Malignant malaria: autopsy findings and morphological features

Abstract

Background

Malignant malaria, resulting from Plasmodium falciparum infection transmitted by Anopheles mosquitoes, is a life-threatening emergency leading to high mortality rate in sub-Saharan Africa. P. falciparum infects red blood cells causing their aggregation and adhesion to the endothelial lining of small vessels. This microvascular sequestration can obstruct blood flow, leading to ischemia and perivascular hemorrhages caused by rupture of small vessels. In case of sudden death, diagnosis is possible only post-mortem by autopsy that play a crucial role in determining the accurate cause. Here, a case of cerebral malaria that resulted in death, detailing the relevant autopsy findings.

Case report

A case of severe malaria in a 54 years old woman, with a history of untreated multiple myeloma, who travelled for business purpose in Central Africa without taking antimalarial chemoprophylaxis, is reported. She presented at the hospital with fever, headache and asthenia with rapid progression to multiorgan failure (MOF) leading to death on day four since hospitalization.

Conclusion

As Plasmodium falciparum infection does not invariably lead to death, an autopsy was requested to determine the cause of death and to assess whether the infection was directly responsible or other factors were involved. This case highlights its iconographic importance, demonstrates scenarios relevant to pathologists, and underscores the need to always consider Plasmodium falciparum infection in the differential diagnosis of febrile travellers from malaria-endemic regions.

Introduction

In 2024, the WHO reported that malaria affected approximately 282 million people worldwide and caused 610,000 deaths, with 95% of these fatalities occurring in Africa [1]. Malaria is an infectious disease caused by protozoa of the genus Plasmodium and transmitted to humans through the bite of the female Anopheles mosquito, which acts as the biological vector. Human malaria may be sustained by six different Plasmodium species: P. falciparum, P. vivax, P. ovale curtisi, P. ovale wallikeri, P. malariae and P. knowlesi [2]. P. falciparum is the most frequently associated to the rapid progression toward severe clinical complications, with high risk for death, especially in young children, elderly, pregnant women and non-immune travellers [3]. Nevertheless, multi organ failure (MOF), with lung involvement and respiratory distress, have been described in other Plasmodia infections such as P.ovale and P. knowlesi [4, 5]. The life cycle of Plasmodium genus involves both mosquitoes and humans. When the mosquito injects the parasite in humans, it is incapable of infecting red blood cells (PRBCs) and must first pass through the liver. The parasite grows rapidly within hepatocytes, producing merozoites that can infect RBCs. The type of tissue damage is both ischemic and toxic. The ischemic damage is due to the loss of elasticity of the parasitized red blood cells (PRBCs) and consequent less ability to adapt to the wall of small vessels where they aggregate causing ischemia [6]. At the same time PRBCs produce TNF which induces endothelial cells to express tissue factor which is the main activator of coagulation [7]. It has been demonstrated that the more severe is the infection and the higher parasitemia the more coagulation cascade is altered leading to thrombocytopenia and hemostatic alterations in a procoagulant state [8]. Although the pathogenesis of Disseminated intravascular coagulation (DIC) in patients with severe malaria remains incompletely understood, a systematic review found that the estimated prevalence rate of DIC among individuals with malaria was 11.6%, ranging from 8.9 to 14.3% [9]. The repeated and continuous consumption of coagulation factors triggered by PRBCs lead to haemorrhagic diathesis with the appearance of petechiae (heart, lung, liver, brain, spleen), gastrointestinal and mucosal haemorrhages and severe brain bleeding. Ischemic, toxic and haemorrhagic damage lead to MOF, and eventually to death. This severe form of malaria primarily affects the Sub-Saharan Africa region; however, migration and travel from endemic areas have introduced this serious disease into non-endemic or malaria-free zones, such as Italy, which was declared malaria-free by the WHO in 1970 [10]. Healthcare providers in these regions might lack sufficient training to promptly recognize and effectively manage cases of severe malaria [3].

