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Differentiate stages of malaria life cycle, identify species of plasmodium, and list down signs, symptoms, and complications associated w/ malaria as well as treatment options and prophylaxis

Life Cycle

Has 2 hosts: vertebrate (interm­ediate) and mosquito (definitive)
Definitive Host: Sporul­ating Cycle (Sporo­gony)
Interm­ediate Host: Asexual Cycle (Schiz­ogony)
EXO-ER­YTH­ROCYTIC CYCLE
1. Anopheles mosquito (defin­itive host), inoculates sporoz­oites into human host (inter­med­iate)
Sporoz­oites are the infective stage to man
2. Sporoz­oites infect liver parenc­hymal cells and mature into schizonts, which produce merozoites
P. vivax and P. ovale assume a dormant stage (hypnoz­oites), and can persist in the liver
3. Infected cell ruptures and releases merozoites
ERYTHR­OCYTIC CYCLE
4. Merozoites infect RBCs and become tropho­zoites (ring stage)
Merozoites are the infective stage for RBCs
5. Tropho­zoites mature into schizonts, which rupture and release merozoites
Some differ­entiate into gameto­cytes, which are ingested by the mosquito looking for a blood meal
6. Ruptured schizonts are respon­sible for the clinical manife­sta­tions of the disease
SPOROGONIC CYCLE
7. The gameto­cytes are ingested by an anopheles mosquito and make their way into the stomach of the mosquito
8. While in the stomach, the microg­ametes (male) penetrate the macrog­ametes (female), which generate zygotes
Microg­ame­tocyte exflag­ellates and produces 8 sperm-like microg­ametes
9. The zygotes become motile and elongated
These are called ookinetes
10. The ookinetes invade the midgut wall of the mosquito, where they develop into oocysts
11. The oocysts grow, rupture, and release sporoz­oites, which makes their way into the salivary glands of the mosquito
12. Inocul­ation of the sporoz­oites into a new human host perpet­uates the malaria life cycle
The merozoite recognizes a specific receptor site on the RBC and exposes several organelles for attach­ment. The red cells becomes deformed and the merozoite enters through an invagi­nation of the RBC membrane

For P. vivax, the receptor site on the RBC is associated with the Duffy Blood Group Antigen. Over 90% of Africans are Duffy Negative and are resistant to Vivax Malaria

Path­oge­nicity and Virule­nce

Pathol­ogical process is the result of erythr­ocytic cycle
1. Hemolysis
 
RBC invasion by merozoites induces changes in cytosk­eleton and decreases in deform­ability
 
Increased capillary permea­bility, which allows fluid to lead into surrou­nding tissues, causing congestion in blood vessels and tissue infarction and necrosis
2. Liberation of Metabo­lites
 
Rupture of RBCs bring on malarial paroxysm and increased hemosi­derin in the liver, spleen, and other organs, which become black in color
 
Lysis of cells & phagoc­ytosis of cell remnants, debris, and hemozoin congest the kupffer cells of the liver, resulting in hepato­spl­eno­megaly. Tears of splenic capsule may occur due to trauma or coughing & may require surgery
3. Immuno­logic Response
 
Antigens of P. falciparum induces cytokines, which stimulate the release of TNF or Cachexin, which causes fever, paroxysms, HA, pains, and prostr­ation
 
TNF produces neurologic symptoms, which play a role in cerebral malaria
 
Repeated attacks of malaria produce anemia
 
Immune complexes are formed and may be deposited in the kidney
4. Formation of Malarial Pigment
 
In infected RBC, Hgb is digested forming the pigment hemozoin, which can get deposited to various organs
 
Hemozoin formation depletes iron stores, which leads to anemia
VIRULENCE FACTORS
Knobs develop for adhesion to parasi­tized and non-pa­ras­itized cells and platelets
 
P. falciparum erythr­ocyte membrane Pr1 (PfEMP1) is the most adhesive protein among the knobs
 
Knobs contain Histid­ine­-Rich Pr (HRP)
 
