2. OVERVIEW
Malaria, which predominantly occurs in tropical areas, is a
potentially life-threatening disease caused by infection with
Plasmodium protozoa transmitted by an infective
female Anopheles mosquito.
The 5 Plasmodium species known to cause malaria in humans are:
P. falciparum,
P. vivax,
P. ovale,
P. malariae, and
P. knowlesi
Each Plasmodium species has a defined area of endemicity,
although geographic overlap is common.
3. P. Vivax and P. falciparum are the most common.
P. Falciparum cause the most severe disease
P. knowlesi: The natural primate host of P. knowlesi is
the macaque. Naturally acquired human infections were thought to
be extremely rare until a large focus of human infections was
reported in Malaysian
P. malariae is a relatively mild form of malaria. Deaths associated with P.
malariae are not from acute infection but rather caused by end-stage renal
disease (nephrotic syndrome caused by an immune complex),
P. ovale causes a relatively mild form of malaria that is very rarely severe
or fatal. Although P. ovale has been reported from all continents, it is
edemic only in tropical Africa
OVERVIEW
4. Cosmopolitan especially in temperate, subtropical and tropical
zones. In Egypt, P. vivax malaria cases were identified in village of
the Aswan and Faiyum Governorates
Worldwide, an estimated 300-500 million cases occurring annually.
Malaria is responsible for approximately 1-3 million deaths per year,
typically in children in sub-Saharan Africa. P. falciparum is the
primary species responsible for increased morbidity and mortality.
Epidemiology
Young children aged 6 months to 3 years who live in endemic areas
are at an increased risk of death due to malaria. Travelers without
immunity are at an increased mortality risk, regardless of age.
Geographical distribution:
5. P. vivax P. ovale P. malariae P. falciparum
Infected R.B.C:
size
shape
+
distorted
+
Oval
-
Round
-
Round
Trophozoite:
Ring
Ameboid
Large
vacuoled
Large
compact
Large
Band like
Small, 2 or
more. Compact
Schizont
(merozoites No.) 12-24 4-12 6-12
rare
12-30
Gametocytes Large, round Large, round Compact, round Crescent shape
Stippling Schuffner’s
dots
Schuffner’s
dots
Ziemann’s dots Maurer’s dots
Hemozoin Fine granules
Light brown
Scatered
Light brown
Coarse granules
Dark brown
One or 2 solid
masses. Dark
Morphology
6.
7.
8. In the cytoplasm of the parasite
Malarial pigment (hemozoin):
Hemozoin is formed in the developing intra-erythrocytic parasites, as toxic heme
remaining after digestion of hemoglobin. Hemozoin released after the lysis of
infected RBC is phagocytosed by the RES, where it is readily observed within
macrophages of the bone marrow and spleen.
In the cytoplasm of the erythrocyte
Stippling (Punctate granulations):
Granules appear in the cytoplasm of the infected RBCs demonstrated in stained
thin blood film, due to alterations in/on the erythrocyte (as a consequence of
being parasitized by the plasmodia) and are not in the trophozoites. It is named
Schuffner’s dots (in vivax & ovale infections), Ziemann’s dots (in malariae
infection) and Maurer’s dots (in falciparum infection)
9. Habitat R.B.Cs. and liver cells
Hosts: D.H.: (invertebrate host): female Anopheles
mosquito; where sexual cycle takes place
(sporogony).
I.H.: man; where the asexual cycle occurs (asexual
multiplication by schizogony).
R.H.: Chimpanzee may be a reservoir host for P.
malariae in some parts of Africa.
Infective
stage:
Sporozoite transmitted by female Anopheles
Erythrocytic stages (except gametocytes) in induced
malaria
10. Modes of
infection:
• Biological transmission by female Anopheles mosquito.
• Blood transfusion from an infected donor (No hepatic phase).
• The use of contaminated syringes as in addicts (No hepatic phase).
• Rarely congenital transmission through the placenta (No hepatic
phase).
• Organ transplantation from a donor infected with P. falciparum or
with P. vivax and P. oval (hypnozoites in the liver).
