Tropical Medicine

موضوع: Tropical Medicine الأحد يونيو 30, 2024 1:20 pm

Malaria

course Description

Many clinicians lack the experience and caseload necessary to master malaria. This course will teach you to confidently tackle this disease in your clinical practice. You’ll learn about the parasite’s life cycle and epidemiology, taking a proper travel history, how to prevent, diagnose, and treat infections as well as get your patients to experts in time to save their life.
Malaria results from infection with various species of the parasite plasmodium
Plasmodia are classified according to the features of the apicomplexan seen on the apex of the organism, which helps them attach to the RBSs & entery.
when this parasite begins to divide, plasmodium like any other coccidian parasite it will fill up the RBC with berri-like structures
90%of malaria distributionis in the subsaharan areain africa. most of these about 190 million cases a year are caused by plasmodium falcipaurm, the most deadly form.

Plasmodium vivax is the next mostly common form, then p. ovale & P.malariae. P. knowlesi is the rarest form in SE Asia & is a zoonosis since it is passed from animals to humans.
P.ovale & malariae have world-wide distribution but are not very common overall with low incidence.
How can one become infected with malaria {malaria transmission & infection}?
1st, one has to be bitten with one or several species of Anopheline mosquitoes. after this infected mosquito takes a blood meal, it injects crescent-shaped or needle-like structures called sporozites into the victim's blood stream.
Like any other foreign body in the blood stream, sporozites are picked by one of the main RES organs the liver. waiting in the liver, foriegn bodies as sporozites & tissue macrophages called Kupffer cells ingest the sporozites, but donot stay there; as it is able to escape the kupffer cell, & enter a hepatocyte.
the sporozoite transitions to the Asexual form of the organism & can multiply Asexually until they fill up the hepatocyte
Plasmodium reproduces by multiple fissions.The nucleus produces many nuclei by undergoing division. The nuclei result in the formation of daughter cells.
The hepatocyte (liver cell) which of full of dividing malaria parasites is called a liver schizont

This Asexual proliferation occurs in splitting in a process called schizogony

Up to this stage, the pt not yet show any clinical signs of malaria.
Eventually this schizont (infected liver cell), ruptures releasing these little coccidian parasites called Merozoites into the blood stream.
Merozoites invade the RBCs in the blood stream & continue the process of schizogony in the RBCs producing Red cell schizonts.
Eventually, this RBC will burst releasing more of these merozoites, which will find another RBC & the process starts again; this cycle is what causes the periodic fever & chills which are the classic very early manifestations of malaria.
Every time a schizont bursts releasing merozites into the blood stream, the immune sytem is activated causing
fever & chills.
next is the sexual cycle

https://app.medmastery.com/courses/7005/lessons/7560

موضوع: Plasmodium sexual cycle الإثنين يوليو 01, 2024 3:54 pm

For the sexual cycle to take place the mosquito has to bite somebody who actually has malaria.
After being taken by a Red cell, some merozites don't undergo schizogny; instead these cells become sexual structures called Gametocytes.
There are approximately 5 million Red blood cells in each cubic milliliter of blood; So when a mosqiuto bites someone with malaria, that is a very good chance to pick up one or more of these cells which have just became gametocytes.
The mosquito takes a male & female gametocytes into her proboscis with the blood meal.
Down there in the belly of the mosquito, they mate to form an egg which moves, & called an Ookinete (a kinetic egg). The egg eventually becomes a cyst (an Oocyst) which as it matures releases sporozoites
The sprozoites then travel to the probosis of the mosquito where they can be injected into it's next victim infecting them with malaria; Now the lifecycle is cpmpete.

The proboscis is an essential head appendage in insects that processes gustatory code during food intake, particularly useful considering that blood-sucking arthropods routinely reach vessels under the host skin using this proboscis as a probe.

موضوع: plasmodium life cycle الثلاثاء يوليو 02, 2024 2:29 pm

Identifying RBC invasion
How does the parasite invade RBCs
As stated earlier, the malaria parasite has a unique apical complex. Once the merozoite bumps into a red cell,

The process of invasion involves attachment to the erythrocyte surface, orientation so that the apical complex (which protrudes slightly from one end of the merozoite and contains the rhoptries, the micronemes and dense granules) abuts the red cell and then interiorization takes place by a wriggling or boring motion
Merozoites attach to erythro- cytes by specific receptors that determine the host cell range for each species of malarial parasite. The attachment triggers the parasite to release a chemical mediator that induces deformation and endocytosis of the erythrocyte membrane.
Each merozoite can infect a red blood cell. Within the red cell, the merozoite develops to form either an erythrocytic-stage (blood-stage) schizont (by the process of erythrocytic schizogony) or a spherical or banana-shaped, uninucleate gametocyte.
During the blood-stage of infection with Plasmodium spp., the merozoite form of the parasite invades red blood cells (RBCs; reticulocytes and mature erythrocytes) and replicates inside them. Cycles of blood-stage replication take approximately 48 h for P. falciparum and P. malariae.
In the bloodstream, the merozoites invade red blood cells (erythrocytes) and multiply again until the cells burst. Then they invade more erythrocytes. This cycle is repeated, causing fever each time parasites break free and invade blood cells.

When an infected mosquito takes a blood meal from a vertebrate, it also injects sporozoites into the skin. The motile sporozoite enters the bloodstream, which enables it to reach the liver and thereby escape host immunity or drainage through the lymphatic system. Once sporozoites have reached the liver sinusoids, they cross the sinusoidal barrier and enter into hepatocytes, in which they establish a parasitophorous vacuole and differentiate in a first round of asexual replication. Over the course of 2 days to several days (dependent on species), a multinucleated exo-erythrocytic schizont (or meront) containing thousands of daughter merozoites forms.

The parasitophorous vacuole is a vacuole found in the host cells where most apicomplexan parasites reside and develop. During host cell invasion, the apicomplexan parasites initiate the formation of a membrane (the parasitophorous vacuolar membrane), which surrounds the intracellular parasite.

Some parasite species, such as P. vivax and P. ovale, can then enter a period of latency by forming a non-replicating hypnozoite instead of a schizont. These hypnozoites enable long-term survival of the parasite and can lead to relapses. Upon egress from the hepatocyte, merozoites are clustered in membrane-bound vesicles called merosomes and released back into the bloodstream via the liver sinusoids.
Merozoites invade red blood cells (RBCs), in which a second asexual schizogony takes place. This asexual replication cycle produces up to 32 merozoites over the course of 24–72 h (both parameters vary between species). Through repeated rounds of invasion and growth, the parasite establishes acute and, eventually, chronic infections. Some species, such as P. vivax, are restricted to reticulocytes, which make up a small fraction of circulating RBCs, thereby limiting total parasitaemia. Others, such as P. falciparum, are not restricted and may infect a high proportion of RBCs leading to high parasite burden, a factor implicated in the capacity of P. falciparum to cause severe disease.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7223625/

plasmodium life cycle contd

Life cycle of Plasmodium falciparum in humans and mosquitoes.
P. falciparum sporozoites are injected into the skin during the blood meal of an infected mosquito. They will migrate to and enter a blood capillary. Through the bloodstream, the sporozoites reach the liver sinusoids and there they leave the blood circulation to invade a hepatocyte, after multiple transmigration events. In the hepatocyte, they undergo one asexual replication cycle that results in a liver schizont containing thousands of merozoites. The merozoites enter the bloodstream in membrane-bound structures termed merosomes. Once released, merozoites infect red blood cells to initiate the intra-erythrocytic parasite cycle. In the blood, P. falciparum parasites undergo cycles of asexual replication. After invasion of a red blood cell, they develop from ring stages to trophozoites and then to schizonts. Mature schizonts burst to release merozoites that initiate another replication cycle.
A subpopulation of parasites commits to produce male and female sexual progeny or gametocytes