In Falciparum, cytoad­herence causes plugging of small vessels by masses of parasi­tized RBCs and RBCs sticking to endoth­elium causing: ischemia of the brain, heart, kidney, lungs, and GIT
PREFERENCE
Vivax and Ovale
Only reticu­locytes and young RBC
Malariae
Senescent cells
infections with these 3 parasites (vivax, ovale, and malariae) limits number of RBCs that can be parasi­tized to less than 3% of all erythr­ocytes
Falciparum and Knowlesi
All ages of RBC
Results in increased parasi­temia, early anemia, and increased severity of compli­cations and mortality
 

Morphology

Ring Form (Early Tropho­zoite)
Earliest stage after invasion of RBC. The ring has a dot-like nucleus of red chromatin
Falciparum ring: headphone type with a double chromatin dot.

Plasmodium Falciparum Ring Form

Headphone type is also seen in P. knowlesi

Plasmodium Malariae Bird's Eye Ring Form


Mature Tropho­zoites

The erythr­ocyte hemoglobin is metabo­lized to produce a darkly staining pigment hemozoin
Maurer's Clefts: P. falciparum infections containing older ring-form tropho­zoites and asexual stages
Schüff­ner's Dots: seen in P. vivax and P. ovale
Parasite nutrition is hemoglobin and the metabolite is hemozoin or hematin

Maurer's Clefts

Schüff­ner’s Dots

Schizont

When parasite divides and shows multiple masses of nuclear chromatin. Mature schizonts contain merozoites.

Rarely seen in peripheral blood of P. falciparum except in severe infections

Falciparum schizonts stay in capill­aries of organs and muscles. If schizont spills into general circul­ation, indicates bad prognosis

Gameto­cytes

Sexual form ingested by the mosquito (infective stage for mosquito)
Macrog­ame­tocyte: nucleus is dense and compact
Microg­ame­tocyte: nucleus is a pale, loose network

Falciparum Gametocyte

Banana shaped

Knowlesi Gametocyte

Gameto­cytes of vivax, ovale, malariae, and knowlesi are similar, except that malariae is smaller and darker

Diagnosis

MICROS­COPIC IDENTI­FIC­ATION
 
Gold standard
 
Specimens can be taken any time
 
Giemsa stain is preferred for visual­ization of certain structures (ex. Maurer's Clefts)
 
If high degree of synchrony exist, late develo­pmental stages can be demons­trated in the repeated smears every 4-6hrs (not recomm­ended for falciparum)
 
Repeated testing is not recomm­ended if parasites are not found initially
 
Blood smears are obtained to monitor response to treatment
 
Thick Film: reveals if parasite is present and is most efficient method of detection
 
Thin Film: identi­fic­ation of species
MALARIAL RDT
 
Uses Immuno­chr­oma­tog­raphy to detect Plasmodium specific antigens in a finger prick blood sample
 
Antigens utilized are: HRP II, pLDH, Plasmodium Aldolase
 
HRP II: produced by tropho­zoites and young gameto­cytes of P. falciparum
 
pLDH: produced by both sexual and asexual stages, and can distin­guish between falciparum and non-fa­lci­parum. Sensitive for severe malaria
 
Plasmodium Aldolase: PA + HRP II = PMA which has 90% specif­icity and can be performed in 30 minutes
SEROLOGY
Cannot differ­entiate past from current infection
 
Indirect Hemagg­lut­ination (IHA)
 
Indirect Fluore­scent Antibody Test (IFAT)
 
ELISA
PCR
low parasi­temia or mixed infection
 

Plas­modium Falcip­arum

MALIGNANT TERTIAN MALARIA
 
Also known as subtertian or Aestiv­oau­tumnal Malaria
 
Deadliest species of plasmodium
 
Causes 50% of all malaria cases
 
Erythr­ocytic cycle of 48hrs
 
Found in tropics, subtro­pics, and sub saharan Africa
 
Infected cell is same size as normal RBC
 
Associated with the develo­pment of Burkitt's Lymphoma
RING-FORM TROPHO­ZOITES
 
Headphone Type: Rings may possess 1 or 2 chromatin dots
 
They may be found on the periphery of the RBC (accolé, appliqué) and multip­ly-­inf­ected RBCs may be seen.
 