14. The incubation period: defined as the time between sporozoite
inoculation and the onset of symptoms.
o P falciparum 9-14 days
o P vivax 12-17 days
o P ovale 16-18 days
o P malariae 18-40 days
During the hepatic phase: No clinically manifestations or
slight enlargement and tenderness of the liver.
During erythrocytic phase: Rupture of the infected RBCs and
release of merozoites, malarial pigment, and toxins into the
circulation cause the main clinical manifestations of malaria.
15. The erythrocytic phase: Pathology associated with all malarial
species is related to the rupture of infected erythrocytes and
the release of parasite material and metabolites, malaria
pigment and cellular debris clinical manifestations of
malaria:
Pathogenesis and clinical picture
After the incubation period (8-30 days according to the species),
the following clinical aspects occur in all types of malaria:
The pre-erythrocytic phase: Affects only a very few
hepatocytes. This phase passes off as a ‘silent’ phase
without any symptoms or very slight enlargement and
tenderness of the liver.
16. Clinical Picture
During the initial days of following the incubation period:
The classical clinical manifestations of malaria may not be seen
in many patients, as schizogonic cycles are not synchronized
and parasite populations are heterogeneous, resulting in
irregular or continuous fever, or no fever with prodromal
symptoms.
18. Malarial paroxysm
After the incubation period and the initial days post infection,
synchronization of schizont rupture is established producing the
classical pattern of malarial paroxysm:
19. Cold stage: feeling of extreme cold, rigors and
chattering of teeth.
Hot stage: fever (39-41°C), flushed face,
restlessness, rapid pulse, intense frontal headache,
nausea and vomiting, disorientation or even
delirium and convulsions especially in children.
Sweating stage: profuse sweating, decline of fever
and relief of symptoms.
Following the sweating stage, the temperature becomes normal, the
patient is exhausted and falls asleep.
Between paroxysms the patient feels well, whereas, the trophozoites
complete their cycle in erythrocytes till its rupture.
Malarial paroxysm
20. Periodicity and duration of malarial paroxysms
Species Disease Periodicity Duration
P. vivax
Benign tertian
malaria
48 hours cycles 3-8+ weeks
P. ovale
Benign tertian
malaria
48 hours cycles 2-3 weeks
P. falciparum
Malignant tertian
malaria
Irregular (1-3
days)
2-3 weeks
P. malariae Quartan malaria 72 hours cycle 3-24 weeks
P. knowlesi Quotidian malaria 24 hour cycle undefined
21. 1) Hemolytic anaemia and jaundice due to destruction of
a large number of red blood cells.
2) Hepatosplenomegaly due to hyperplasia of the
reticuloendothelial cells as a result of engulfment of
merozoites, malarial pigment, proteinaceous and toxins
3) Grey or black pigmentation of visceral organs due to
deposition of malarial pigment.
The consequences of the repeated malaria paroxysms:
In areas with endemic malaria, older children and adults are
immune to clinical illness and hence may not have fever despite
parasitemia. However, loss of immunity due to pregnancy or
immunosuppression can result in severe disease.
22. o Severe malaria primarily involves P falciparum infection.
o P. falciparum infection causes malignant malaria due to:
1) Short hepatic cycle
2) Asynchronized maturation and rupture of the schizonts.
3) Adhesion phenomenon
4) Pernicious malaria
Malignant Malaria
Short hepatic cycle (6 days) with large numbers of merozoites in
liver schizont (40,000). These merozoites invade RBCs of all ages
resulting in high parasitaemia, more severe anaemia and jaundice.
Erythrocytic schizogony is completed in 36-48 hours, so, schizogonic
cycles are not synchronized leading to irregular paroxysm pattern
and difficult diagnosis.