A female Anopheles mosquito picks up gametocytes while feeding on an infected human. Male and female gametocytes undergo gametogenesis within the midgut of the mosquito. The gametes then fertilize to form a zygote, which further develops into motile ookinetes. Ookinetes cross the midgut epithelium to form an oocyst beneath the basal lamina. In the oocyst, thousands of sporozoites form, which upon bursting of the oocyst wall enter the haemolymph to invade the salivary gland. From there, sporozoites are transmitted to the next human during the subsequent mosquito bite, closing the complex life cycle of the parasite.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7223625/

Tropical Medicine 41579_2019_306_Fig1_HTML

Tropical Medicine 41579_2019_306_Fig1_HTML

موضوع: The sexual cycle الثلاثاء يوليو 02, 2024 6:50 pm

The sexual cycle is initiated when a small proportion of asexual parasites commit to produce sexual progeny, that is, gametocytes. 1/Mature gametocytes can circulate in the human blood for several days, which maximizes their chance of transmission to mosquitoes. 2/A few minutes after entering the mosquito midgut, both male and female gametocytes use proteases to exit the RBCs 3/and differentiate into A/eight microgametes and B/one macrogamete, respectively, which C/fuse to produce the zygote. 4/The zygote transforms into a motile ookinete, which 5/crosses the epithelial layer of the midgut wall to form an oocyst. In the oocyst, parasites undergo the 6/third cycle of asexual replication to produce thousands of sporozoites that are released into the haemolymph. Sporozoites that reach the 7/salivary glands of the mosquito A/ attach and B/invade the gland, where they remain until C/ transmitted to a new vertebrate host through a mosquito bite, to start the cycle again.

Gametocytogenesis

The rate of commitment to sexual development varies widely between species and is determined by a combination of genetic, epigenetic and environmental factors. Initial studies identified chromosomal deletions that lead to the loss of gametocytogenesis of P. falciparum during in vitro culture and of P. berghei in mice^7,8. A few years ago, genetic studies in P. falciparum and P. berghei^9,10 identified an essential transcriptional activator of sexual commitment, ap2-g. The ap2-g locus is epigenetically silenced in asexual parasites through the cooperative action of heterochromatin protein 1 (HP1)¹¹ and histone deacetylase 2 (HDA2)¹².
Recently, it was demonstrated that the perinuclear protein gametocyte development 1 (GDV1)¹³ directly interacts with HP1 and derepresses the ap2-g locus¹⁴, leading to ap2-g transcription and sexual commitment in a subset of schizonts.
In P. falciparum, the rate of sexual commitment is sensitive to environmental factors and can be altered depending on in vitro culture conditions^15–17.
Recent work revealed that physiological levels of the human serum phospholipid lysophosphatidylcholine (LysoPC) can repress sexual commitment in vitro^17,18. LysoPC thereby functions as an environmental signal for nutrient availability in the host as its metabolites are required for membrane biosynthesis and, hence, parasite replication. Whereas ap2-g is conserved across Plasmodium species, the gdv1 locus and the repressive activity of LysoPC are absent in the subgenus Vinckeia, a rodent malaria lineage of Plasmodium. Besides ap2-g, the earliest detectable transcriptional signature of sexual commitment is an increased expression of a subset of invasion markers^17–20. A second wave of induced genes encodes many proteins that are exported into the host RBC, the functions of which are discussed below. The process of sexual commitment has been summarized and discussed in detail elsewhere^21,22.
Depending on the species, gametocyte development takes 1–12 days and results in infectious male and female forms (Fig. 2). At 9–12 days, P. falciparum has the longest (known) gametocyte development, which spans five morphologically distinct phases (stages I–V)²³. All other studied species from the primate, rodent and avian lineages show subtle morphological changes during gametocyte development and a cycle time between 24 and 60 h (ref.²⁴).
During gametocyte development in P. falciparum a continuous sheath of microtubules assembles. The microtubules are attached to an array of alveolar sacs beneath the plasma membrane of the parasite, which is called the inner membrane complex (IMC). An IMC can also be found in sporozoites and ookinetes, in which it is required for cellular motility and passage across the sinusoidal and epithelial barrier, respectively. In P. falciparum, the establishment of the IMC during early gametocyte development coincides with modifications of the cytoskeleton of the infected RBC (iRBC), including integration of exported parasite antigens, and results in a reversible stiffening of the iRBC^25–27. Consequently, stage II–IV gametocytes are more rigid than stage V gametocytes. Interestingly, the characteristic features of the P. falciparum gametocytes (continuous IMC and alterations to RBC cytoskeleton and rigidity) are absent in asexual blood-stage parasites, suggesting fundamental differences in the biology between these two blood stages. It is unclear whether these features are limited to P. falciparum gametocytes (and closely related species of the subgenus Laverania) or whether they are more conserved across the Plasmodium lineage.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7223625/

Tropical Medicine 41579_2019_306_Fig2_HTML

Tropical Medicine 41579_2019_306_Fig2_HTML

Sexual development of Plasmodium falciparum.
A subset of schizonts commit to the sexual cycle, producing sexual merozoites. Merozoites and young gametocytes (green) home to the bone marrow, leave the sinusoids and enter the parenchyma. Alternatively, the gametocytes form in the parenchyma from committed schizonts. In the bone marrow parenchyma, gametocytes develop from stage I to stage IV. Remodelling of the membrane of the host red blood cell (red) results in transient deposition of surface antigens (orange) and a reversible increase in cellular rigidity (purple). Restored deformability during maturation to stage V gametocytes triggers their release back into the bloodstream, where they can be taken up during another mosquito bite. Asexual replication in the bone marrow parenchyma most likely contributes to the accumulation of asexual parasites and sexual commitment in this compartment.

Vascular sequestration

P. falciparum can induce cytoadherence of iRBCs to the endothelial cell lining of capillaries and venules in various tissues (Fig. 3), and this process is a major pathogenic mechanism in cerebral and placental malaria^28–30. Only trophozoites and schizonts cause cytoadherence and sequestration of iRBCs, whereas iRBCs containing ring-stage parasites remain in circulation. Uninfected RBCs and ring-stage iRBCs are biconcave; by contrast, RBCs infected with later asexual stages are spherical, less deformable³¹ and more permeable for small solutes³², and their cytoadherence prevents clearance in the spleen. In vitro studies under static and physiological shear flow highlighted the similarities between iRBC cytoadherence and the mechanisms of vascular adherence of leukocytes during an inflammatory immune response after injury³³. In P. falciparum, the variant surface antigen P. falciparum erythrocyte membrane protein 1 (PfEMP1)^34,35 is the major determinant of cytoadherence. Electron-dense structures called knobs lift PfEMP1 above the dense coat of RBC surface receptors, which facilitates interactions between PfEMP1 and endothelial receptors, such as CD36, intercellular adhesion molecule 1 (ICAM1), chondroitin sulfate A (CSA) and endothelial protein C receptor (EPCR), causing iRBCs to adhere and sequester in the microvasculature and removing them from circulation. Individual PfEMP1 variants have differential binding affinities to host receptors, and the organ-specific distribution or activation of these host receptors determines disease development. Binding of PfEMP1 to EPCR²⁸ and ICAM1 (ref.³⁶) is crucial for brain sequestration (and causal for cerebral malaria), whereas the interactions with CSA³⁷ and IgM³⁸ are required for sequestration in the placenta (and causal for placental malaria). PfEMP1 is the major target of host immunity on the iRBC³⁹ and is under strong selection to maximize its ability both to evade immunity and to bind host receptors. The role of other surface antigens, such as repetitive interspersed families of polypeptides (RIFIN)^40,41 and subtelomeric variant open reading frame (STEVOR)^41,42, in cytoadherence of P. falciparum is less clear. However, both variant antigens have been implicated in rosetting, a sequestration mechanism in which iRBCs bind to uninfected RBCs to form clusters that obstruct the microvasculature^42,43. Parasite-induced modifications of the cytoskeleton and surface of iRBCs, in particular knob structures, increase the likelihood of clearance in the spleen owing to altered biophysical properties of the iRBC. Hence, cytoadherence of iRBCs actively prevents parasites from being in the circulation and, thereby, passing through the spleen. Plasmodium coatneyi is the only parasite in the primate malaria lineage that is known to induce knob-like structures and cytoadherence⁴⁴. The parasite determinants are unknown, however, as both of the major knob components — knob-associated histidine-rich protein (KAHRP) and the major surface ligand, PfEMP1 — are limited to P. falciparum and other members of the Laverania subgenus and, therefore, are absent from P. coatneyi. On the other hand, P. vivax increases the deformability of host cells during asexual blood-stage development to facilitate passage through the spleen, and there is no conclusive evidence for parasite accumulation in the brain or placenta and associated pathology in this species⁴⁵.
Tropical Medicine 41579_2019_306_Fig3_HTML