Case report

A 54-year-old woman with a history of multiple myeloma, diagnosed in 2019, was referred to the emergency room of a hospital in Rome due to asthenia, headache, and fever that had started the previous day. She reported having recently returned from a business trip to Central Africa without taking antimalarial prophylaxis. A chest CT scan revealed mild posterobasal interstitial edema bilaterally, accompanied by bilateral apical fibrotic thickening, but it was negative for pulmonary embolism. A malaria rapid diagnostic test (RDT) was positive for Plasmodium falciparum and peripheral blood smear confirmed the diagnosis showing a high level of parasitaemia (4.6%; 167,383 trophozoites/μL). The patient was subsequently transferred to National Institute for Infectious Diseases Lazzaro Spallanzani-IRCCS, Rome, Italy, where clinical examination was performed. At hospital admission the patient revealed normal consciousness (Glasgow Coma Scale 15), mild fever (T = 37.5 °C), normal blood pressure, normal breathing in room air and no neurological or meningeal signs. Blood tests showed mild anaemia (Hb 11,8 g/dl), thrombocytopenia (31.000 cells/μL) and leukopenia (1950 cells/µL), with mixed hyperbilirubinemia (4 mg/dl) and mild rise of creatinine (1,45 mg/dl), blood aminotransferases (AST 168 IU/L, ALT 202 IU/L) and lactate dehydrogenase (LDH 472 IU/L). At admission therapy with piperaquine tetraphosphate/dihydroartemisinin 320/40 mg (3 tablets daily) and ceftriaxone 2 g daily was started. The next day, her condition deteriorated rapidly with severe acidosis, intravenous artesunate 120 mg was initiated and she was subsequently transferred to the Intensive Care unit (ICU) with SpO2 at 91–92% and decreased urine output, requiring CVVHD. Extensive ischemic regions were noted on the patient's limbs and trunk. Gas exchange was profoundly compromised. Hemodynamic stability was maintained with noradrenaline administration. The patient required transfusions due to a haemoglobin decrease to 7 g/dL. Blood Polimerase chain reaction (PCR) confirmed P. falciparum positivity with no signs of mixed infection. Within 3 days, her condition progressed to critical, characterized by refractory hypotension and severe electrolyte imbalances. The patient died on the fourth day of hospitalization. Treating physicians required an autopsy. Brain injury is illustrated in Fig. 1 (macroscopical appearance) and Fig. 2 (histological picture). Brain sections showed a diffuse and severe subdural hematoma and markedly hyperaemic leptomeninges (Fig. 1a) associated with cerebral oedema. Pronounced haemorrhagic infarction (red softening) predominantly affecting the left cerebellar lobe (Fig. 1b), focally the right cerebellar cortex and the right temporal cortical region was observed. On coronal sectioning, multiple ovoid haemorrhagic areas (about 1 cm in diameter) were seen in the subcortical white matter of the right and left parietal region and the right and left parieto-occipital region (Fig. 1c). On cut surface a large area of red softening is showed in Fig. 1d. Hyperaemic areas (petechiae) were noted in the visceral pericardium and affecting the interventricular septum and the anterior wall of the left ventricle of the heart which appeared reduced in consistency. Lungs were slightly increased in volume (left lung 719 g, right lung 839 g). On cut surface the lower lobes of both lungs were diffusely and uniformly firm and consolidated while the upper lobes, in the apical subpleural region, showed thickened fibrous septa giving to the parenchyma a crazy paving-like appearance. The spleen and liver were normal in shape and volume (just a mild spleen weight increase of 225 gr) and congested on cut surface. No other remarkable findings were noted in the remaining organs except haemorrhagic areas in the medullary region of both kidneys. Microscopically several trophozoites and abundant malarial pigment (hemozoin) were present in most tissues such as brain, lung, liver, spleen, kidney. The brain parenchyma showed marked subarachnoid haemorrhage involving the pons, the occipital lobe and the cerebellar hemispheres, extending throughout all layers (molecular, granular, Purkinje cell layer, and deep white matter) of the left cerebellar hemisphere (Fig. 2a). Brain tissue showed widespread colonization of both intravascular and extravascular erythrocytes by protozoal parasites referable to P. falciparum (Fig. 2b). Brain vessels plugged with parasitized red cells were often occluded by microthrombi causing micro-haemorrhage and micro-infarcts. The “ring hemorrages” (Fig. 2c) as well as Dürck granuloma (Fig. 2d) are a hallmark of cerebral malaria and they demonstrate ischemic necrotic vascular lesions, vessel rupture, and immune reaction sustained by glial cells and macrophages. A widespread accumulation of hemozoin (malarial pigment) and trophozoites parasitizing red blood cells were found in spleen, kidney and liver and are shown showed in Fig. 3 (hemozoin accumulation and trophozoites parasitizing RBCs). Renal parenchyma revealed glomerulosclerosis associated with vascular wall fibrotic thickening and intraluminal accumulation of hemozoin and fibrin deposition. Glomeruli presented capillary dilation, caused by inflammation end endothelial dysfunction triggered by toxic products and cytokines induced by PRBCs (Fig. 3b, detail of Fig. 3a). Bilateral renal sinus haemorrhages surrounding necrotic vessel were visible, accompanied by neutrophils, hemozoin, and parasitized erythrocytes (Fig. 3c). Microscopic analysis of liver tissue highlighted hyperplastic Kupffer cells and macrophages in the sinusoids and within the portal tracts, both rich in malarial pigment (Fig. 3d); PRBCs were also noted in hepatic sinusoids. The spleen showed haemorrhagic suffusion. Numerous red blood cells containing parasites occupied the pulp cords of the spleen and were phagocytized by hyperplastic reticuloendothelial cells along with their fragments, free parasites, and hemozoin pigment; extramedullary hematopoiesis was also noted. Alterations of the myocardium are shown in Fig. 4 (macroscopic and histopathological changes of the myocardium). The myocardium showed cardiomyocyte hypertrophy, myofibers disarray (Fig. 4a) and dilation of vascular lumen filled by red blood cells parasitized by trophozoites associated with interstitial oedema and inflammatory infiltrates. Inflammation was represented by macrophages laden of hemozoin, lymphocytes and neutrophils that, occasionally, formed clusters around necrotic myocytes such as in the haemorrhagic necrotic area involving the anteroseptal wall, showed in Fig. 4b. The hyperaemic areas macroscopically seen within the myocardium (Fig. 4c) corresponded, histologically, to inflammatory infiltrates composed of CD3⁺/CD4⁺ T-lymphocytes (> 7/mm²), fulfilling Dallas criteria for myocarditis (Fig. 4d).