23. Adhesion phenomenon:
Infected erythrocytes tend to adhere to each other
and to the capillary endothelium in internal organs
forming thrombi and obstruction of the small blood
vessels. Ischemia and anoxia of these organs in
addition to rupture of the blocked capillaries and
haemorrhage cause destruction of the surrounding
tissue
Pernicious malaria:
are the result of capillary blockage arises from
agglutination of parasitized erythrocytes in the
internal organs. So, it is a consequence of adhesion
phenomenon. The clinical manifestations are
variable according to the affected organ and the
degree of ischemia and tissue damage
24. Complications of malaria:
• Severe anemia
• Pernicious syndrome
• Respiratory symptoms
• Complications in Pregnancy
• Black water fever
• Nephrotic syndrome
• Metabolic complications
• Hyperreactive malarial
splenomegaly
• Recrudescence and Relapse
25. The anemia associated with malaria is multifactorial due to:
1) Rupture of infected RBCs may occur with all Plasmodium
species especially P. falciparum infection.
2) Autoimmune hemolysis of uninfected RBCs due to
hypersplenism
3) Impaired hemopoiesis due to toxic bone marrow suppression.
Severe anemia
Pernicious syndrome
In P. falciparum Infection:
The adhesion phenomenon (vascular obstruction +
ischemia + hemorrhage) Pernicious syndrome
In Pernicious syndrome the clinical manifestations are
variable according to the affected organ and the degree of
tissue damage as follows:
26. Cerebral malaria: severe headache, hyperpyrexia, delirium,
paralysis, convulsions, coma, and death.
Gastrointestinal manifestation: thrombosis in the capillary bed of
the intestinal wall, ischemia and bleeding leading to:
Hematemesis
Cholera-like diarrhoea
Dysentery
Algid malaria: shock, collapse and peripheral circulatory failure due
to generalized vascular thrombosis, haemorrhage in gastrointestinal
tract and adrenal glands necrosis .
Renal failure: Infected erythrocytes adhere to the
microvasculature in the renal cortex, often resulting in acute
tubular necrosis and renal failure.
Loss of vision: due to malarial retinopathy or retinal haemorrhage
27. Maternal: Immuno-suppression and loss of
acquired immunity to malaria cause severe malaria
Fetal: Placental hemorrhage and insufficiency lead to spontaneous
abortion or still birth, Low birth weight, and placental spread of the
infection to the fetus can result in congenital malaria.
Complications in Pregnancy
Metabolic acidosis and pulmonary edema
Signs of malarial hyperpneic syndrome include:
Alar flaring,
Intercostals retraction,
Use of accessory muscles for respiration, or
Abnormally deep breathing.
Respiratory symptoms
28. Black water fever:
Acute massive intravascular haemolysis as
an autoimmune reaction occurs with
o inadequate quinine treatment or
o repeated infection with P. falciparum in
partially immune (previously infected)
patients.
It usually occurs during the malarial
paroxysm and is characterized by fever,
severe hemolytic anemia, jaundice,
haemoglobinaemia and haemoglobinurea
with dark red or black urine.
Blocking of the kidney tubules may lead to
anurea, renal failure and death.
29. Immune complex deposition in the renal glomeruli may occur in
chronic Plasmodium malariae infection especially in children.
It is characterized by oedema and ascites, hypertension and
proteinuria.
Nephrotic syndrome
Hypoglycemia; Hypoglycemia often occurs in young children and
pregnant women
Lactic acidosis; This occurs when the microvasculature becomes
clogged with P falciparum
Metabolic complications
30. Also known as Tropical splenomegaly syndrome
Etiology: immunological over-stimulation to repeated attacks
of malarial infection over a long period of time.
Condition is usually seen in malaria-endemic areas
like Africa and India.
Hyperreactive malarial splenomegaly
It is characterized by:
Massive splenomegaly, hepatomegaly,
marked elevations in levels of serum anti-
malarial antibodies.
Peripheral smear for malarial parasite is
usually negative.
Condition may show features
of hypersplenism
Splenic rupture may occur spontaneously or
after a minor trauma.
31. Recrudescence and Relapse
Relapse: In P. vivax and P. ovale, some of the sporozoites remain
dormant in the liver cells (as hypnozoites) to be reactivated later
resulting in relapses usually 3~6 mon after “cured”.
Recrudescence: In all species of plasmodium, persistence of drug
resistant parasite leads to a low-grade parasitaemia that can not
initiate a paroxysm and may persist for a long period (even up to
20 years in P. malariae) leading to or reappearance of paroxysms if
the patient becomes debilitated or immunosuppressed for any
reason.
