MALARIA

350-500 million cazuri in lume

MALARIA:
Vector – țânțarul Anopheles

Protozoarul din genul 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
 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
 Etapele patogenetice
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)
 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
 Stages falcipar vivax ovale malaria
Șizogonie
6-9 d 8-12 d 10-14 d 15-18 d
tisulară
Perioada de
7-14 d 12-17 d 16-18 d 18-40 d
incubație
nr. merozoiți la
apariția
manifestărilor 40,000 10,000 15,000 2000
clinice

STAGES of the diseases

Prepatent period = time between sporozoite inoculation & appearance of parasites in blood
~ incubation periods can be prolonged for several months in vivax, ovale, malariae
Perioada prodromală:  Paroxismul malaric clasic
 manifestări nespecifice  Hepatosplenomegalie
 Febră, frison, cefalee, sfârșitul 1 săptămâni
lombalgii, manifestări GI  Anemie hemolitică
 Paroxismul malaric clasic

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

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 <9
• Modificări de conștiință, deliriu, convulsii
• Ar putea fi redoarea mușchilor occipitali, dar alte semne meningiene – sunt negative
• Dispnee (acidoză metabolică)
• Hipotensiune moderată
• Sechele neurologice: 5-30% copii
 Indicators of severe malaria and poor prognosis
Manifestation Features
1. Cerebral malaria: Glasgow <11; Coma persist for >30 min
can be after generalized convulsion

2. Severe anemia Ht <15% or Hb < 50 g/l & parasite count >10000/µl

3. Renal failure Urine output <400 ml/24 hours in adults (<12 ml/kg/24 hours
in children) & serum creatinine >265 µmol/l (> 3.0 mg/dl)
•Sequestration in glomerular capillaries
•Mesangial endothelial cell proliferation
•Immunoglobulin deposits
4. Metabolic / Lactic Metabolic acidosis  arterial blood pH <7.35, plasma
acidosis bicarbonate <22 mmol/L.
Hyperlactatemia  plasma lactate 2-5 mmol/L.
Lactic acidosis  pH <7.25 & plasma lactate >5 mmol/L.
• anaerobic glycolysis due to microvascular obstruction
•failure of hepatic and renal lactate clearance
• production of lactate by the parasite
Manifestation Features
5. Pulmonary edema Breathlessness, bilateral crackles, etc.
or ARDS pulmonary oedema. Basis: Rx, hypoxemia,
positive end-expiratory pressure
6. Hypoglycemia Blood glucose <2.2 mmol/l (<40 mg/dl).
• ↑ peripheral requirement, anaerob glycolysis
• ↑ metabolic demands of febrile illness
• obligatory demand of parasites
7. Hypotension and Systolic BP <50 mmHg in children 1-5 y.o.;
shock (algid malaria) <70mm Hg in pts ≥5 yo;
8. Abnormal bleeding Spontaneous bleeding from the gums, nose,
and/or DIC GI tract, retinal haemorrhages and/or lab.
evidence of DIC

9. Repeated ≥3 generalized seizures within 24 hours

generalised
convulsions
10. Haemoglobinuria Macroscopic black, brown or red urine; not
associated with effects of oxidant drugs or
enzyme defects (like G6PD)
 Indicators of severe malaria and poor prognosis
11. Impaired not falling into the definition of cerebral malaria. These
consciousness 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 Dehydration, postural hypotension, clinical hypovolemia
disturbances
17. Vomiting Pts with persistent vomiting  parenteral therapy.
18. Complicating or Aspiration bronchopneumonia, septicemia, urinary tract
associated infections infection etc.
19. Other indicators of WBC >12,000/cumm; high CSF lactate (>6 mmol/l); low CSF
poor prognosis glucose; AlAt >3xN; low antithrombin III levels; peripheral
schizontemia; papilloedema/retinal oedema
20. Malarial Frequent in children, less adults
Retinopathy
Signs Adults Children
Oncet Part of multi- Suddenly
organ disease
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 <3% 10%
 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 <5g/dl or Ht <15%).
•Thrombocytopenia (< 100 000 platelets/μl).
•Polymorphonuclear leukocytosis
•⇢ hypoglycaemia
•> urea, creatinine, bilirubin, aminotransferases,
creatine phosphokinase
•acidotic, with low plasma pH and bicarbonate
concentrations.
•Electrolyte disturbances (sodium,
potassium, chloride, calcium and phosphate)
•When possible  blood for bacterial culture
 Aims of antimalaria treatment
Aims Causation Drugs class Drugs
Alleviate Blood forms Fast-acting choloroquine (+other 4-aminoquinolines)
sympt. blood quinine, quinidine, mefloquine, halofantrine,
schizontocide antifolates (pyrimethamine, proquanil,
sulfadoxine, dapsone),
artemisinin & its derivatives (artesunate,
artemether, dihydroartemisinin)
Slow-acting
blood doxycycline (+ other tetracycline antibiotics)
schizontocide
Blood + tissue Blood + mild proquanil, pyrimethamine, tetracyclines
tissue
schizontocide
Prevent Hypnozoites Tissue primaquine
relapses schizontocide
Prevent Gametocytes Gametocidal primaquine, artemisinin derivatives, 4-
spread 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 choloroquine (+ other 4-aminoquinolines),

schizontocide quinine, quinidine, mefloquine, halofantrine,
antifolates (pyrimethamine, proquanil, sulfadoxine, dapsone),
artemisinin derivatives (quinhaosu)

Slow-acting blood doxycycline (+ other tetracycline antibiotics)

schizontocide

Blood + mild tissue proquanil, pyrimethamine, tetracyclines

schizontocide

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.
 Chemoprophylaxis
https://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
before therapy (terminal
during afterprophylaxis).
+ Contraindi
travel travel leaving Primaquin cation
Atovaquone/Proguanil 1-2d 1/day 7d last 1we 1 semester
(Malarone) 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.