Lecture of malignant malaria (Pernicious Falciparum Malaria)

2021-01-31 12:00 AM

The embolism of malaria parasitic erythrocytes was explained by these authors to be due to increased vascular permeability that causes plasma drainage.



Malignant malaria is a severe form of malaria, caused by P. falciparum causing blockage of small capillaries of the organs, especially the brain, leading to microcirculation disorders, on the other hand, Immunotherapy and the role of cytokines also influence the development of malignant malaria. If malaria is not treated early, the death rate is very high.


In 1986, Marc Gentilini et al. Used the noun malignancy (Acces pernicieux) of malaria caused by P. falciparum or cerebral malaria (neuropaludisme).

In 1987 Manson - Bahr et al. Used the term P. falciparum malaria (Pernicious falc. Malaria).

WHWernsdofer et al. Used the term malignant malignant malaria (malignant tertian malaria) (1988).

Suvalopva and Russian authors also use the term malignant (1976).

In 1986 DAWarrell et al. Proposed the term "severe and complicated malaria" (Severe and complicated malaria) with 10 main criteria:


Severe anemia (Hb < 5g / 100ml).

Renal impairment (urine < 400 ml / 24 hours and serum creatinine > 265 m ml / l).

Acute pulmonary edema or ARDS.

Hypoglycaemia (blood glucose < 2.2 mmol / l).

Shock (systolic blood pressure < 70mmHg).

Haemorrhage - intravascular scattered coagulation.

Systemic convulsions > 2 episodes / 24 hours

Blood acidosis (PH < 7.25 arterial blood, plasma bicarbonate < 15 mmol / l).

Haemoglobinuria (due to malaria).

There are also some other sub-standards such as:

High density of malaria parasites ( > 5% of the red blood cells infected with the parasite).

Jaundice (bilirubin  50 mmol / l).

High fever (anal temperature 40 ° C).

According to DA Warnell, for every one of the criteria above (both primary and secondary), it is referred to as severe malaria and complications.

In the late 80s and early 90s of the 20th centuries many authors used the term severe and complicated malaria to replace the word malignant malaria. Or, conversely, when reporting the number of malignant malaria cases, the statistics of cases with one of the criteria of severe malaria and complications leads to inconsistencies in concepts.

During a consultation conference on malaria by the Ministry of Health and the head board of the National Malaria Prevention Program in 1995 (in the presence of representatives from the World Health Organization on malaria in Vietnam) went agreed to use the term malignant malaria as before.

Mechanism of the pathogenesis of malignant malaria

A confirmed fundamental phenomenon in malignant malaria is the clumping of malaria parasite-infected erythrocytes in the deep capillaries of the internal organs causing microcirculation disorders. The consequences of this process deplete organizational oxygen and lead to impaired function, degeneration, and organ necrosis. However, the mechanism leading to erythrocyte clumping in capillaries is a complex problem and until now, it is not fully understood. Disorders of the immune response and the role of cytokines have also been referred to as pathogenesis of malignant malaria.

Hypothesis of the pathology of erythrocytes

The authors above suggest that the red blood cells infected with the parasite P. falciparum become hard due to thickening of the red blood cell membrane and bumps (Knobs). As a result, red blood cells cannot always spleen through the capillaries and they clump up, causing blockages. The result of capillary blockage is hypoxia and ultimately cell degeneration and necrosis.

Hypothesis of the pathology of the vessel wall

 The embolism of malaria parasitic erythrocytes was explained by these authors to be due to increased permeability of the vascular wall, causing plasma to escape from the cell space causing blood condensation and blocking. According to these authors, patients with malaria have inflammation of the vessel wall caused by toxins and chemical mediators of the malaria parasite. Thus, the phenomenon of organizational edema (cerebral edema in malignant malaria) is the leading pathological phenomenon to be concerned. Also, for that reason, there has been a long time in the treatment of the mechanism of cerebral malaria, many authors advocate against aggressive brain edema. They believe that the patient's coma is due to brain edema.

The hypothesis of cell adhesion (Cytoadherence)

Many authors found that there was an adhesion between P. falciparum infected erythrocytes and vascular endothelial cells. On the other hand, red blood cells infected with the malaria parasite bind to uninfected red blood cells.

They found adhesion points on the erythrocyte containing in the pot bud and other plaque areas, that is the Protein-rich Protein and Protein of the red blood cell membrane. Howard RJ et al. (1987) found that the sticky points were: HRP1 (Histidin rich Protein1), HRP.2, EMP.1 (erythrocyte membrane Protein 1), EMP.2 in endothelial cells also have Receptor corresponding to the adhesive points of the red blood cell membrane. Muanza K (1996) found 5 different tag receptors: CD36 (CD = Cluster of Differentiation), Thrombospondin, ICAM-1 (Intercellular adhesion molecule 1), VCAM-1 (Vascular Cellular Adhesion Molecular 1), E. Selection.

