MALARIA350-500 million cazuri in lume

Protozoarul din genul Plasmodium

MALARIA:

Vector – țânțarul Anopheles

http://en.wikipedia.org/wiki/Plasmodium

lay 50–200 eggs

larvae pupae

Falciparum (malaria tropică, malignă):

- predomină in Africa.

- 50% din toate cazurile de malarie,

- 90% din cazurile de deces

Vivax (malaria benignă terța):

- tropice / sub-tropice (America Latină, Asia, rar in Africa

- 43% din toate cazurile de malarie din lume

Ovale (malaria beningă terța):

- Africa Vest, sub-sahariană

- poate afecta persoanele gr. sangvin Duffy neg

Malariae (malaria benignă quarta):

- în sub-tropice, toată lume

- 7% din toate cazurile de malarie

- poate cauza malaria cronică (portaj la nivel subpirogenic)

Plasmodium knowlesi

• Malaria primatelor (rar afectează

oamenii)

• Asia Sud-Est (Borneo,

Cambodia,Malaysia, Myanmar,

Philippines, Singapore, Thailand)

• absentă in Africa

• Ciclul asexual erytrocitar 24 ore

• Febră zilnică

• Netratată – letalitate înaltă (similar

cu malaria falciparum)

• Microscopic similar cu Pl.malariae,

dar trophozoiții tineri – similar cu

Plasmodium falciparum

• Incubația 10-12 zile

• treatment: chloroquine și

primaquine

http://en.wikipedia.org/wiki/Borneohttp://en.wikipedia.org/wiki/Cambodiahttp://en.wikipedia.org/wiki/Malaysiahttp://en.wikipedia.org/wiki/Myanmarhttp://en.wikipedia.org/wiki/Philippineshttp://en.wikipedia.org/wiki/Singaporehttp://en.wikipedia.org/wiki/Thailandhttp://en.wikipedia.org/wiki/Africahttp://en.wikipedia.org/wiki/Chloroquinehttp://en.wikipedia.org/wiki/Primaquine

Dezvoltarea în țânțar:

Gametocit sporozoit

= 7-10 ≈21 zile

depende de:

1. specia parazitului

2. T0 >160C, optimal 25-300C

3. umeditate

4. altitudine (sub 2000 m)

Dezvoltare în hepatocit (etapa pre-eritrocitară)

Etapa eritrocitară

1. Modificarea structurii, proprietăților biochimice și mecanice ale

eritrocitelor

2. Eliberarea pigmentului malaric (heozoin), toxic p-u organismul uman,

la distrugerea eritrocitelor

3. Eliberarea în exces a citokinelor proinflamatorii TNF-a, IL-1b, IF-g

4. Creșterea permiabilității capilarelor

5. Activează moleculele de adeziune (CD36, ICAM1..) din celulele

endoteliale trigger p-u coagulare și formarea de rozete în malaria

Falciparum

6. Micșorează gluconeogeneza hipoglicemie

7. Afectare multiorganică: ficat, splina, SNC, rinichi, plămâni, cord, GI

(congestie venoasă, edem, depunere de hemozoin, regiuni de

microinfarct, ect)

Etapele patogenetice

The outcome of malaria is determined by

the balance between the pro- and anti-inflammatory cytokines

Confer degrees of protection from severe falciparum:

•α-thalassemia

risk reduced 70% homozygous HbC

risc reduced 90% by heterozygous HbS (sickle-cell trait)

In Duffy blood group neg. (No FyFy antigen) resistance to

vivax = explains the rarity of P. vivax in Africa

Prepatent period = time between sporozoite inoculation & appearance of parasites in blood

~ incubation periods can be prolonged for several months in vivax, ovale, malariae

Stages falcipar vivax ovale malaria

Șizogonie

tisulară6-9 d 8-12 d 10-14 d 15-18 d

Perioada de

incubație7-14 d 12-17 d 16-18 d 18-40 d

nr. merozoiți la

apariția

manifestărilor

clinice

40,000 10,000 15,000 2000

STAGES of the diseases

Perioada prodromală:

manifestări nespecifice

Febră, frison, cefalee,

lombalgii, manifestări GI

Paroxismul malaric clasic

Hepatosplenomegaliesfârșitul 1 săptămâni

Anemie hemolitică

A. FRISON

durata 15 min – 1 oră

Cefalee, mialgii, ↑ Ps, tusea, dispnee, dureri toracale, dureri abdominale,

manifestări GI, ~convulsii

Cauza: distrugerea în masă a eritrocitelor

B. CĂLDURĂ

durata 2-6 ore,

Febra 40C, fatigabilitate, astenie, cefalee

Merozoiții invadează noi eritrocite

C. TRANSPIRAȚII

Durata 2-4 ore,

transpirații profuze, scăderea litică a t0C

Durata totală a paroxismului malaric: 4-8 ore, foarte rar 12 ore

Paroxismul malaric clasic

Periodicitatea paroxismului malaric

= chea spre diagnostic

Plasmodiul î-si sincronizează

șizogonia eritrocitară

eșirea simultană a merozoiților din

eritrocite

șizogonia eritrocitară :

