Pathology of Malaria

1. Introduction

Malaria is an acute febrile illness that is caused by infection with Plasmodium spp. parasites. Malaria is a serious illness and sometimes it may be fatal resulting in mortality and morbidity.

There were an estimated 241 million malarial cases in 2020 higher than malarial cases in 2019 (227 million cases), a difference of 14 million cases. The rise in malarial cases is thought to be associated with the COVID-19 pandemic, that led to service disruption. The case incidence of malaria from 2000 has declined from 81 per 1000 populations at risk to 56 per 1000 populations at risk. However, in 2020 the case incidence has increased to 59 per 1000 populations at risk. Globally, death due to malaria in 2020 is reported at 627000 which is a rise as compared to the trends in malaria death that has a seen a drop from 896,000 cases in 2000 to 558,000 cases in 2019. It is estimated that 68% (47,000 cases) of the additional deaths due to Malaria are attributed to disruption of services following COVID-19 pandemic. Globally, the malaria mortality rate as of 2020 is 15 per 100,000 population at risk which is higher compared to 2019 which was 14 per 100,000 population at risk. Among children under 5 years, the mortality rate in 2020 increased to 77% as compared to 76% in 2019. Globally, 96% of the malaria cases and deaths were from 29 out of 85 countries with malaria-endemic. Nigeria (26.8%), the Democratic Republic of Congo (12.0%), Uganda (5.4%), Mozambique (4.2%), Angola (3.4%), and Burkina Faso (3.4%) account for 55% of the cases globally. Half of the mortality cases were from Nigeria (31.9%), the Democratic Republic of Congo (13.2%), The United Republic of Tanzania (4.1%), and Mozambique (3.8%). The WHO African region accounts for 95% of the malarial cases and 96% of the malarial deaths. In the African region, 80% of the cases are among children under 5 years. In Africa, the number of malaria cases in 2020 is 233 per 1000 populations at risk higher than in 2019 at cases per 1000 population cases. The South-east Asia region accounts for 2% of the malaria cases globally among the nine malaria-endemic countries in 2020. India accounts for 83% of malaria cases due to infection by Plasmodium vivax. The WHO Eastern Mediterranean Region accounted for 5.7 million cases in 2020 with the increase seen in Sudan, Somalia, and Djibouti. P. vivax accounted for about 18% of the cases mainly in Afghanistan and Pakistan. In WHO western Pacific region contributed to 1.7 million cases with an increase of 19% from 2019 cases. The malaria death increased to 3200 death in 2020 as compared to 2600 in 2019. WHO region of Americas registered a reduction in the case incidences by 58% between 2000 and 2020 with a resultant reduction in malaria death by 56% since 2000. Most of the cases in this region were due to P. vivax. In WHO European region, there has been free of malaria cases since 2015 with the last case reported in 2014 in Tajikistan with no malaria death from 2000 to 2020.

There are attempts globally to eliminate malaria in different countries. According to WHO a country is declared malaria-free following at least 3 consecutive years with zero indigenous cases. Islamic Republic of Iran and Malaysia reported zero indigenous malaria cases for the third consecutive year and while Belize and Cabo Verde for the second consecutive time. China and El Salvador were certified malaria-free in 2021 following 4 years of zero malaria cases [1].

2. Malaria pathogenesis and pathophysiology

The clinical picture painted in patients with malarial infection occurs following the release of the merozoites into the bloodstream following the rupture of infected red cells. The malaria parasite has a wide variety of symptoms which ranges from absent or very mild symptoms to severe cases and even death. Owing to this the infection is categorized into uncomplicated malaria and severe malaria. The incubation period varies depending on the individual factors and the species of plasmodium. The incubation period is the period of the introduction of the sporozoites to the development of the first symptoms. The incubation period varies from 7 to 30 days. However, P. falciparum has a short incubation period while P. malariae has a longer period.