The phenomenon of adhesion between the erythrocytes infected with the malaria parasite and the uninfected erythrocytes is the rose-forming phenomenon. In 1992, Wahlgren M. found two components involved in rose-forming (rosettine) on the face of infected red blood cells.

The above three hypotheses explain the mechanical obstruction of malaria parasitic erythrocytes in the capillaries.

Hypothesis of an immune response disorder

Research by Michael F. Good (1997) and many other authors showed that cellular immune response has an important role in the pathogenesis of malignant malaria, especially TCD4. According to the authors, Lymphocyte T is crucial in host's immune response to malaria parasites. However, clinicians have found that malignant malaria usually occurs only in people who are new to malaria, not yet immune. In malaria endemic areas, in local people, malignant malaria is found only in children, rarely in adults and the elderly. Karlon DC (1994) demonstrated that the structure of the malaria parasitic antigen system is very complex. In addition to antibodies against the muscle malaria parasite antigens, the body also produces antibodies against toxins,

In the pathogenesis of malignant malaria, Cytokines were also seen such as: TNF (Tumour necrosis factor), NPT (Neopterin), IL- 6 (Interleukin- 6), IL- 10, IFN g (Interferon gama).). Many recent studies have demonstrated that in malignant malaria patients, TNF is greatly increased. On experiment, the authors also found that TNF caused some symptoms such as in malignant malaria such as hypoglycaemia, shock, increased cell adhesion. Conversely, using anti-TNF can prevent malaria from occurring or limit death in malignant malaria patients. Other cytokines (NPT, IL-6, IL-10, IFN g ) were also elevated in malignant malaria.

When using substances that resist or inhibit the above cytokines also reduce the disease situation of malignant malaria

Malignant malaria is an inflammatory process

Inflammation is simply understood as a pathological process manifested by symptoms: swelling, heat, redness, pain and dysfunction. In the late nineteenth century, Elic Metchloric discovered the role of macrophages in inflammation and was awarded the Nobel Prize. In the second half of the twentieth century, thanks to the development of biochemistry, researchers have found that many substances secreted in the inflammatory foci have high biological activity, playing an important role in the pathogenesis of the inflammatory process such as: Kinin, Serotonin, bradykinin, histamine ... In recent years, the development of immunology has allowed people to expand the concept of inflammation as a manifestation of the immune response, which plays a very important role. important in the root (NO) and the cytokines. Clark I> A (1996) found that when NO increases, it causes vasodilation, inhibits cellular respiration, causes cell necrosis of internal organs and leads to shock, heart failure. In 1996 Anstey NM also demonstrated an elevated NO in malaria patients. The level of NO increase is consistent with the severity of the disease. Thus malignant malaria in this respect is also an inflammatory process.

Above are just some theories about the pathogenesis mechanism in malignant malaria. This issue is under further study.

Classification of malignant malaria

As in the pathogenetic mechanism, the embolism of malaria parasitized erythrocytes can occur in any internal organs, when this phenomenon is prominent in any organ, we have malignant malaria. that body. However, it was found that mainly embolism occurs in the brain, so the cerebral body is also dominant. Malaria is divided into 2 groups: the group with coma and the group without coma (with visceral syndrome only). In other words, malignant malaria has 2 possible: The brain (coma) and the viscera (no coma). In the cerebral body is also divided: The brain is simple (usually the early stage) and the cerebral body combines with the viscera (usually the late stage).                                       

Malignant cerebral malaria (malaria caused by P. falciparum with coma and consciousness disorder)

Pure brain:

Cerebral type combined with one or more visceral syndromes with visceral complications:

Brain + circulatory failure / shock.

Brain + acute kidney failure.

Brain + acute liver failure.

Brain + acute respiratory failure (pulmonary edema / ARDS).

Visceral malignant malaria (pure visceral injury only, no coma)

Circulatory failure / shock.

Severe digestive disorders / cholera.

Acute liver failure.

Acute renal failure.

Acute pulmonary edema / ARDS.

Haemorrhage / CIVD (scattered intravascular coagulation).


Acute abdominal syndrome.

Clinical and diagnostic cerebral malaria


The clinical manifestations of cerebral malignant malaria are:

Coma (Severe consciousness disorder)

Approximately 80% of malignant coma cases of malignant malaria occur slowly after a few days of malaria attacks, then gradually go into a lethargic state or arousing delirium and then coma. About 20% of the remaining malignant cases have coma that occurs suddenly. A normally functioning patient suddenly falls unconscious and is struggling and may be accompanied by epileptic seizures. There are cases where the patient went into a coma and then had a fever later. The vast majority of coma cases are not accompanied by localized symptoms. Usually, with proper treatment with malaria drugs, the coma lasts only 1-3 days, very rarely have a coma lasting> 6 days if there are no complications of infarction or cerebral haemorrhage. After coming out of the coma, the patient fully recovers, with very little sequelae.