Tropical Medicine 41579_2019_306_Fig3_HTML

Intravascular sequestration of Plasmodium falciparum.
Trophozoite and schizont stages of asexual P. falciparum parasites (blue) sequester in the capillaries of several organs, including the brain, lung, spleen and bone marrow. Cytoadherence of infected red blood cells (red) to endothelial cells and to uninfected red blood cells (rosetting) facilitates sequestration. The main parasite ligand is P. falciparum erythrocyte membrane protein 1 (PfEMP1), which is exposed on the surface of infected red blood cells by knob-like structures. The different variants of PfEMP1 interact with diverse endothelial cell receptors, such as endothelial protein C receptor (EPCR), intercellular adhesion molecule 1 (ICAM1), platelet and endothelial cell adhesion molecule 1 (PECAM1) and CD36. In pregnant women, P. falciparum also sequesters in the placenta through the interaction of the PfEMP1 variant var2CSA and the placental receptor chondroitin sulfate A (CSA). Ligand receptor interactions involved in rosetting are not clearly defined, but likely involve repetitive interspersed families of polypeptides (RIFIN) and subtelomeric variant open reading frame (STEVOR) as well as PfEMP1.

موضوع: GLOSSARY الخميس يوليو 04, 2024 1:03 pm

GLOSSARY

Gametogenesis	Maturation of male and female gametes.
Meiosis	Cell division involving chromosome duplication and genetic exchange.
Sporozoites	The only parasite stage that can invade the vertebrate host upon insect bite.
Sinusoids	Special capillaries lacking a basal lamina and present in the bone marrow, liver, spleen and adrenal glands.
Parasitophorous vacuole	A membrane compartment surrounding the parasite and separating it from the host cell.
Schizont	Or meront. A replicative parasite stage in the vertebrate host producing daughter merozoites.
Merozoites	The only parasite stage that can invade red blood cells.
Hypnozoite	A non-replicative dormant parasite stage in the vertebrate host liver that can reactivate and lead to relapses.
Reticulocytes	Immature red blood cells developing in the bone marrow before final maturation in the blood circulation.
Microgametes	Male gametes.
Macrogamete	Female gamete.
Zygote	A union of male and female gametes where meiosis takes place.
Ookinete	A motile zygote that forms the oocyst upon crossing the basal lamina of the mosquito midgut.
Oocyst	A replicative stage in the mosquito host producing daughter sporozoites.
Haemolymph	Equivalent to blood in arthropods and other invertebrates.
Haematopoietic stem cells	A cell type that gives rise to all blood cells in the process of haematopoiesis.
Parenchyma	An extravascular compartment of the bone marrow where haematopoiesis takes place.
Phanerozoites	Secondary exo-erythrocytic schizonts in avian and reptile malaria parasites.
Dyserythropoiesis	Defective development of red blood cells, or erythropoiesis.
Central tolerance	The process of eliminating developing T and B cells that are reactive to the self.
Recrudescence	The recurrence of detectable parasitaemia upon clearance to submicroscopic levels.

Identifying RBC invasion contd
How does the parasite invade RBCs

As stated earlier, the malaria parasite has a unique apical complex.
Once the merozoite bumps into a red cell, it can rearrange itself by this apical complex & do further things as follows.
On the parasite surface there is a protein referred to as P1 13, which is always* present.
*This parasite makes another protein called RH5 which is able to attach to P113

*The RH5 is able to bind to a receptor on red cell membranes called Basigin, So the organism sticks to red cell & begins to invade.
*This junction then moves up the surface of the parasite allowing the parasite to move further through the membrane till it enters into the red cell.
*In the 1st 5 minutes of invasion, yu will see a tiny bit of cytoplasm & a dark nucleus entering the red cell.
*Then Ring form Trophozites can be identified which is a further develoment of the malaria parasite.
*A trophozite is the active feeding stage of some protozoa.
*These ring trophozites look like a tiny signet ring, which in 24 to 36 hours, take a more amorphous shape.
At the same time yu begin to notice some pigment in the center*

*Then at 36 to 48 hours depending upon the specific parasite, more pigment will appear.
* NOW schizogny splitting is taking place, & there will be a more mature schizont, which is about to get ready to burst the red cell.
*Yu remember that the bursting of the red cell coincides with the development of fever.
SO What actually happens when the parasite invades a red cell?
1 Once inside the red cell, it takes hemoglobin from the red cell by Pincytosis.
2. It 1st breakes it down into Heme, then Hematin. Both of these pigments are lethal to malaria parasite, but lucky for the parasite, it has got heme polymerase, an enzyme that quickly converts these into the non-toxic pigment hemozoin.
3. The parasite will use hemozoin to form its aminoacids.
Types of red cells in a blood smear
1. young red cells known as Reticulcytes are larger than older cells
2. Regular size mature erythrocytes
3.Senescent erythrocytes : as red cells age, they become less osmotically stable & instead of round up, they become smaller.
* Different species of plasmodium are able to invade red cells at different stages of development.
*P. vivax, P. ovale, & P. knowlesi have receptors for reticulocytes & only invade reticulocytes, so only a small percentage of red cell will be infected,& the pt will is not going to have high levels of parasitemia,i.e only low grade parasitemia.

* In contrast, P. malariae only invades senescent (older) red cells which are smaller & less abundant.
* P. falciparum doesn't care, & it will invade any age of red cell, & this is why p. falciparum is so dangerous with high grade parasitemia, & this is why it is so deadly.
* In atypical blood profile, young & old red cells are only minority & comprise 1-2% of all erythrocytes

https://app.medmastery.com/courses/7005/lessons/7562

Discerning factors that affect infection

Humans posses some protective mechanisms against malaria infection :
1/ Genetic Factors

1. Sickle cell trait is A/ one of the commonest genetic defences which B/ is present in about 10% of Africans, & in a smaller percentage in Spanichs & people from middle east C/ individuals with sickle cell trait carry one abnormal Allele of Beta hemoglobin (Hb) gene which D/ causes some cells to take on an abnormal sickle shape. E/ these individuals generally don't show severe symptoms of sickle cell disease But F/ have a reduced susceptibility to infection by P. falciparum.
2. Hb AC is another A/genetic trait that affects the shape & structure of red cells B/ pts generally don't show symptoms, but the presence of this trait also protects against infection by P.falciparum malaria.
3. Beta thalassemia individuals are also A/ at a lower risk of contracting P. falciparum malaria, B/ because pts with Beta thalassemia have a persistence of fetal hemoglobin (Hb F) which C/ is not easy to be broken down by malaria hemogloinases, D/ making these cells somewhat resistant to the malaria parasite.
4. Hereditary Ovalocytosis is A/ another genetic trait that provides some resistance to infection by malaria parasite. B/ The abnomal shape of the cells interfers with the parasite ability to adhere, invade, & grow within the red cells.
5. Glucose 6 Phosphate Dehydrogenase Deficiency (G6PDD) which is also A/ present in about 10% of Aficans, is another genetic trait which is B/ protective against infection with P. falciparum malaria by C/ preventing growth of the parasite.
6. The Duffy antigen, A/ which is present in most RBCs of Caucasians, is an B/ immune chemokine receptor that can be Hijack-jacked by plasmodium vivax to help allow to invade the red cell. C/ Many Africans are Duffy antigen negative, once again a genetic factor that probably protects against vivax malaria.
   How vuruse Hijack part of your immune system

An enzyme intended to prevent autoimmune disease can be hijacked and used by some viruses to avoid immune detection.