Vivax/ovale = 48h (“tertian” malaria)

Malariar = 72h (“quartan” malaria)

Falciparum = 48h (“sub-tertian” ), dar

nu are loc sincronizarea șizogoniei

Knowlesi = 24h

Malaria cerebrală:

• Glasgow

Indicators of severe malaria and poor prognosis

Manifestation Features

1. Cerebral malaria: Glasgow 30 min

can be after generalized convulsion

2. Severe anemia Ht 10000/µl

3. Renal failure Urine output 3.0 mg/dl) •Sequestration in glomerular capillaries

•Mesangial endothelial cell proliferation

•Immunoglobulin deposits

4. Metabolic / Lactic

acidosis

Metabolic acidosis arterial blood pH

Manifestation Features

5. Pulmonary edema

or ARDS

Breathlessness, bilateral crackles, etc.

pulmonary oedema. Basis: Rx, hypoxemia,

positive end-expiratory pressure

6. Hypoglycemia Blood glucose

11. Impaired

consciousness

not falling into the definition of cerebral malaria. These

patients are generally arousable

12. Prostration Extreme weakness, needs support

13. Hyperparasitemia 5% parasitized RBC or >250 000 parasites/µl (in

nonimmune)

14. Hyperpyrexia Core body temperature above 400C

15. Jaundice Serum bilirubin >43 mmol/l (>2.5 mg/dl).

16. Fluid / electrolyte

disturbances

Dehydration, postural hypotension, clinical hypovolemia

17. Vomiting Pts with persistent vomiting parenteral therapy.

18. Complicating or

associated infections

Aspiration bronchopneumonia, septicemia, urinary tract

infection etc.

19. Other indicators of

poor prognosis

WBC >12,000/cumm; high CSF lactate (>6 mmol/l); low CSF

glucose; AlAt >3xN; low antithrombin III levels; peripheral

schizontemia; papilloedema/retinal oedema

20. Malarial

Retinopathy

Frequent in children, less adults

Indicators of severe malaria and poor prognosis

http://www.malariasite.com/malaria/Hyperparasitemia.htmhttp://www.malariasite.com/malaria/Hyperparasitemia.htmhttp://www.malariasite.com/malaria/Complications8.htmhttp://www.malariasite.com/malaria/Fluid.htmhttp://www.malariasite.com/malaria/secondary_infections.htmhttp://www.malariasite.com/malaria/Complications3.htm

Signs Adults Children

Oncet Part of multi-

organ disease

Suddenly

Cough Uncommon In early stage

Respiratory distress (acidosis) Frequent

Convulsions Rare Frequent

Cerebral malaria Rare Frequent

Anemia Rare Frequent

Hypoglycemia Pregnant, quinine Common

Development of unconsciousness Insidious Rapid

Bleeding/clotting disturbances Up to 10% Rare

Jaundice Frequent Rare

Acute renal failure, hemoglobinuria Frequent Rare

Pulmonary edema, ARDS Frequent Rare

Metabolic acidosis + +

Coma recovery time Slow, 2-4 days Rapid, 1-2 d

Persistent neurological deficits

Tropical splenomegaly syndrome (HIMSS)

Large spleen>1000g

Moderate anaemia

High IgM level

Liver sinusoidal lymphocytosis

Chronic low-grade malarial infection

WHO is recommend:

• parasitological confirmation before treatment is started

• Giemsa stain

rapid diagnostic test (RDT) Antigen Detection Tests for Malaria

Vivax

enlarged RBC

Schüffner's dots

'ameboid' trophozoite

prefer reticulocytes

Ovale

similar to vivax

compact trophozoite

fewer merozoites in schizont

elongated RBC

prefer reticulocytes

Malariae

compact parasite

merozoites in rosette

prefers senescent RBC

Under the microscope, mature P.knowlesi are indistinguishable from

those of P. malariae

Falciparum

numerous rings

smaller rings

no trophozoites or schizonts

cresent-shaped gametocytes

all RBC

Monitoring of parasitaemia every 12h during the first 2–3 days of treatment

response to the antimalarials

RDTs can remain positive for up to 4 weeks after clearance of parasitaemia.

Haematological and biochemical findings in severe malaria

•Normocytic anaemia (⇢Hb

Aims of antimalaria treatment

Aims Causation Drugs class Drugs

Alleviate

sympt.