Seizure type seizures

About 20-30% of cerebral malignant malaria cases have epileptic seizures. Convulsions usually occur late when the patient has entered a deep coma. However, in patients with sudden coma, seizures can also occur from the first hours, day one. The majority of cases are convulsions of the whole body, lasting 1-2 minutes or less, sometimes 2-3 attacks / day or quickly 1-2 attacks / hour. Cases of rapid seizures are often accompanied by dyspnoea, cyanosis and a threat of suffocation, which require intensive resuscitation. A few patients with cerebral malignant malaria have Bravais-Jackson localized seizures (often jerky hands, feet, chewing muscles, eyeballs).

Localized neurological syndrome

In malignant cerebral malaria rarely has focal neurological syndrome. Often only localized signs are seen in complications of infarction or cerebral haemorrhage. However, in some cases of malignant malaria alone, when examining signs of pyramid damage (Babinski, Oppenheim, Gordon ...), both sides were positive due to the stimulated bundle.


Some patients with cerebral malignant malaria, whose coma occurs slowly, may develop psychotic manifestations before entering a coma. Psychological disorder manifestations are manifold, such as: Depressed, delirious, frantic walking, talking wildly. A few cases of psychosis reoccur after a patient exit the coma. However, these disorders only persisted for a few days and then returned to normal.

Diagnosis of brain malignant malaria

The goal of clinicians is to early diagnose malignant malaria from the pre-malignant stage because it is already late in the malignancy. Many studies summarize to show symptoms that have significant predictability of brain malignancy, also known as the threat of malignancy. These symptoms usually occur 1-2 days before malaria occurs.

Symptoms of 'pre-malignant syndrome' ranked in order of high to low predictive value are:

(1) Constant fever, WM-type fluctuations, flare-ups (2-3 attacks in 24 hours) or attacks lasting > 24 hours.

(2) Sometimes transient disorientation.

(3) Sleepless night 1-2 days.

(4) Sweat drops into drops.

(5) Lustful or stimulating (fluttering, struggling or sluggish lethargy).

(6) Severe headache.

(7) Enema (though not lethargic but forgotten).

(8) Gagging.

(9) The density of malaria parasites is > 40,000 / mm.

(10) Poop looseness water.

Warnell DA emphasizes four signs

High fever > 390C persistently.

Mental alteration (stimulation or inhibition).

Dense malaria parasites (> 2% of red blood cells are infected with malaria parasites)

Visceral damage, liver and kidney failure.

Diagnosis of malignant cerebral malaria when in malaria patients (with the parasite P. falciparum) is comatose. Therefore, it can be said that the first important symptom of cerebral malaria is coma, so some countries also call it "coma malaria". Of course, it is important to exclude coma from causes other than malaria (differential diagnosis).

Differential diagnosis of brain malignant malaria

With viral encephalitis.

With cerebral dengue.

With cerebral haemorrhage.

With a number of coma due to different etiologies: Hypoglycaemia, electrolyte water disturbances.


Diagnosis of cerebral malignant malaria is based on the following basic criteria:

There are symptoms of malaria and is confirmed by testing for the parasite (+) P. falciparum.

There is a coma whether it appears slowly or suddenly. After eliminating coma caused by other diseases. However, in order to avoid omission in the diagnosis, it is necessary to note the following points:

When no malaria parasites are found in peripheral blood, malignant malaria should not be excluded because the test depends on the staining, staining and examination experience. On the other hand, in some patients in the malignant phase (coma), malaria parasites in peripheral blood are very few but mainly concentrated in internal blood, so after treatment, patients out of the coma and then the peripheral blood test found the malaria parasite again.

Some cases of brain malignant malaria go into a sudden coma when the patient has never had a fever. Sometimes some of the first symptoms are atypical (diarrheal, abdominal pain, convulsions ...) mislead the diagnosis.

When exploiting the history of the escort, the patient was not known in the malaria endemic area, so he did not declare.

Treatment of brain malignant malaria

General principles of treatment of cerebral malignant malaria

Early detection and urgent emergency at the grassroots level. When there are symptoms predicting malignant malaria (pre-malignant), the patient must be treated with emergency care and treated like real malaria.

Specific treatment in accordance with the regimen: It is necessary to use fast-acting drugs, preferably by injection, especially intravenously. Pay attention to the correct dosage and the interval between giving drugs to maintain a constant concentration of drugs to kill parasites in the blood.  