2/ Acquird Immunity
1.If yu are A/ exposed to malaria, yu will develop anti-malaria antibody which B/ will confere some resistance against future infection. So those who had been C/ previously infected with malaria & survivSed especially those in endemic areas will be less susceptible to future infection. D/ Those with Acquired immunity who are re-infected will generally exhibit a lower disease severity
2. However there are certain populations who are more susceptible to infection with a higher morbidity & mortality than others :
1.Pregnant women : A/ The mortality rate of Pregnant women infected with Falciparum malaria is up to 50%

B/ infection can cause massive hemolysis in the developing baby
2. Many African mothers have had A/ several bouts of malaria & have some antibodies So their B/ babies may well be protected after birth for 3-6 months by maternal antibodies, C/ that not complete protection but it is some. & D/ because of their immature immune system between 6 month of age & less than 5 ys old, they are quite susceptible to Falciparum malaria. D/ In fact they have the heighest morbidity & mortality rate close to 10%
https://app.medmastery.com/courses/7005/lessons/7562

موضوع: Diagnosis & treatment السبت يوليو 06, 2024 1:31 pm

Diagnosis & treatment
This chapter deals with 1.the clinical manifestations of the various types of malaria 2. why falciparum malaria kills so many people 3. teaching the learners how to get confident in looking at the blood film making a specific diagnosis of the species causing the malaria by 4. showing them the different morphologies in RBCs 5. to show.
them the mechanisms of action of each of the most common Antimalarial dugs 6. how to choose which drug to which pt 7. to talk about prevention current strategies & take a peak in what future prevention strategis might be.
*Remember that after infection sporozoites are transported into the liver where passes through a kupffer cell into a hepatocyte.
* The parasite then divides within the hepatocyte To form a liver scizont
* The liver cell eventually bursts releasing merizoites into the blood stream
*The cycle continues in RBCs to release merozoites in a cyclic fashion *Along with these merozoites

* Along with these merozoites, some malaria pigment & DNA from these broken malaria parasites will also be released.
* These components are picked up by the immune system, activating the production of the pro-inflamatory Citokine TNF alpha which targets the Hypothalamus Resetting yur Thermostat too high.
@This process from the initial infection to the clinical manifestations is known as the incubation period & takes approximately 6 weeks.
@When body temp reaches 39 degrees celzius, yur body says wait a minute I'm not hot enough, so i'm I've got to shiver so as to reach that temp which was set by in the hypothalamus; this represents the cold stage of malaria, with the pt exhibiting (A/ bed shaking B/ bone rattling C/ chills & D/ fever) which typically lasts from 15 mins to one hour
@Eventually, the shivering will help the body reach that threshold of high fever & chills & shaking are gone ; this represents the hot stage of malaria
@Like any other fever it is accompanied by muscle aches & other symptoms that generally make the pt feel horrible
Unfortunately, this hot stage my last from 6-10 hours
@After a while when the thermostat begins to reset, the body will seek to cool it'self, & the pt will begin to sweat ; this is the defervescence stage in which pts experience drenching sweats which rapidly reduce the body temp
@After devervescence, pt may have no symptoms at all

@ But every time a red cell bursts releasing merozoites, the immune system is activated & these cycles will start over.
About the cycles :
The cycles are based 1. on the time it typically takes between the parasite invades a red cell & the resulting schizont bursts releasing merozoites into the blood stream, 2. which is different for different types of malaria.
The most common types are 3. P. falciparum, vivax & ovale which cycle 4. approximately every 48 hours. That is fever on day one, no fever on day two, fever again on day three; the so called Tertian malaria.
Plasmodium malariae 5. cycles 72 hours before the red cells burst; there is fever on day one, no fever on day two & three, fever again on day four; the so called Quartan malaria
6. in contrast P. knowlesi malaria cycles daily, thus yu see all the stages every twenty four hours
7. Yu can imagine if y've got bitten by only one mosquito, yu might cycle like that
8. But if yu in a malarious area, yu may bitten by different mosquitoes on different days even carrying a different type of malaria.
9. So pure cycles are seen only in text books, because the stages may end up overlapping.
10. The bottom line is when yu see a pt with fever & chills especially when it seems to come & go even remotely, yu should consider malaria & obtain a detailed travel history especially in the past six or more weeks. This is a must..

https://www.youtube.com/results?search_query=medmastery+malaria

Treating Uncomplicated Malaria
Now we know how malaria develops & how we can recognize the symptoms
We remember what the parasite is doing when invading a red blood cell:
# The parasite takes in hemoglobin by Pinocytosis & breakes it down into Aminoacids that it can use
Each Hemoglobin is made up of 4 subunits, 2 alpha subunits and 2 beta subunits (The hemoglobin molecule is made up of four polypeptide chains (Alpha 1, Beta 1, Alpha 2, Beta 2), noncovalently bound to each other. There are four heme-iron complexes.). Each subunit surrounds the central heme group that contains iron and binds to one oxygen molecule. Hematin is a bluish black compound derived from haemoglobin by removing of protein part and oxidation of the iron atom.
Haematin (also known as hematin, ferriheme, hematosin, hydroxyhemin, oxyheme, phenodin, or oxyhemochromogen) is a dark bluish or brownish pigment containing iron in the ferric state, obtained by the oxidation of haem.
The term heme defines an organic compound containing an iron atom between the structure of the porphyrin ring. Porphyrin is an organic compound that has a ring-like structure. The heme attached with the hemoglobin molecule or myoglobin is known as the heme group, while the separate heme is known as the heme molecule.
Hematin is a type of gelatin that is derived through the hydrolysis of collagen from animal sources and can be modified for various drug delivery purposes.
The main hematinics are iron, Vitamin B12, and folate.
Hematin crystallization is the primary mechanism of heme detoxification in malaria parasites and the target of the quinoline class of antimalarials. Despite numerous studies of malaria pathophysiology, fundamental questions regarding hematin growth and inhibition remain.Mar 23, 2015

#How to treat this disease?
*Pts diagnosed with malaria are categorized either to have uncomplicated or severe malaria
1/ Pts with uncomplicated malaria can be effectively treated with oral antimalarials
* It is preferable that treatment for malaria Not to be initiated until the diagnosed has been established by laboratory testing
* presumptive treatment without the benefit of prior laboratory confirmation should be reserved for extreme circumstances such as strong clinical suspicion or severe disease in the setting of prompt laboratory diagnosis is not available.
Treatment of uncomplicatedmalaria caused by P. vivax, ovale, or knowlesi, usually involves the drug chloroquine
A/ how does chloroquine work?
We remember what the parasite is doing when invading a red blood cell:
* The parasite takes in hemoglobin by Pinocytosis & breakes it down into Aminoacids that it can use
* The parasite has heme polymerase which detoxifies heme & hematin to turn it to hemozoin which it can use
* Heme polymerase is a target for a family of drugs known as 8-aminoquinolones, the most common of which is chloroquine
* These drugs work by blocking the parasite heme polymerase which makes heme & hematin toxic to the parasite leading to its death.
* With P. vivax & ovale, a small number of the parasites remain dormant inside the liver cells & known as hypnozoites.
* In those pts with these 2 types, even if yu treat & kill the active malaria in the the red cells yu may not be able to kill these hypnozoites in the dormant form inside the liver cells; this means the pt could have a relapse
of vivax & ovale if yu don't target the dormant hypnozoites in the liver.
* So, uncomplicated vivax & ovale malaria are treated with chloroquine to target the active malaria; & then yu come back after treatment with primaquin; This agent penerates into the liver cells & kills the hypnozites
So, yu use chloroquine & primaquine to prevent relapse of these 2 types of malaria.
xxx CAUTION to primaquine
1. Primaquine can cause massive hemolysis to pts with G8PDD
* Pts with African descent are tesed first for the presence of G6PDD before giving them primaquine
2. primaquine should not be given to pregnant women because it has been shown to cause develomental abnormalities in the babies.
* In addition, if the fetus is G6PD deficient, massive hemolysis can occur which can be fatal
* So primaquine is contraindicated in pregnancy; Instead yu generally treat with chloroquine first then wait untill after delivery to treat mother & baby with primaquine.