Fig. 1.

Hemorrhagic dura madre, hyperemic leptominges and cerebral edema (a); hemorrhage involving mostly left cerebellar hemisphere (b); multiple ovoid hemorrhagic areas (about 1 cm in diameter) within the subcortical white matter of the right and left parietal region and the right and left parieto-occipital region associated with infarction of the right temporal cortical region (c arrow and arrowhead); massive hemorrhagic infarction (red softening) affecting the left cerebellar lobe (d arrow)

Fig. 2.

Microscopic appearance of haemorrhage involving all layers (molecular, granular, Purkinje cell layer, and deep white matter) of the left cerebellar hemisphere (a H&E stain, original magnification × 100); several red blood cells, intra ed extravascular, parasitized by trophozoites of Plasmodium Falciparum, a yellow circle highlighted the accumulation of hemozoin pigment in RBCs (b H&E stain, original magnification × 200); necrotic, ring-shaped lesions of extravasated red blood cells called “ring hemorrhages”, the hallmark of cerebral malaria (c H&E stain, original magnification × 100); Durck Granuloma with macrophages highlighted by CD68 immunostaining (d anti-CD68 immunohistochemistry original magnification × 200)

Fig. 3.

Dilation of capillaries of the glomerulus (a H&E stain, original magnification × 100) and occasional parasitized RBCs (b H&E stain, original magnification × 400; a detail of a, highlighted by an arrow); renal sinus haemorrhages surrounding necrotic vessel (c H&E stain, original magnification × 100); Kupffer cells of the liver rich in hemozoin (d   H&E stain original magnification × 200, arrow highlights hemozoin in Kupffer cells)

Fig. 4.

Disarray of myocardial fibers (a H&E stain, original magnification × 100); haemorrhagic necrotic area involving the anteroseptal wall (b H&E stain, original magnification × 200); macroscopic appearance of the myocardium on transversal cut showing hyperaemic areas involving anterior and septal wall (c arrows) and the corresponding histological aspect with several lymphocytes within myocardium causing myocarditis according to Dallas criteria (d H&E stain, original magnification × 100)

Discussion

Neurological complications associated with malaria arise from infection by Plasmodium falciparum. Nonetheless, the mechanisms by which infected erythrocytes result in cerebral malaria, coma and eventually death remain incompletely understood. In-vitro studies demonstrate that parasitized erythrocytes adhere to endothelial cells through specific, receptor-mediated interactions involving host adhesion molecules such as ICAM-1. Notably, the expression of ICAM-1 on cerebral endothelial cells is upregulated during cerebral malaria as a component of systemic endothelial activation. Induction of local neuro-active mediators (like TNF alpha) may be responsible for the rapidly reversible symptoms of the coma of malaria [11]. The brain, and especially the cerebral cortex, are diffusely hyperemic due to the presence of numerous red blood cells in the capillaries, almost all of which are parasitized. The same is true for the leptomeninges, where the vessels are sometimes surrounded by yellowish-green streaks due to inflammatory infiltration by lymphocytes. Within the nervous system, hemorrhagic areas are observed, which microscopically correspond to occluded capillaries surrounded by blood leaks. Neurons exhibit progressive degenerative alterations culminating in neuronal loss. Areas of demyelination are evident, reflecting disruption of myelin sheaths. Notably, glial responses are characterized by the formation of Dürck's granulomas, which are indicative of a reactive process involving glial cell proliferation and macrophage infiltration in response to ischemic and necrotic vascular damage. These lesions, known as nodular formations, develop around blood vessels containing erythrocytes parasitized by Plasmodium or residual malarial pigment. The nodules are composed of glial and inflammatory cells arranged in a characteristic radial pattern. Notably, these lesions are persistent and do not resolve spontaneously. Despite appropriate therapeutic intervention, the associated mortality remains high, estimated at 15–20% [12]. Initial symptoms are often mild and resemble those of other acute febrile syndromes, making malaria difficult to identify without a clear epidemiological link. Traditionally, cardiac involvement has not been included as a frequent cause of morbidity and mortality. This could be due to underdiagnosing. Specific cardiovascular complications include electrocardiogram abnormalities, myocarditis, pericarditis, pericardial effusion, ischemic disease, and heart failure [13]. Our case showed severe myocarditis with disarray and necrosis of myocytes. Cardiac involvement seems to be rare from the low reporting incidence. In our case myocardial involvement, revealed by autopsy as acute myocarditis, has been responsible along with brain damage of severe course of the disease. Myocarditis is a potentially serious complication of P. falciparum infection, but it has also been reported with P. vivax [14, 15]. Our case report adds iconographic documentation to studies reporting cardiac involvement in malaria.