The release of the merozoites from the rupture of the liver cells infects the red cells. In the infection with the P. falciparum, all stages of red cells are infected making the infection quite severe as compared to infection with other species which infects the old and young red cells only which contributes to a small percentage of red cells. The malarial parasites while in the red blood cells derive their energy primarily from the red cells. They can metabolize 70 times faster as compared to the red cells resulting in hypoglycemia and lactic acidosis. The rupture of the infected red cells releases the merozoites alongside the waste and toxic substances from the red cells. The released merozoites infect other healthy red cells in the circulation. Since the infected red cells are destroyed, and red cells are destroyed every time the merozoites infect new red cells, the patient experiences intravascular hemolysis. Intravascular hemolysis results in worsening anemia requiring immediate treatment and transfusion in a patient with very low hemoglobin levels (<5 g/dL). The intravascular hemolysis results in the production of hemoglobin that causes the urine to change and appear as dark colored in the patient. The intravascular hemolysis also causes an increased amount of yellow discoloration due to overloading the ability of the body to conjugate bilirubin causing jaundice on the sclera and mucous membrane and skin. The released products and toxic substances in ruptured red cells cause the body to release cytokines such as tumor necrosis factor (TNF) which contributes to fevers. An increase in body temperature results in sweating and chills. The merozoite surface antigen being foreign to the body as well evokes immune responses that lead to the production of the cytokines. These cytokines such as TNF, Interferon-gamma, and Interleukin-1 have the potential of suppressing the red blood cell production thus reducing the restoration of hemoglobin concentration, increasing fever, stimulating reactive nitrogen species production that causes tissue damage, and inducing endothelial receptor expression of P. falciparum erythrocyte membrane protein 1 (PfEMP1) which is responsible for sequestration. These cytokines as well irritate the vomiting centers resulting in the vomiting as part of clinical presentation.

The infected red cells appear sticky and adhered to the blood vessels causing obstruction of the blood flow and causing ischemia in the affected areas and organs. The sticky red cells as well clump together forming a rosette that if large enough have the potential to obstruct blood flow in major blood vessels. In addition, several proteins such as PfEMP1 contribute to the attachment of red cells on the endothelium leading to sequestration. The PfEMP1 bind to the endothelial cells through CD36, thrombospondin, VCAM1, ICAM1, and E-selectin. The sequestration of the red cells in the blood vessel endothelium and the ability of the body to take away damaged red cells mostly occur in the spleen contributing to splenomegaly in some patients. Sequestration of the red cells, and destruction of the red cells leading to anemia coupled with obstruction of blood flow results in the reduction of tissue perfusion causing fatigue, general body weakness, and ischemia.

3. Genetic factors and malaria

Genetic factors play a crucial role in influencing malaria infection. Two biological characteristics identified in protecting the certain type of malaria are sickle cell trait and negative for Duffy blood group [2].

Individuals with sickle cell traits are relatively protected from infection by P. falciparum. Sickle cell traits are individuals with heterozygous for abnormal hemoglobin gene S. The individuals have one copy of the abnormal hemoglobin gene HbS and a copy of normal hemoglobin gene HbA. P. falciparum cannot survive in the red cells with HbS conferring protection to individuals. The presence of sickle cell traits is mainly in areas with a high prevalence of P. falciparum in the WHO African region. According to the cohort study, the presence of the sickle cell trait confers 60% of the protection against overall mortality with the protection occurring between 2 and 16 months of life, before the development of the immunity.

People who are negative for the Duffy blood group have shown to be resistant to infection with P. vivax. The P. vivax infection is rare in West Africa because of the presence of Duffy-negative individuals that confer protection against the infection. P. ovale which can infect the Duffy negative red cells predominates in this setting.

Blood cell dyscrasias such as hemoglobin C. thalassemia and G6PD deficiency are prevalent in the malaria areas which confer protection against the infection.