https://www.youtube.com/watch?v=J-1gigkCWho&t=9s

Uncomplicated malaria treatment contd
Treatment of Falciparum malaria
A/ Milder case of F. malaria may occur in individulas previously infected, who developed antibodies to the disease
B/ For uncomplicated P. falciparum infections acquired in areas without chloroquine resistant strains which include (Central America, west of Penama canal, Hiyeti, & domenican republic), pts can also be treated with oral chloroquine.
C/ For uncomplicated malaria acquired in areas with chloroquine resistance, 4 treatment options are available :
1. Artemether/Lmefantrin combination, with brand name Coartem is the preferred option if available
* Artemether is related to artesunate, which works by disrupting the mitochondrial membrane & the energy production of the mitochondria leading to death of parasite.
*Lumefantrine precise mechanism of action is unknown, but available data suggest inhibition of nucleic acid & protein synthesis.
2. Atovaquone/Proguanil combination with brand name Malarone

*Atovaquone is a structural analogue of coenzyme Q found in the mitochondrial-electron transport system
* Proguanil inhibits the synthesis of folic acid in the parasite
3. Quinine sulphate plus doxycycline, tetracycline, or clindamycin
* Quinine is one of the 8-aminoquinolones which blocks heme polymerase
* Doxycycline, tetracycline, clindamycin all inhibit proteine synthesis in the parasite
* Either of the tetracyclins are preferred to clindamycin because of the more efficacy data
4. Mefloquine acts as a blood schizonticide, however it's exact mechanism of action is not known
* Mefloquine is generally reserved for cases when the other options can't be used, because when used in therapeutic doses in contrast to preventive doses, where neuropsychic reactions can occur.
https://www.youtube.com/watch?v=J-1gigkCWho&t=9s

The clinical features of severe malaria
Malaria caused by Plasmodium falciparum is the deadliest form of malaria and is often referred to as severe malaria. While it typically begins with cyclic fever and chills, if left untreated, much more severe, life-threatening symptoms can develop quickly such as hemolysis, red blood cell (RBC) clots, and coagulation disruption.

Malaria-induced hemolytic anemia

Because P. falciparum can infect red blood cells (RBCs) of any age, more than 60% of RBCs may be parasitized, and when these cells burst it can quickly lead to massive hemolysis. This massive hemolysis causes symptoms such as hemoglobinemia and jaundice.
Hemoglobinemia overwhelms the ability of the RBCs to carry hemoglobin, so much of that hemoglobin spills over into the urine. In the acidic urine, hemoglobin is converted to the black pigment hematin, which may cause patients with severe malaria to develop a dark urine. Once severe falciparum malaria gets to this point, mortality is close to 80% if not treated, and many patients are dead within one to two days.

In comparison, because of the lower proportion of RBC infection seen in P. vivax or P. ovale malaria, the extent of hemolysis, and associated anemia, would be much lower.

Coagulopathy in malaria

Once P. falciparum invades RBCs, these parasitized RBCs, or schizonts, produce what are known as sticky knobs on the cell. These knobs cause the cell to stick to the lining of blood vessels, other schizonts, and normal red blood cells.
So, these masses of schizonts and normal RBCs can get stuck in the capillaries or venules, making it difficult for other blood cells to pass through.
This effectively blocks up the microcirculation which has a number of dangerous effects including infarcts and coagulation disruption.

Infarcts

Clots made up of schizonts and normal RBCs often get caught up in the microcirculation of the brain causing potentially devastating infarcts and seizures. They can disrupt other organs causing issues like retinal infarcts or kidney failure. And when caught in the venous microcirculation—the venules—clots can lead to decreased venous blood flow, pulmonary and cerebral edema. Cerebral edema can cause elevations of intracranial pressure, subsequent brain herniation and death.

Disseminated intravascular coagulation (DIC)

In addition to causing various types of infarcts, the accumulation of red blood cells in the microcirculation can consume all the patient’s coagulation factors, leading to disseminated intravascular coagulation (DIC), a common feature of severe malaria.

Again, let’s compare to P. vivax or P. ovale malaria. We see that the infected RBCs do not develop these sticky knobs, so don’t get hung up in the microcirculation like P. falciparum malaria, making these strains much less deadly.
https://www.medmastery.com/guides/malaria-clinical-guide/clinical-features-severe-malaria

What Does Malaria Do to the Human Body?
   There is only a small percentage of mosquitoes that can get infected & can transmit malaria.
These mosquitoes are anopheles & only a small proportion are anopheles, & only female anopheles which can infect humans, because mosquitoes are usually vegeterian.
The reason they stop being vegetarian, is that females need the protein in blood to produce &                                            lay eggs .So an infected mosquito, bites a human & inject sporozoites in human blood & reach the liver. The parasite wants to get into a cell fast to avoid the patrolling immune cells
The parasite heads to the liver 1st wrapping itself in an invisibility cloak of sorts (as an outer coat protecting)- the liver cell membrane.
Since our body not yet know the parasite is there, there won't be any resulting symptoms.                                                     The parasite replicates in the liver cells until it bursts out, setting its sight now in the blood stream ON the red blood cells. These RBCs are another good place to take shelter from the immune system & perfectly suited for the parasite's needs to replicate.
As soon as the parasite is inside the cell it starts to drastically alter the makeup of the cell. the Parasites will take sometime to settle down & feel comfortable inside the cell. Then they will start their differentiation & reproduction processes.
As it replicates, the parasite will snack on hemoglobin inside the RBCs (Hb is a protein in RBCs which carries Oxygen throughout the body). ONLY By this point, the human immune system knows that something sketchy (includes the major points but lacks detail) is going on.
For one thing, this red cell looks nothing like it used to-it's stiffer, sticker & is no longer smooth from the outside.
So as soon as the parasite gets in, the host immune system realize that the RBCs are transformed & that there are strange things going on inside.
The host immune system is going to try to directly target the the infected red cell. The immune system will recognize the infected red cell based on the parasite proteins exported on the outside & destroy it. But in this case the parasite has found a way to escape this by repeatedly changing the protein it expresses. It becomes essentially a cat & mouse game where the immune system can't keep up.
As soon as it knows what to destroy, the parasite puts on a new protein mask on its host cell & gets away unscathed (unharmed). While its evading detection, it uses human cells to replicate Asexually & eventually differentiate into male & female versions of itself, something that only happens in human host.
Then it needs to be picked up by a mosquito in order for those versions to reproduce, which can only happen in the mosquito host. This cycle really needs an infected human to infect mosquitoes, & yu need an infected mosquito to infect a human.   And as if that weren't enough when the red cells burst, they release toxins into the blood.
The major symptoms of malaria, a nasty fever, chills, headache, vomiting are caused in part by these toxins. These can actually cause the pt to get into coma & stop the oxygen exchange between blood & brain.
So how can yu vaccinate or treat a parasite that is constantly on the move & changing what it looks like ? this is a big issue & needs a lot of money & research.