Despite improvements in antimalarial treatments and supportive care, mortality rates for malaria patients admitted to the ICU continue to be high. Severe malaria, often due to P. falciparum, can cause life-threatening complications like cerebral malaria, respiratory distress, acute kidney injury, shock, and co-infections, all increasing the risk of death. Recent analyses show that case-fatality rates for severe malaria in the ICU range from approximately 10% to 50%, depending on severity, complications, and quality of care provided. Additionally, cerebral malaria- a major neurological complication- carries an estimated 15–25% mortality rate even with intensive care management. Identify severe malaria patients at higher risk of death is of paramount importance. In the 400-patient cohort study conducted in France by Bruneel et al. three baseline variables independently predicted death: older age, coma and high parasite density [16]. Parasitemia > 2% is a major predictor of death in severe malaria. Impaired consciousness and coma, manifestations of cerebral malaria, is strongly associated with increased mortality. Renal dysfunction with elevated creatinine (≥ 3 mg/dL) and acute kidney injury correlate strongly with poor prognosis [17]. Variations in parasitic virulence, together with differences in the host’s immune response and underlying genetic polymorphisms, play a crucial role in shaping the distribution and severity of malaria across different geographic regions and among various age groups. Parasite strains differ in their ability to invade red blood cells, evade immune detection, and cause severe disease, which contributes to distinct regional patterns of infection. At the same time, host factors—such as the maturation of the immune system in children, acquired immunity in adults living in endemic areas, and inherited genetic traits like sickle-cell trait or G6PD deficiency- significantly influence susceptibility to malaria. These interactions between parasite biology and human genetics help to explain why malaria burden is often higher in certain tropical regions and why children typically experience more severe disease than adults, who gradually develop partial immunity after repeated exposure [18].

Conclusion

A detailed travel history and prompt recognition of epidemiological risk remain essential for the timely diagnosis of Plasmodium falciparum infection, especially in non-endemic settings. In cases of sudden or rapidly fatal disease, autopsy plays a crucial role in establishing the cause of death, revealing characteristic pathological findings of severemalaria such as disseminated intravascular coagulation, ring hemorrhages, and Dürck’s granulomas. This case highlights the value of comprehensive histopathological analysis, which demonstrated widespread multiorgan involvement and unexpectedly revealed, acute myocarditis—an underrecognized but potentially fatal complication of P. falciparum infection. Given the increasing frequency of imported malaria in Europe, pathologists and clinicians should remain vigilant for severe and atypical presentations, even in regions where malaria is not endemic. Autopsy findings such as those documented here are fundamental to improving recognition of life-threatening complications and deepening understanding of the disease’s pathogenic mechanisms.

Abbreviations

WHO

World Health Organization

MOF

Multi organ failure

RBCs

Red blood cells

PRBCs

Parasitized red blood cells

TNF

Tumor necrosis factor

DIC

Disseminated intravascular coagulation

CVVHD

Continuous veno-venous hemodialysis

PCR

Polimerase chain reaction

ICU

Intensive Care Unit

Author contributions

DC and FD: Conceptualization, data analysis, writing original draft. EN, AC, ADA, TAB interpretation of clinical data, contribution in writing original draft. PDM and EN supervision and resources. GG, MGB collected the data, supervision of the draft. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by funds allocated to the National Institute for Infectious Diseases “Lazzaro Spallanzani”, IRCCS, 00149, Rome, Italy, from the Italian Ministry of Healt Progetto P3,.Linea di Ricerca Corrente 1 “Malattie infettive tropicali e neglette: aspetti patogenetici, immunologici e diagnostici, 2025–2027”.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Formal approval from the Institutional Ethical Committee is not required by Italian law for publication of case reports regarding patients cured in research Institutes. Data are completely anonymized.

Consent for publication

Patient had written specific informed consent at hospital admission.

Competing interests

The authors declare no competing interests.