4. Acquired immunity against malaria infection

Acquired immunity influences malaria infection in individuals and communities. Through repeated infection, an individual develops partially protective immunity. Despite the acquired immunity, the individuals may get infected by the malaria parasite but the severity of the illness will be less ad they may lack the typical symptoms. The acquired immunity allows the individual to mount the immune response to the presence of the parasite in the circulation leading to a reduction in the severity of the infection. The areas that have a high malarial infection such as P. falciparum in the south Saharan region in Africa have individuals with acquired immunity. The mother who has repeated infection with P. falciparum can confer protection to the newborn. While the newborn is in-utero, the maternal antibodies are transferred through the placenta to the fetus which confers protection to the newborn up to the first few months of life. After the reduction of the maternal antibodies in the circulation, the young children become susceptible to infection leading to an increase the infection. If the children survive the repeated infection to an older age of about 2–5 years, they attain acquired immunity. Owing to the acquired immunity in the areas of high transmission such as the WHO African region, there is increased mortality affecting the young population (90% of the mortalities were children in 2020 mortality cases) with less mortality affecting the adults. In areas where there is lower transmission such as Asia and Latin America, infection is minimal and few individuals are exposed to repeated infection. The individuals do not develop acquired immunity. Following the lack of acquired immunity, a larger proportion of the older children are as well affected by the epidemic of malaria infection.

5. Sickle cell disease and malaria

Despite the presence of sickle cell trait conferring protestation against malarial infection over the healthy population, the presence of sickle cell disease does not confer any protection. Sickle cell disease occurs when the individual has a mutation in both alleles resulting in homozygous HbS. Sickle cell disease carries the worst prognosis with infection by the malarial parasite, especially P. falciparum. The worst prognosis contributed to the reduced half-life of sickled red cells and increased ability to undergo sequestration. Coupled with hemolysis and reduced hemoglobin concentration among the sicklers, they easily undergo severe anemia and severe hypoxia which worsen sickling and obstruction of the blood vessel resulting in end-organ disease. Sickle cell disease does not tolerate infection with malaria infection requires immediate and aggressive management to improve the prognosis [2, 3, 4].

6. Clinical features of cerebral malaria

Cerebral malaria is the most severe neurological complication that arises following infection with P. falciparum. It is estimated that annually, 575,000 cases of children in the sub-Saharan region are affected by cerebral malaria. According to WHO, cerebral malaria refers to the clinical syndrome where there is coma at least 1 hour after termination of seizure or correction of hypoglycemia and presence of parasitemia for P. falciparum on the peripheral blood smear with other causes evident to causing coma. Loss of consciousness is the hallmark of cerebral malaria with coma being the most severe presentation. However, for a diagnosis of cerebral malaria to be made, the patient should have no other cause of coma such as viral encephalitis, metabolic disorder, and poisoning among others. Apart from the altered mental status, cerebral malaria may be followed by progressive weakness and prostration. In adults, cerebral malaria presents as one of the organ failures following end-organ disease with severe P. falciparum infection.

The development of cerebral malaria following infection with P. falciparum occurs in cases of high parasitemia. It is thought that infected red cells are sequestrated through the attachment on the endothelium that causes occlusion of the cerebral capillaries. This coupled with sequestration of the parasites cause reduction in blood circulation in the microvasculature resulting in a decreased supply of nutrients and oxygen. The obstruction of the blood flow shuts down energy production which is needed to maintain the blood–brain barrier. As a result, ischemia ensues and there is a neuronal alteration that causes cerebral swelling and increased the cerebral intracranial pressure. This leads to altered consciousness and retinal changes. The damage to the blood vessels as well leads to intracranial hemorrhage the leads to altered mental status. Cytokines and chemokine are also described as through a complex role in protecting and posing harmful effects in the pathogenesis of cerebral malaria. Schizogony triggers pro-inflammatory cytokines that may contribute to cerebral malaria while anti-inflammatory cytokine poses protective benefits. Unlike in bacterial and viral infections, altered mental status following P. falciparum infection does not result from the presence of the parasite in the brain parenchyma but due to cerebral occlusion that causes end ran tissue damage due to disruption of brain parenchyma.