Right now we have a vaccine that can protect 30-40% against the strongest side effects of the disease but not compelte protection as we are familiar with. The goal of the lab is really to stop the parasite in its intensive replication steps, or to make sure we just inhibit replication & division of the parasite inside the human host.       And as we come up with new treatments, the parasite itself is always evolving & evading us in new ways.
In order to eradicate the disease, we really have to become more clever than the parasites are.
https://www.youtube.com/watch?v=nFcvDVf1XRI

The process from initial infection to the clinical manifestations of malaria is known as the incubation period and takes approximately six weeks.?
The process from initial infection to the clinical manifestations of malaria is known as the incubation period and takes approximately six weeks.
But what clinical signs help us to identify malaria?

Malaria infection and the hypothalamus

Remember, in the life cycle of malaria, that after infection, the Plasmodium sporozoites travel to the liver where they divide. Once inside the liver merozoites, or small parasitic cells, are released into the bloodstream. From there, red blood cells (RBCs) are invaded, and the merozoites continue to divide, filling the RBCs until they burst. This releases parasites, along with malaria pigment and deoxyribonucleic acid (DNA). These components are picked up by the immune system, activating inflammatory processes that target the hypothalamus. The hypothalamus responds by resetting the patient’s central thermostat to a higher than normal temperature, say 39°C.
Tropical Medicine Malaria-infection-hypothalamus-central-temperature

Tropical Medicine Malaria-infection-hypothalamus-central-temperature

During the cold stage, the body aggressively shivers to elevate body temperature in response to hypothalamic elevation of the central thermostat after malaria infection. This may last 15 minutes to 1 hour.
Tropical Medicine Table-malaria-cycles

A comparison of the clinical patterns of fever and associated classifications for five main strains of Plasmodium.

How to identify the type of malaria on a blood smear
learn how to identify the subtype of malaria from a blood smear. See photos.
There are a number of ways to make a diagnosis of malaria, but one of the fastest is to look at a patient’s blood smear under a microscope. This allows us to determine the presence of malaria and the type of malaria. If we use a blood sample with more than 50 parasitized red blood cells / µL, we can diagnose malaria with about 70% sensitivity.
So how do we use a blood smear to distinguish between the different types of malaria? Well, each type of malaria displays a unique set of characteristics in infected red blood cells (RBCs) that can be seen under a microscope. Let’s take a closer look at how to identify each of the four main types of malaria—Plasmodium falciparum, Plasmodium malariae, Plasmodium ovale, and Plasmodium vivax.

Identifying Plasmodium falciparum on a blood smear

Let’s review the main characteristics of Plasmodium falciparum that can be identified with microscopic examination of a blood smear:

High-grade parasitemia
Crescent-shaped gametocytes

High-grade parasitemia

Figure 1 highlights the classic presentation of falciparum malaria in a blood smear. Notice just how many RBCs are infected, including some RBCs that are doubly parasitized with two ring trophozoites in one cell. Remember that P. falciparum can infect RBCs of any age. So, seeing a high-grade parasitemia, or a lot of infected cells, should immediately cue us to consider a diagnosis of falciparum malaria. Tropical Medicine Falciparum-high-grade-parasitemia-blood-smear

Figure 1. Ring trophozoites can be seen in a blood smear when viewed under a microscope. The high proportion of infected red blood cells seen here, including doubly parasitized cells, is characteristic of Plasmodium
falciparum. Image source: CDC Public Health Image Library (PHIL), ID#5856
https://www.medmastery.com/guides/malaria-clinical-guide/how-identify-type-malaria-blood-smear

Crescent-shaped gametocytes

The most definitive finding of P. falciparum is the shape of the gametocytes. Unlike what we see in the other species of malaria, they are crescent-shaped or banana-shaped.
Tropical Medicine Falciparum-crescent-shaped-gametocytes-blood-smear

Figure 2. A definitive finding of Plasmodium falciparum in a blood smear is the presence of crescent-shaped gametophytes. Image source: CDC Public Health Image Library (PHIL), ID#5856
Tropical Medicine Falciparum-appliqu%C3%A9-forms-blood-smear

Tropical Medicine Falciparum-appliqu%C3%A9-forms-blood-smear

Appliqué forms

There is one other feature of P. falciparum to be aware of. Some of the trophozoites may look like they are on the surface of the RBC. These are the appliqué forms. They are much more common to see with falciparum than other types of malaria.
Tropical Medicine Falciparum-appliqu%C3%A9-forms-blood-smear

Figure 3. In Plasmodium falciparum infection it is common to see appliqué forms where the ring trophozoites appear on the periphery of the red blood cell. Image source: CDC Public Health Image Library (PHIL), ID#5856
So, when using microscopy to make a diagnosis of Plasmodium falciparum malaria, remember to look for high-grade parasitemia and crescent-shaped gametocytes.
Tropical Medicine Malariae-blood-smear-senescent-RBC

Tropical Medicine Malariae-blood-smear-senescent-RBC

Figure 4. When looking at a blood smear under a microscope, Plasmodium falciparum can be identified by the presence of a high proportion of infected red blood cells and crescent-shaped gametocytes.
https://www.medmastery.com/guides/malaria-clinical-guide/how-identify-type-malaria-blood-smear

موضوع: رد: Tropical Medicine الأربعاء يوليو 10, 2024 2:09 pm

Identifying Plasmodium malariae on a blood smear

Plasmodium malariae can be identified by its three unique characteristics:

Senescent RBC infection
Band-like trophozoites
Rosette forms

Senescent RBC infection

Remember that P. malariae primarily infects senescent cells, which are typically smaller than other red blood cells. If we identify a ring trophozoite, the only way to determine if it is P. malariae is to decide if the infected RBC is smaller than the surrounding cells.
Tropical Medicine Malariae-blood-smear-ring-trophozoite

Tropical Medicine Malariae-blood-smear-ring-trophozoite

Figure 5. Microscopic view of the ring trophozoite of Plasmodium malariae. Image source: CDC Public Health Image Library (PHIL), ID#5127

Band-like trophozoites

Now as the P. malariae trophozoites mature, they become more distinctive with a band-like or sash-like structure. This is unique to malariae malaria.
Tropical Medicine Malariae-blood-smear-band-trophozoites

Tropical Medicine Malariae-blood-smear-band-trophozoites

Figure 6. Developing Plasmodium malariae trophozoites can be distinguished by their band-like structure. Image source: CDC Public Health Image Library (PHIL), ID#639

Rosette forms

Lastly, we may find merozoites lined up around the perimeter of the schizont with pigment in the center. This is called the rosette form of P. malariae malaria.
Tropical Medicine Malariae-blood-smear-rosette-form

Tropical Medicine Malariae-blood-smear-rosette-form

Figure 7. The rosette form of a Plasmodium malariae schizont, where the merozoites line up around the perimeter with pigment in the center of the cell, can be seen under a microscope. Image source: CDC Public Health Image Library (PHIL), ID#5860
So, for Plasmodium malariae, look for infection in smaller cells, as well as the presence of a band-like structure in the developing trophozoite, and a rosette form of the schizont.
Tropical Medicine Malariae-malaria-characteristics-blood-smear

Tropical Medicine Malariae-malaria-characteristics-blood-smear

Figure 8. Plasmodium malariae can be identified using a microscope by looking for infection in the smallest red blood cells, band-like trophozoites, and rosette schizonts.

Identifying Plasmodium ovale on a blood smear

Let's consider Plasmodium ovale. There are four main features that will be useful to consider when looking at the blood smear:

Reticulocyte infection
Schuffner’s dots
Oval shape
Feathering

Reticulocyte infection

Remember that P. ovale likes young red blood cells—reticulocytes—which are generally bigger than the other forms of red blood cells. So, look for ring forms inside large cells on the blood smear.
Tropical Medicine Ovale-blood-smear-reticulocyte-infection

Figure 9. When viewing a blood smear under a microscope, ring trophozoites seen inside large reticulocytes are characteristic of Plasmodium ovale infection. Image source: CDC Public Health Image Library (PHIL), ID#5056

Schuffner's dots

Another common feature of P. ovale is the eosinophilic dots, or Schuffner’s dots, that you see throughout the cytoplasm of an infected RBC. Schuffner's dots are classic findings of P. ovale and P. vivax infection.