Usually no enlarg­ement of infected RBC
 
Maurer's Clefts: can be seen in infections w/ older ring-form tropho­zoites, and resembles the Schüff­ner’s dots but are larger and coarser
DEVELOPING AND OLDER TROPHO­ZOITES
 
Remain in ring-form, but may become thicker and more compact
 
Amount of pigment and chromatin may also increase
SCHIZONTS
 
Schizogony DOES NOT take place in the peripheral blood, but in capill­aries of organs and muscles.
 
The only stages seen in peripheral blood are rings and gameto­cytes
 
Contain anywhere from 8-24 merozoites
 
Mature schizont usually fills 2/3 of infected RBC
GAMETO­CYTES
 
Crescent or sausage or banana shaped
 
Pigment is more coarse and concen­trated in macrog­ame­tocyte than microg­ame­tocyte
 
Laveran's Bib: remnants of host RBC

Plas­modium Ovale

OVALE MALARIA
 
Has an erythr­ocytic cycle of 48hrs
 
Has a hypnozoite stage in the liver, which is the cause of relapse
 
Infected RBC is slightly enlarged compared to normal RBC
 
Found in Tropical Africa, West Africa, South America, and Asia
RING-FORM TROPHO­ZOITES
 
Contains single chromatin dot. Difficult to differ­entiate from vivax.
 
Multip­ly-­Inf­ected RBC may be see
MATURE TROPHO­ZOITES
 
As tropho­zoite matures, infected RBCs may exhibit fimbri­ation and Schüff­ner’s dots
SCHIZONTS
 
Similar to P. vivax, though tend to contain fewer merozoites (4-16, on average 8)
 
Elongation to an oval shape and fimbri­ation are common
 
Schüff­ner’s dots can be observed with proper staining
GAMETO­CYTES
 
Difficult to distin­guish from P. vivax
 
Slight enlarg­ement of infected RBC

Plasmodium Vivax

BENIGN TERTIAN MALARIA
 
Erythr­ocytic cycle of 48 hours
 
Hypnozoite: persistant dormant stage in the liver, which is the cause of relapse
 
Predom­inant malarial species
 
Infected RBC is enlarged due to affinity for young RBCs or reticu­locytes
RING-FORM TROPHO­ZOITES
 
Has a thick cytoplasm w/ single, large chromatin dot. Difficult to distin­guish from P. ovale
 
Cytoplasm becomes ameboid and Schüff­ner’s dots may appear as tropho­zoites mature
LATE TROPHO­ZOITES
 
Developing tropho­zoi­tes­ become amoeboid, with pseudo­podial processes and large vacuoles.  Schüff­ner’s dots are visible with proper staining
 
band-form appearance of tropho­zoite may occur
 
May be mistaken for P. Malariae or P. knowlesi
SCHIZONTS
 
Pigment is organized in 1-2 clumps
 
Mature schizonts contain 12-24 merozoites, each of which contains a dot of chromatin and a mass of cytoplasm
GAMETOCYTE
 
Macrog­ame­tocyte: round to oval and usually fill host cell. Infected RBC is larger and cytoplasm is usually a darker blue with fine brown pigments throughout
 
Microg­ame­tocyte: usually the size of an uninfected RBC and has a paler blue, pink or grey cytoplasm

Plas­modium Knowlesi

KNOWLESI MALARIA
 
Vector is A. balaba­censis & A. maculatus
 
Primate malaria in macaques in South East Asia
 
Infects ALL stages of RBC, and causes severe malaria
 
Erythr­ocytic cycle has quotidian pattern (every 24hrs)
 
Non-re­lapsing due to absence of hynozoites
 
Micros­cop­ically indist­ing­uis­hable from P. malariae (Use PCR to distin­guish)
 
Quotidian pattern results in high levels of parasi­temia and severe disease with fatal conseq­uence
TREATMENT
 
Chloro­quine
 
Primaquine
 
Should be treated aggres­sively and urgently
RING-FORM TROPHO­ZOITES
 
Normal to 0.75x smaller than uninfected RBC
 
Rings may show double chromatin dots
 
Appliqué forms may be seen as well as rectan­gular rings harboring one or more accessory chromatin dots
 