Cerebral malaria is fatal and without treatment, the mortality rates increase exponentially. In children treated with intravenous antimalarial medication, the mortality is about 5–20%. However, despite the recovery, many children sustain significant brain injuries. About 11% have gross neurological deficits which may improve with time while 25% have long-term impairments, especially in cognition, motor, and behavior domain. About 10% develops epilepsy. The risk factors include seizures, deep and prolonged coma, intracranial hypertension, and hypoglycemia.

7. Congenital malaria

Congenital malaria refers to the infection with malaria parasite present in the peripheral smear of the newborn from 24 hours to 7 days of life. It is thought that the parasite can infect the placenta and gain access to fetal circulation. Congenital malaria is rare but it is fatal if not detected earlier in newborns. However, in areas where malaria is endemic, congenital malaria is rare as compared to other areas. This is because, in malaria-endemic areas, the maternal have had repeated attacks thus developing acquired immunity. The antibodies in the maternal circulation are therefore protected against the development of congenital malaria and protection in the early stages of life. The occurrence of congenital malaria is at 0.3% in the immune mothers and 7.4% in the non-immune mothers. The symptoms of congenital malaria occur within 10 to 30 days of life. They include fever, anemia, and splenomegaly in most cases. Other presentations may include hepatomegaly, jaundice, loose stool, and poor feeding among others. Since this presentation mimics most conditions in the neonates such as neonatal jaundice and neonatal sepsis, the diagnosis is often missed leading to mortality and morbidity [5, 6].

Congenital malaria is of concern among neonates. Given that the parasite is present in utero, the human body learns to recognize the parasite as self, contrary to the normal case where the parasite is considered an antigen to cause activation of immune responses. The parasite, therefore, can multiply and cause damage to red cells without evoking immune responses as in the case of a healthy individual. Therefore, the newborn experience excessive hemolysis and resultant organomegaly. Lack of the ability to recognize the parasite as an antigen coupled with an immature immune system allows the parasite to multiply necessitating immediate treatment to improve the outcome among the neonates. Owing to intravascular hemolysis, the neonates present with anemia and splenomegaly which are the most common forms of presentation. Intravenous antimalarial medication is essential in management [5, 6].

8. Gross and microscopic pathology

8.8 Central nervous system

As mentioned, the CNS presentation is due to the dissemination of malarial parasites into the brain, paroxysmal fever and side effects of antimalarial drugs. The patient presents with headache, vomiting, delirium, anxiety and restlessness during fever paroxysms, with symptoms resolving once the fever normalizes. Chloroquine, quinine, mefloquine and halofantrine can lead to vertigo, restlessness, hallucinations, confusion, delirium, tinnitus, dizziness, convulsions and sometimes frank psychosis. Quinine is associated with hypoglycemic coma, while artemisinin cause brainstem dysfunction based on animal studies [7, 9].

P. falciparum in CNS causes cerebral hypoxia and anoxia through impairing microcirculation as the parasitized red cells have decreased deformability and increased cytoadherence, causing occlusion of microcirculation. Malarial encephalitis and meningoencephalitis arise due to cerebral anoxia, the development of malarial granulomas and punctate hemorrhages [9].

Macroscopically, the brain is usually edematous during the autopsy, appearing leaden or plum colored with a cut surface slatey gray hue. The sulci are narrowed, and the gyri flattened due to brain swelling. The small blood vessels are congested with parasitized red cells. Mature forms of parasites including schizonts are found in brain biopsies. The large vessels demonstrate evidence of margination, where the parasites are arranged in a layer along the endothelium. Despite this, the endothelium also shows pseudopodial projections, which may be in close apposition to the knobs on the surface of parasitized red cells. There is numerous petechial hemorrhage proximal to the occlusive plug of end arterioles in the white matter. The ring hemorrhage is diffuse in the brain with hemorrhage containing fibrin, pigmented parasites, free pigments and admixed fibrin. The uninfected red cells are seen in surrounding hemorrhage. Diirck’s granulomata may be seen in areas of hemorrhage characterized by a small collection of microglial cells surrounding an area of demyelination. In addition, the brain demonstrates the abrupt transition from gray to white matter which, together with ring hemorrhage, are classical findings of cerebral malaria (Figures 1-3) [9].