Oval shape

Schuffner’s dots will distort the parasitized RBC into an oval, giving P. ovale its distinctive namesake shape.
Tropical Medicine Ovale-blood-smear-schuffners-dots

Tropical Medicine Ovale-blood-smear-schuffners-dots

Figure 10. A developing Plasmodium ovale trophozoite, with Schuffner’s dots in the cytoplasm of the oval-shaped red blood cell, is visible under a microscope. Image source: CDC Public Health Image Library (PHIL), ID#5934

Feathering

Lastly, close inspection of an RBC infected with P. ovale will reveal the cell’s edges are feathered.
When diagnosing Plasmodium ovale, remember that infection occurs in larger cells. Look for the presence of Schuffner’s dots inside cells that are distorted into an oval shape with feathering around the edges of the cell.
Tropical Medicine Ovale-malaria-characteristics-blood-smear

Tropical Medicine Ovale-malaria-characteristics-blood-smear

Figure 11. Look for infection in large red blood cells, Schuffner’s dots in the cytoplasm, oval-shaped cells, and feathering around the cell’s edges when identifying Plasmodium ovale in a blood smear.

https://www.medmastery.com/guides/malaria-clinical-guide/how-identify-type-malaria-blood-smear

Identifying Plasmodium vivax on a blood smear

Finally, let's look at the second most common type of malaria worldwide—Plasmodium vivax. There are three things to look for in blood smears with P. vivax infection:

Reticulocyte infection
Schuffner’s dots
Absence of RBC shape changes

Reticulocyte infection

P. vivax selectively infects reticulocytes, so we would expect to see a low-grade parasitemia, with ring trophozoites in the largest red blood cells.
Tropical Medicine Vivax-blood-smear-reticulocyte-infection

Figure 12. Plasmodium vivax ring trophozoites can be seen in the large reticulocytes in a blood smear. Image source: CDC Public Health Image Library (PHIL), ID#3709

Schuffner's dots

And like P. ovale, many infected red blood cells will have Schuffner’s dots.

Absence of RBC shape changes

But unlike P. ovale infections, the Schuffner’s dots seen in P. vivax don’t distort the red blood cell. It actually stays more rounded without a feathered edge.
Tropical Medicine Vivax-blood-smear-schuffners-dots

Tropical Medicine Vivax-blood-smear-schuffners-dots

Figure 13. Under a microscope, Schuffner’s dots can be seen in a developing Plasmodium vivax trophozoite. The cell stays rounded and lacks feathered edges which distinguishes it from Plasmodium ovale infection. Image source: CDC Public Health Image Library (PHIL), ID#5819
So, like P. ovale, Plasmodium vivax affects larger reticulocytes and develops Schuffner’s dots. But in P. vivax infections the cells are more rounded and do not show feathering around the edges.
Tropical Medicine Vivax-malaria-characteristics-blood-smear

Tropical Medicine Vivax-malaria-characteristics-blood-smear

Figure 14. In Plasmodium vivax infections, the blood smear will show characteristic low-grade parasitemia with infected reticulocytes only. Schuffner’s dots will be present but the red blood cells will remain round and will not have feathered edges.
While microscopy is a quick and sensitive way to diagnose malaria, don’t forget that there are other options. Rapid diagnostic tests (RDTs) and polymerase chain reaction (PCR) are both effective. RDTs are often used when microscopic analysis is unavailable. PCR is the most sensitive option but requires specialized equipment and is much slower to produce results.
That’s it for now. If you want to improve your understanding of key concepts in medicine and improve your clinical skills, make sure to register for a free trial account, which will give you access to free videos and
downloads. We’ll help you make the right decisions for yourself and your patients
https://www.medmastery.com/guides/malaria-clinical-guide/how-identify-type-malaria-blood-smear

Testing for malaria: Rapid diagnostic tests and PCR
In this Medmastery article, read about the most common tests used worldwide for diagnosing malaria: RDTs and PCR.
We’ve seen that diagnosing malaria subtypes can be achieved by looking at the blood film—in fact, you should still review a smear for each patient suspected to have malaria. But in developing countries, where malaria is common, and access to microscopy may be limited, rapid diagnostic tests (RDTs) are needed.

What you need to know about rapid diagnostic tests (RDTs) for malaria

Rapid diagnostic tests allow us to screen for malaria. These tests are conducted using filter paper strips that contain three types of antibodies—anti-falciparum malaria antibodies, general anti-malaria antibodies, and anti-human antibodies.
To test for malaria place serum from a patient on one of these filter paper strips, and allow it to soak in. After about 15 minutes, look at the strip. If only the control line is visible, the patient doesn't likely have malaria. If they have something other than falciparum malaria, the anti-malaria strip will be visible, but not the anti-falciparum strip. And if the patient is infected with falciparum malaria—severe malaria—all the lines will be visible. These tests have a sensitivity and specificity of greater than 90%. Tropical Medicine Rapid-diagnostic-tests-malaria

Tropical Medicine Rapid-diagnostic-tests-malaria

Figure 1. Rapid diagnostic tests (RDTs) are conducted using filter paper strips with anti-falciparum antibodies, general anti-malaria antibodies, and control or anti-human antibodies. Applying a patient’s serum to the strip will cause visible lines to form, a) if the patient does not have malaria, the control line will be visible, b) If the patient has non-falciparum malaria, the anti-malaria line will be visible, c) If the patient has falciparum malaria, all of the lines will be visible.
Tropical Medicine Medmastery-note-RDTs-common-malaria

Tropical Medicine Medmastery-note-RDTs-common-malaria

Using polymerase chain reaction (PCR) to test for malaria

Polymerase chain reaction (PCR) is the most sensitive test for malaria at more than 90% sensitivity. While microscopy can detect infected red blood cells with a parasite load of 50 parasites / µL, PCR is able to detect as few as 1 parasite / µL. But of course, it’s also the most labor-intensive, the most expensive, and takes the longest to get results. PCR is available, to a limited extent, in developing countries. But in the developed world, it’s a common way to make the diagnosis, especially in returning travelers.
PCR uses a polymerase enzyme to copy the deoxyribonucleic acid (DNA) of the malaria parasite. This process increases or amplifies, the number of DNA nucleic acids so they can be more easily picked up by laboratory tests such as protein assays. So PCR can be used to diagnose malaria from a very small blood sample volume, or a blood sample that has been dried on filter paper. Tropical Medicine Polymerase-chain-reaction-testing-malaria

Tropical Medicine Polymerase-chain-reaction-testing-malaria

Figure 2. Polymerase chain reaction (PCR) is labor- and time-intensive, expensive, and most commonly used in developed countries to diagnose malaria in returning travelers.
That’s it for now. If you want to improve your understanding of key concepts in medicine, and improve your clinical skills, make sure to register for a free trial account, which will give you access to free videos and downloads. We’ll help you make the right decisions for yourself and your patients.
https://www.medmastery.com/guides/malaria-clinical-guide/testing-malaria-rapid-diagnostic-tests-rdts-and-polymerase-chain

How to treat severe malaria
Learn how to treat and manage severe malaria in your patients from an expert in this Medmastery article.

Patients with severe malaria should be treated aggressively with intravenous therapy (IV) anti-malarials. But first, let’s take a closer look at what severe malaria looks like, and how we manage patients with severe malaria.

What is severe malaria?

