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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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