Blood forms Fast-acting

blood

schizontocide

Slow-acting

blood

schizontocide

choloroquine (+other 4-aminoquinolines)

quinine, quinidine, mefloquine, halofantrine,

antifolates (pyrimethamine, proquanil,

sulfadoxine, dapsone),

artemisinin & its derivatives (artesunate,

artemether, dihydroartemisinin)

doxycycline (+ other tetracycline antibiotics)

Blood + tissue Blood + mild

tissue

schizontocide

proquanil, pyrimethamine, tetracyclines

Prevent

relapses

Hypnozoites Tissue

schizontocide

primaquine

Prevent

spread

Gametocytes Gametocidal primaquine, artemisinin derivatives, 4-

aminoquinolines (limited?)

Sporozoytes Sporontocidal proquanil, pyrimethamine, atovaquone

Never use mefloquine after quinine (may increase myocardial toxicity)

• La administrarea tratamentului antimalaric vor fi

luați în considerație factorii:

– Specia plasmodiumului

– Statutul clinic al pacientului

– Susceptibilitatea la antimalatice:

• regiunea geografică

• Administrarea de antimalarice în scop profilactic

Drug Class Examples

Fast-acting blood

schizontocide

choloroquine (+ other 4-aminoquinolines),

quinine, quinidine, mefloquine, halofantrine,

antifolates (pyrimethamine, proquanil, sulfadoxine, dapsone),

artemisinin derivatives (quinhaosu)

Slow-acting blood

schizontocide

doxycycline (+ other tetracycline antibiotics)

Blood + mild tissue

schizontocide

proquanil, pyrimethamine, tetracyclines

Tissue schizontocide primaquine

Gametocidal primaquine, artemisinin derivatives, 4-aminoquinolines

Combinations Fansidar (pyrimethamine + sulfadoxine), Maloprim (pyrimethamine +

dapsone), Malarone (atovaquone + proquanil)

Tratamentul cazurilor non-complicate de P.Falciparum

Combinarea a ≥2 antimalarice cu diferit mecanism de acțiune

Includerea în tratament a artemisin-ului (ACT) :

Durata 3 zile:

• artemether + lumefantrine (Coartem) ,

• artesunate + amodiaquine,

• artesunate + mefloquine,

• artesunate + sulfadoxine-pyrimethamine,

• dihydrortemisinin + piperaquine.

or

• Atovaquone-proguanil (Malarone)

Antimalarice de linia II:

• artesunate + tetracycline /doxycycline /clindamycin 7 zile;

• quinine + tetracycline /doxycycline /clindamycin

• Mefloquine (Lariam)

1 doză de primaquine la sfârșitul tratamentului = scop: gametocid

Teatment Falciparum malaria severe

Antimalarice timp de ≥24 h:

• Artesunate 2.4 mg/kg IV/IM; la 0ore 12ore 24ore 1/d/zi.

Alternativa:

• Quinine 20mg salt/kg IV (I doză 10mg/kg x la 8 ore lent

rata de infuzie = 5mg/kg/oră); risc de hipoglicemie la gravide

Artemether IM 3.2mg/kg 1.6mg/kg/day

Apoi 3 zile:

– artemether plus lumefantrine,

– artesunate plus amodiaquine,

– dihydroartemisinin plus piperaquine,

– artesunate plus sulfadoxine-pyrimethamine,

– artesunate plus clindamycin or doxycycline,

– quinine plus clindamycin or doxycycline

https://www.malariasite.com/antimalarial-

combinations/

vivax & ovlae

Treatment of malaria in pregnancy

Chloroquine can be used safely in all trimesters of pregnancy.

Artemisinin can be considered if the situation demands.

Quinine can be used in pregnancy, but watchful about hypoglycemia.

Mefloquine contraindicated in the first trimester of pregnancy

Pyrimethamine/ sulphadoxine contraindicated in the first and last trimesters.

Halofantrine, tetracycline, doxycycline absolutely contraindicated

Primaquine contraindicated in pregnancy

Therefore pregnant with P. vivax chloroquine 500 mg weekly as

suppressive chemoprophylaxis against relapse of malaria.

In the I with uncomplicated falciparum quinine + clindamycin for 7 days

and quinine monotherapy if clindamycin is not available.

Artesunate + clindamycin for 7 days if this treatment fails.

Chemoprophylaxishttps://www.cdc.gov/malaria/travelers/country_table/a.html

Primary chemoprophylaxis regimens involve:

a) taking a medicine before travel

b) during travel

c) a period of time after leaving the malaria endemic area

Presumptive antirelapse therapy (terminal prophylaxis). before travel

during

travel

after

leaving

+

Primaquin

Contraindi

cation

Atovaquone/Proguanil

(Malarone)

1-2d 1/day 7d last 1we 1 semester

pregnacy

Mefloquine (> 6 we) 2we 1/we 4we last 2we depression

Doxycycline (up to 6 we) 1-2d 1/day 4we last 2we pregnacy

Chloroquine 1-2we 1/we 4we last 2we

Primaquine 1-2d 1/day 7d - G6PD-

deficiency

Pregnant + P. vivax: chloroquine 500mg weekly = suppressive chemoprophyl.