We classify Plasmodium falciparum infection as severe malaria when a positive diagnostic test for malaria is accompanied by the presence of at least one of a number of clinical criteria:

Impaired consciousness or coma
Severe anemia (hemoglobin < 7g / dL)
Acute kidney injury
Acute respiratory distress syndrome (ARDS)
Disseminated intravascular coagulation (DIC)
Spontaneous bleeding
Acidosis
Jaundice
More than 5% of red blood cells (RBCs) on a blood film are infected

Tropical Medicine Clinical-features-adult-severe-malaria

Figure 1. Clinical features of severe malaria in adults include impaired consciousness, severe anemia, acute kidney injury, acute respiratory distress syndrome (ARDS), disseminated intravascular coagulation (DIC), spontaneous bleeding, acidosis, jaundice, and high parasite load when more than 5% of red blood cells (RBCs) on a blood film are infected.

What anti-malaria drugs should I use to treat severe malaria?

When treating severe malaria, obviously we first want to get rid of the cause—the parasite—using anti-malaria drugs.
Historically, for severe malaria, we used quinidine, an anti-arrhythmic related to quinine. However, recent studies have shown that the anti-malarial drug, artesunate, results in much lower mortality than quinidine when used to treat severe malaria, so it has become the standard treatment over quinidine.
Artesunate, given intravenously, works by disrupting the mitochondrial membrane and the energy production of the mitochondrion, causing the parasite to die.
Tropical Medicine Artesunate-treatment-severe-malaria

Tropical Medicine Artesunate-treatment-severe-malaria

Figure 2. Artesunate disrupts the mitochondrial membrane and mitochondrial energy production which kills Plasmodium falciparum parasites.
Artesunate can also be used in patients with less severe malaria who cannot take quinine-based medications.

How should I address the other symptoms that are associated with severe malaria?

So, we’ve addressed treatment to eliminate the parasite. But remember that a patient may already be quite sick, so we’ll likely also need to treat their symptoms.
A patient may need mechanical ventilation, benzodiazepines for controlling seizures, or fluids for the accompanying DIC.
In very severe cases, exchange transfusions may help to get rid of the blood containing the high-grade parasitemia by replacing it with some uninfected blood. This technique has been life-saving in a few individuals.
Although coinfection is uncommon, keep in mind that patients with severe malaria can have two infections going on simultaneously. So, it’s prudent to draw blood cultures to check for other infections.
Finally, if the patient has severe malaria and the neurological presentation is the least bit atypical, consider a lumbar puncture to test the cerebrospinal fluid for infection. For instance, cerebral malaria is generally associated with increased intracranial pressure, but not with neck stiffness. So a patient complaining of neck stiffness suggests meningitis and warrants a lumbar puncture to rule out other causes of central nervous system (CNS) infections.
Tropical Medicine Treating-symptoms-of-severe-malaria

Tropical Medicine Treating-symptoms-of-severe-malaria

Figure 3. When treating severe malaria, in addition to administering antimalarials, other actions to manage symptoms and rule out infections may include the use of benzodiazepines, intravenous (IV) fluids, mechanical ventilation, exchange transfusion, blood cultures, and lumbar punctures.
Tropical Medicine Medmastery-note-treatment-severe-malaria

Tropical Medicine Medmastery-note-treatment-severe-malaria

That’s it for now. If you want to improve your understanding of key concepts in medicine, and improve your clinical skills, make sure to register for a free trial account, which will give you access to free videos and downloads. We’ll help you make the right decisions for yourself and your patients.

https://www.medmastery.com/guides/malaria-clinical-guide/how-treat-severe-malaria

موضوع: How to prevent malaria الأربعاء يوليو 10, 2024 8:58 pm

How to prevent malaria
Learn everything you need to know about malaria prophylaxis (and vaccines) in this Medmastery article.
Is it possible to prevent malaria in the first place?
Although there are several anti-malarial drugs, there isn’t one that’s 100% effective, so it’s important to take personal protective measures such as wearing insect repellent, long sleeves and pants, sleeping in a mosquito-free setting, or using an insecticide-treated bed net. With this in mind, let’s take a closer look at the available oral anti-malarials.

Oral anti-malarial prophylaxis

As anyone who has traveled to an area with endemic malaria knows, it is important to take anti-malarial prophylaxis. Because the mosquitoes in these areas are so prevalent, it’s almost a guarantee that travelers will end up exposed to malaria. So, these prophylactic medications generally don’t actually prevent a person from being infected with malaria, but instead they are treating the malaria that the traveler is almost certain to contract.
Anti-malarial prophylaxis can be taken daily or weekly.

Daily anti-malarial prophylaxis

There are three medications that travelers should take daily:

Atovaquone-proguanil
Doxycycline
Primaquine

Atovaquone-proguanil

The combination of atovaquone and proguanil is given as prevention for Plasmodium falciparum malaria. But some falciparum malaria are resistant to atovaquone, so this may not be the ideal combination for individuals travelling to certain areas. Additionally, this combination cannot be used by women who are pregnant or breastfeeding a child less than 5 kg. Tropical Medicine Contraindications-atovaquone-proguanil-treatment-malaria

Figure 1. Atovaquone-proguanil should not be used as anti-malarial prophylaxis for women who are pregnant or breastfeeding a child less than 5 kg.

Doxycycline

Doxycycline tends to be the least expensive anti-malarial. It is also good for last-minute travelers because the drug is started one to two days before traveling to an area where malaria transmission occurs.
Doxycycline use comes with an increased risk of sun sensitivity so avoid considerable sun exposure when taking it.
Pregnant women and children under 8-years-old should not use this drug.
^{Figure 2. Doxycycline should not be used in pregnant women, children less than 8-years-old, and prolonged sun exposure should be avoided.}
Tropical Medicine Contraindications-doxycycline-treatment-malaria

Primaquine

Primaquine is one of the most effective medicines for preventing P. vivax, so it is a good choice for travel to places with > 90% P. vivax prevalence.
But primaquine cannot be used in patients with glucose-6-phosphatase dehydrogenase (G6PD) deficiency or in patients who have not been tested for the deficiency. Primaquine should also not be used by pregnant women or in women who are breastfeeding unless the infant has also been tested for G6PD deficiency. Tropical Medicine Contraindications-primaquine-treatment-malaria

Figure 3. Primaquine cannot be used as anti-malarial prophylaxis in patients with glucose-6-phosphatase dehydrogenase (G6PD) deficiency, patients who have not been tested for G6PD deficiency, pregnant women, or women who are breastfeeding an infant who has not been tested for G6PD deficiency.

Weekly anti-malarial prophylaxis

Some people would prefer a weekly dose instead of daily, especially during a long trip. So, in addition to daily options, we have two weekly anti-malarial prophylaxis medications to consider:

Chloroquine
Mefloquine

These medications have the added benefit of being safe for use in pregnancy. Tropical Medicine Chloroquine-mefloquine-treatment-malaria-pregnancy

Figure 4. Chloroquine and mefloquine are safe for use in all trimesters of pregnancy.

Chloroquine

Chloroquine is a good choice when weekly dosing is preferred. But some strains of malaria will be resistant to chloroquine, so it cannot be used in areas where chloroquine-resistant malaria is found.

Mefloquine

Mefloquine is another weekly medication. However, at prophylactic doses, it has been associated with rare but serious adverse reactions, such as psychosis or seizures. Tropical Medicine Prophylactic-doses-mefloquine-adverse-events

Figure 5. Prophylactic doses of mefloquine have been associated with rare but serious adverse reactions such as psychosis or seizures.
So, there are several options for anti-malarial prophylaxis we can choose based on the traveler’s preference, destination, contraindications, and precautions of the medications. Tropical Medicine Table-common-antimalarial-prophylaxis

Tropical Medicine Table-common-antimalarial-prophylaxis

Figure 6. Common oral anti-malarial prophylaxis dosing intervals, contraindications, and precautions.

Anti-malarial vaccines

So, what about vaccines?
Most current research is focused on anti-sporozoite vaccines where attenuated sporozoites are injected to try to prevent the initial infection of liver cells by the parasites. While these are promising, they are all still in experimental stages.

https://www.medmastery.com/guides/malaria-clinical-guide/how-prevent-malaria

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