 10⁹/L). The white blood cell count was within the normal range (7.59 × 10⁹/L). Reticulocyte count was significantly elevated (12.57%), with a strikingly high proportion being the immature fraction (50.8%), indicating a robust bone marrow erythropoietic response. Definitive evidence of intravascular hemolysis included markedly elevated lactate dehydrogenase (1188.5 U/L), unconjugated hyperbilirubinemia (total bilirubin 46.1 µmol/L), and hemoglobinuria (2 + occult blood). Glucose was mildly elevated (6.5 mmol/L), while the initial potassium level remained within normal limits (4.00 mmol/L). Glycated hemoglobin (HbA1c) was 5.70%, within the normal range. Cardiac enzyme profiles including creatine kinase (CK) and CK-MB isoenzyme were within normal limits. Autoimmune hemolysis was excluded (negative direct Coombs test), and G6PD activity was normal. Additional findings included markedly elevated inflammatory markers (C-reactive protein 92.28 mg/L, procalcitonin 0.93 ng/mL), significantly increased NT-proBNP (3672 pg/mL) and ferritin (1640.29 ng/mL) levels, and decreased serum albumin (26.61 g/L). Abdominal CT revealed splenomegaly. Bone marrow aspiration was performed to investigate the cause of severe hemolytic anemia, showing erythroid hyperplasia (49.75% nucleated RBCs) without dysplasia. Subsequently, on hospital day 5, the definitive diagnosis was unexpectedly established by microscopic examination of peripheral blood and bone marrow smears, which revealed P. falciparum infection with a peripheral parasitemia of 0.9% (approximately 1746 parasites/µL) (Fig. 1A-F). The diagnosis was confirmed by positive HRP-2 antigen testing and species-specific PCR. He was then immediately transferred to a specialized infectious disease hospital where he completed an additional 8 days of treatment and monitoring (total hospitalization: 13 days). The patient received packed red blood cell transfusions totaling 3.5 units for severe anemia during his hospitalization—2 units at our institution and 1.5 units at the infectious disease hospital. Antimalarial treatment consisted of intramuscular artesunate (available through local CDC stock), administered once daily with an initial dose of 160 mg on day 1 followed by 80 mg on days 2 and 4, and then oral dihydroartemisinin-piperaquine. The patient remained afebrile throughout his hospitalization.

Fig. 1.

Microscopic findings (Giemsa stain, ×1000). (A–C): Peripheral blood showing P. falciparum ring forms with “headphone” morphology and multiple infected erythrocytes. (D): Bone marrow aspirate with trophozoites. (E–F): Crescent-shaped gametocytes in peripheral blood (E) and bone marrow (F)

At 3-month follow-up, his hematologic parameters had normalized. No recrudescence occurred during 12 months of monitoring, with repeated smears confirming parasite clearance.

Discussion

This case of severe falciparum malaria presenting with afebrile hemolytic anemia provides important insights into both disease pathogenesis and clinical management challenges [1]. The patient’s clinical course was characterized by severe hemolytic anemia and acute neurological symptoms in the absence of fever, which directly contributed to diagnostic delay as clinicians initially focused on primary hematologic and neurologic disorders.

The observed hemolytic anemia stems from P. falciparum’s unique biological characteristics, including its ability to invade erythrocytes of all ages and induce membrane modifications through PfEMP1 expression, resulting in intravascular hemolysis and splenic sequestration [2, 3]. Significant thrombocytopenia was also seen—another known feature of severe malaria [4, 5].The underlying pathogenesis of afebrile Plasmodium falciparum infection in our patient remains unclear. The pathogenesis of these infections is complex, involving a delicate interplay between parasite factors, host immune responses, and environmental influences. Several mechanisms underpin the atypical presentation of afebrile malaria, including immune modulation, T-cell exhaustion, low parasite biomass, and strain-specific virulence [6–11]. In endemic areas, recurrent exposure leads to immune modulation, evidenced by elevated IL-10 production that downregulates proinflammatory cytokine responses [6]. Chronic antigen exposure may additionally induce T-cell exhaustion phenotypes, further blunting the inflammatory cascade [7]. While our patient had no documented malaria history during his three-year residence in Rwanda, the possibility of subclinical infections cannot be excluded. This immunological background, combined with potential low parasite biomass that fails to trigger robust immune activation [9] and strain-specific virulence variations [8], may collectively explain the atypical presentation.

The diagnostic challenges were particularly apparent in our non-endemic setting, where the absence of fever typically lowers suspicion for malaria, leading to a narrower differential diagnosis. In our patient, diagnosis didn’t occur until hospital day 5. The malaria was ultimately found almost by accident - during routine review of blood and bone marrow smears.

The patient’s acute neurological manifestations—transient confusion and limb weakness—initially raised suspicion for stroke. However, the absence of acute abnormalities on neuroimaging and rapid symptom resolution without neurological intervention argued against cerebrovascular etiology. Instead, the temporal correlation between severe anemia nadir and neurological symptoms, coupled with marked clinical improvement following transfusion, strongly supports cerebral hypoperfusion secondary to anemia as the underlying mechanism.

Although the confirmed malaria diagnosis raised consideration of cerebral malaria, the patient’s presentation didn’t meet WHO criteria, which require unarousable coma. His preserved consciousness apart from a brief syncopal episode, and lack of characteristic neuroimaging signs of cerebral malaria supported excluding this complication. The prompt neurological recovery with supportive care and antimalarial treatment further corroborated that the symptoms represented systemic consequences of severe anemia rather than direct parenchymal invasion by parasites.

These findings underscore a critical clinical imperative: malaria must be considered in any traveler from endemic regions, irrespective of fever history. This vigilance is particularly warranted when laboratory evidence indicates hemolysis or when acute neurological symptoms emerge. Our experience vividly illustrates the diagnostic pitfalls in malaria elimination settings, where atypical presentations can easily be misinterpreted. This case reaffirms the fundamental importance of meticulous travel history-taking and sustained competency in peripheral blood smear microscopy—practices that remain essential even in non-endemic regions.

Conclusion

In summary, this report reinforces that afebrile malaria represents a substantial diagnostic challenge, particularly when manifesting as severe hemolytic anemia. Heightened clinical suspicion, coupled with routine peripheral smear examination in at-risk returnees, is crucial to prevent diagnostic delays. Our case adds to the evolving understanding of non-classical malaria presentations and underscores the need for sustained diagnostic vigilance in elimination settings.

Abbreviations

MRI

Magnetic resonance imaging

MRA

Magnetic resonance angiography

G6PD

Glucose-6-phosphate dehydrogenase

CT

Computed Tomography

HRP-2

Histidine-rich protein-2

PCR

Polymerase chain reaction

CDC

Centers for Disease Control

WHO

World Health Organization

Author contributions

JL managed clinical care and drafted the manuscript. XC performed laboratory testing and data curation. JY conducted follow-up. JX assisted in figure preparation. ZL supervised and edited the manuscript. All authors read and approved the final manuscript.

Funding

None.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

This study was approved by the Ethics Committee of Ganzhou People’s Hospital (Approval No. PJB2025-186-01).

Consent for publication

Written informed consent was obtained from the patient for publication of this case report and accompanying images.

Competing interests

The authors declare no competing interests.