RBC may be Multip­ly-­inf­ected
OLDER, DEVELOPING TROPHO­ZOITES
 
Band forms may appear similar to P. malariae
 
Sinton and Mulligan's stippling may appear
SCHIZONTS
 
Sinton and Mulligan's stippling may appear
 
10-16 merozoites
Gameto­cytes
 
Mature Macrog­ame­tocyte: usually spherical and fill the host RBC. Cytoplasm stains blue and eccentric nucleus stains red
 
Microg­ame­tocyte: smaller and cytoplasm stains pale pink, while nucleus stains a darker red

Plas­modium Malariae

QUARTAN MALARIA
 
Erythr­ocytic cycle of 72hrs
 
Found in subtro­pical and temperate areas
 
Infected cells are normal to smaller in size than most RBCs
 
Old cells are prefer­ent­ially infected**
RING-FORM TROPHO­ZOITES
 
Have 1 chromatin dot and a cytoplasm ring that is thicker than P. falciparum.
 
Infected RBC is normal to smaller
 
Bird's-eye forms may appear
MATURE TROPHO­ZOITES
 
Rounded chromatin and compact cytoplasm
 
As the tropho­zoite matures, the cytoplasm may elongate across the host RBC, forming a band-form
 
Pigment granules become larger and tend to have a more peripheral arrang­ement
 
Zeimann's stippling may be present
SCHIZONTS
 
6-12 merozoites, often arranged in a rosette or irregular cluster
 
Mature schizonts nearly fill the normal­-sized host
GAMETO­CYTES
 
Compact and fills* host RBC
 
Sometimes, there is a reduction in size of the infected RBC
 
Cytoplasm stains blue and the chromatin is pink to red.
 
Abundant dark pigment may be scattered throughout the cytoplasm
Band forms are present in malariae, vivax, and knowlesi
 

Clinical Manife­sta­tions

PRE-PATENT PERIOD
Interval from sporozoite injection to detection of parasites in blood
 
P.falc­iparum: 11-14 days
 
vivax: 11-15 days
 
ovale: 14-26 days
 
malariae: 3-4 weeks
 
knowlesi: 9-12 days
INCUBATION PERIOD
time between sporozoite injection and appearance of clinical symptoms (8-40)
 
falcip­arum: 8-15 days
 
vivax: 12-20 days
 
ovale: 11-16 days
 
malariae: 18-40 days
 
knowlesi: 5 days- few weeks
PRODROMAL SYMPTOMS
Weakness, exhaus­tion, aching bones, limbs, and back; loss of appetite; nausea; vomiting
 
malaise, backache, diarrhea, and epigastric discomfort
MALARIAL PAROXYSM
1. Cold Stage
 
Sudden feelings of coldness and appreh­ension
 
Mild shivering quickly turns to violent teeth chattering and shaking of entire body
 
Vomiting may occur
 
Rigors last for 15min-1hr, then stops
2. Hot Stage or Flush Phase
 
Patient becomes hot (41° C ), with headache, palpit­ations, tachypnea, epigastric discom­fort, thirst, nausea, and vomiting
 
Skin is hot and flushed, patient is confused and delerious
 
Lasts 2-6hrs
3. Sweating Stage
 
Deferv­esence and diapho­resis or profuse sweating occurs
 
Temper­ature lowers in the next 2-4hrs and symptoms diminish accord­ingly
 
Total duration is 8-12hrs
Period­icity of attack only occurs if patient is left untreated
Interval length is determined by length of erythr­ocytic cycle
 
falcip­arum, vivax and ovale – 48 hours
 
malariae – 72 hours
 
knowlesi – 24 hours
COMPLI­CATIONS
Vivax, ovale and quartan malaria are relatively benign
Knowlesi
 
Severe thromb­ocy­top­enia, jaundice, deranged liver enzymes.
 
Acute Respir­atory Distress Syndrome with tachypnea, hypoxemia, and pulmonary infilt­rates on CXR.
 