Great importance to the care, monitoring and nutrition of malaria patients from the beginning.

Specific treatment

Specific treatment

Take one of the following drugs and regimens in order of preference:


Artesulfate: 60mg powder vial mixed with 0.6 ml of 5% sodium bicarbonate shake well, intramuscularly. In case of intravenous administration: add 5.4 ml of isotonic sodium chloride 9 0/00 or 6 ml of isotonic glucose (5%) for the full 6 ml, intravenously slowly 2-3 minutes.

How to inject: First hour: 2 vials, 8th hour: 1 vial. Days after each day inject 2 vials (if lethargic) or 1 vial if patient is awake. Use for 7 days.

Artemether: The drug dissolves in oil, so it is only injected intramuscularly, 100mg ampoules

How to inject: On the first day, inject 2 ampoules 8 hours apart. The days after each day 1 tube. Use for 7 days

Quinine dichlohydrate: 0.5g tube mixed with 250 ml of 5% glucose or 0.9% NaCL by intravenous infusion, every 6-8 hours, using 1 tube until the patient is awake, then switch to intramuscular injection or oral administration. Course of treatment 7-10 days.

Quinine chlohydrate: 0.5g tube intramuscularly, dose and time the same as quinine dichlohydrate.


Artesunat 50 mg tablet, dissolved in gastric tube.

Usage: When still in coma, take 1 capsule every 6 hours. When out of coma, take 1 capsule every 12 hours for 7 days.

Artemisinin 0.25g tablet, dissolved in gastric tube

How to use: At first 2 tablets, then take 1 capsule every 6 hours until awake 8 hours to take 1 capsule. Since the fever is gone, give 2 capsules / day for full 7 days.


Artemisinin suppositories: There are types of bullets 100mg, 200mg, 300mg. Using paediatric patients, people with malignant malaria who have vomiting a lot and in remote and isolated areas where there is no injectable drug, the gastric tube cannot be placed.

Dosage: 20mg / kg / day for anal administration until the patient is awake, then switch to drink for full 7 days.

Note: Do not use artemisinin suppositories for patients with diarrheal.

Combination therapy

To limit recurrence, add mefloquine or doxycycline (mefloquine 0.25 dose of 15-25mg / kg orally once. Doxycycline 100mg / day for 5-7 days)

Treatment of symptoms and complications

Adjust water disturbances, electrolytes and acid-base balance

Up to 75% of malaria patients lack water, electrolytes due to high fever, perspiration, vomiting, and diarrheal. Therefore, the addition of electrolyte water is very necessary. Isotonic solutions of NaCL 0.9%, glucose% or ringer lactate can be infused depending on the degree of loss. Adjusting metabolic acidosis by infusion of Sodium carbonate solution (1.4%, 5%, 7.5%).

Reduce fever, sedate, cut convulsions

When there is a high fever > 40 0 C ( > 390C in children), it is necessary to cool down with physical measures and paracetamol at a dose of 15mg / kg / 24 hours.

When the patient is restless and delirious, it is necessary to give sedative sedatives.

If the patient has epileptic seizures, depending on the severity from mild to severe, use: high dose Valium; seduxen + dolacgan; seduxen + dolacgan + gardenal. If the convulsions are continuous but the above methods cannot cut, then use 1% intravenous thiopental, intubated for mechanical ventilation.

Prevention and treatment of respiratory failure

Cerebral malignant malaria patients easily lead to respiratory failure due to sputum congestion, tongue drop, bronchitis inflammation due to superinfection ... Therefore, it is necessary to regularly suck phlegm to clear airways. Replace the barrel of a Krishaberg or endotracheal tube, carefully disinfect it. Regularly change the lying position, clap the lungs. Daily oral hygiene.

Monitoring, care, nurturing and nurturing

Malignant malaria patients should be monitored 24/24 hours (appoint a private nurse), often change positions for the patient (minimum 3-4 hours / time). Monitoring and timely detection of symptoms of dehydration, airway congestion, pressure sores, superinfection. Measure the amount of water in and out. Measure central venous pressure once a day and as needed.

Ensure nutrition from the start with soup and fluids through the gastrostomy tube. Get enough calories (about 3000 calories / day).

Tests to follow:

Malaria parasite, blood count, Haematocrit.

Urea, creatinine, electrolyte map (note K +).

Blood pH, lactic acid, HCO3-, PCO2, PO2, blood glucose.

Blood culture when infection is suspected.

Standard of discharge

Patient is completely awake, fever-free, malaria parasite free (at least 2 times negative).

Red blood cells > 3.5 million / mm3 of blood, leukocyte normal white blood cell formula.

Indicators: Pulse, blood pressure, breathing, normal urination.