Acute Renal Failure with elevated serum creatinine
 
Hypote­nsion
 
Acidosis
Chronic Malariae
 
immune­-co­mplex deposition on the glomerular walls, leading to nephrotic syndrome in children
Falciparum
 
Cerebral Malaria (requires prompt admini­str­ation of quinidine IV and then quinine PO)
 
Anemia
 
Acute Renal Failure (tubular necrosis and nephrotic syndrome)
 
Blackwater fever: from massive intrav­ascular hemolysis and hemogl­obi­nuria
 
Dysenteric Malaria
 
Algid Malaria: rapid develo­pment of hypote­nsion and impairment of vascular perfusion
 
Pulmonary Edema
 
Tropical Spleno­megaly Syndrome
 
Hyperp­ara­sitemia (>1­0-20% of RBC mean high mortality rate)
 
Hypogl­ycemia

Treatment

Proper use of the antima­larial drugs is based on knowledge of their effects on the parasite at various stages of the life cycle
Suppre­ssive therapy:
destroy the parasites as they enter the bloods­tream; effective against the erythr­ocytic stages.
Clinical Cure:
full and rapid elimin­ation of plasmo­diu­mfrom the blood to prevent compli­cations
Radical cure:
elimin­ation of not only the bloods­tream infection but the tissue stages in the liver as well.
BLOOD SCHIZO­NTI­CIDES
Clinical cure of an acute attack, no effect on pre-er­yth­rocytic and gametocyte stage
1. Quinine
blood schizo­nticide against all five species of human malarial parasites. Side effects of treatment include tinnitus and headache, vertigo
2. Quinidine
3. Chloro­quine
4. Amodia­quine
5. Mefloquine
effective against both chloro­qui­ne-­sen­sitive and –resistant strains of P. falciparum and P. vivax. It is also effective against P. malariae and P. ovale
6. Doxycy­cline
7. Proguanil
Prevents develo­pment of oocysts in mosquito
8. Halofa­ntrine
9. Artemi­sinin
effective against P. falciparum , P. knowlesi and P. vivax, and in patients with cerebral malaria
TISSUE SCHIZO­NTI­CIDES
destroy the develo­pmental stages in the liver
1. Primaquine
effective against the hypnoz­oites of P. vivax and P. ovale.
*GAMET­OCY­TICIDES
1. Primaquine
gameto­cyt­icidal for all five species of malaria parasites and acts to render the patient noninf­ectious to the mosquito
UNCOMP­LICATED P. FALCIPARUM
1. Atovaq­uon­e-P­rog­uanil
(Malar­one™) 4 adult tabs po qd x 3 days
2. Arteme­the­r-L­ume­fan­trine
(Coartem™) 1 tablet = 20mg artemether and 120 mg lumefa­ntrine . 4 tabs initial dose, followed by 4 tabs as second dose 8 hours later, then 4 tabs po bid for the following 2 days.
3. Quinine Sulfate
plus one of the following: Doxycy­cline, Tetrac­ycline, or Clinda­mycin (for pregnant)
4. Mefloquine
CHLORO­QUI­NE-­SEN­SITIVE FALCIPARUM OR UNCOMP­LICATED P. MALARIAE
1. Chloro­quine phosphate
UNCOMP­LICATED P. VIVAX OR OVALE
1. Chloro­quine phosphate plus Primaquine phosphate
CHLORO­QUINE RESISTANT VIVAX
1. Quinine sulfate plus either Doxycy­cline or Tetrac­ycline plus Primaquine phosphate
SEVERE MALARIA
1. Quinidine gluconate plus one of the following: Doxycy­cline, Tetrac­ycline, or Clinda­mycin
2. Exchange transf­usion has been recomm­ended for very severe falciparum malaria associated with high parasi­temia ( >10% of RBCs )
P. KNOWLESI
Uncomp­licated
1. Chloro­quine
2. Primaquine
Severe
1. Quinine
2. Arteme­the­r-L­ume­fan­trine
MALARIA PROPHY­LAXIS
1.Atov­aqu­one­/Pr­oguanil
2. Doxycy­cline
3. Chloro­quine
4. Mefloquine
5. Primaquine
 

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