32. Diagnosis
• Clinical Diagnosis:
o History of visiting or living in endemic
areas
o Characteristic clinical manifestations.
Clinical findings should always be confirmed
by a laboratory test for malaria.
• Direct Laboratory diagnosis:
o Microscopic examination of blood films,
o The quantitative buffy coat technique.
o Ascoli’s test
o Bone marrow puncture
• Indirect Laboratory diagnosis (immunologic
tests):
o Antibodies Detection
o Antigen Detection (Rapid diagnostic
test)
• Molecular Diagnosis:
o PCR is useful for diagnosis and
identification of species of Plasmodium.
• Imaging studies:
33. Microscopic examination of blood films
Identification of the parasites on a thin or thick blood smear
(stained with Giemsa or leishman stains) reveal all erythrocytic
stages except in P. falciparum (only ring & gametocyte stages).
Thick smears are 20 times more sensitive than thin smears,
but speciation may be more difficult. The parasitemia can be
calculated based on the number of infected RBCs, so, it is a
quantitative test.
Thin smears are less sensitive than thick smears, but they
allow identification of the different species. This should be
considered a qualitative test.
37. Alternative direct diagnostic tests:
1) The quantitative buffy coat technique.
2) Ascoli’s test.
3) Bone marrow puncture.
The quantitative buffy coat (QBC): Detection of acridine
orange-stained erythrocytic stages that fluoresce when
viewed by a fluorescent microscope.
It is a technique that is as sensitive as thick smears.
Ascoli’s test: Helpful in case of light chronic infections
0.5 ml of 1/1000 adrenaline injected subcutaneously will lead
to contraction of the spleen and passage of the parasites to
the circulation.
38. Bone marrow puncture:
Bone marrow aspiration studies are of vital importance in
diagnosing malarial infection in endemic areas as being one of
the cause of pancytopenia or thrombocytopenia.
Plasmodium can be detected in the bone marrow aspirate
Bone marrow aspirate demonstrates hemozoin pigment.
Bone marrow aspirate can be used for PCR analysis
39. Indirect Laboratory diagnosis (immunologic tests)
Antibodies Detection:
Serology detects antibodies against malaria parasites, using
either indirect immunofluorescence (IFA) or enzyme-linked
immunosorbent assay (ELISA).
Disadvantage: Serology does not detect current infection but
rather measures past exposure.
Antigen Detection (Rapid Diagnostic Test)
(RDT) is an alternate way of quickly establishing the diagnosis of
malaria infection by detecting specific malaria antigens in a
person’s blood.
Disadvantage: The RDT may not be able to detect some infections
with lower numbers of malaria parasites circulating in the patient’s
bloodstream.
40.
41. Molecular Diagnosis: Polymerase chain reaction assay;
PCR assay testing is a very specific and sensitive means of
diagnosis.
It is very effective at detecting Plasmodium species in patients
with low parasitemia.
However, PCR assay tests are not available in most clinical
situations.
42. Imaging studies
Chest radiography may be helpful if respiratory symptoms are
present.
Computed tomography of the head, if central nervous system
symptoms are present, to evaluate evidence of cerebral
edema or hemorrhage.
43. oOnce the diagnosis of malaria has been made,
appropriate antimalarial treatment must be
initiated immediately.
oTreatment should be guided by the following four
main factors:
Treatment of Malaria
1) Infecting Plasmodium species;
2) Clinical status of the patient;
3) Expected drug susceptibility of the infecting parasite as
determined by the geographic area where the infection
was acquired; and
4) Previous use of antimalarials, including those taken for
malaria chemoprophylaxis. In this case, the treatment
regimen should not involve the drug or drug combination
used for prophylaxis.
44. Determination of the infecting Plasmodium species for treatment purposes is
important for three main reasons:
1) P. falciparum infections can cause rapidly progressive severe illness or death,
while the other species, P. vivax, P. ovale, and P. malariae, are less likely to
cause severe disease.
2) P. vivax and P. ovale infections also require treatment for the hypnozoites,
which remain dormant in the liver and can cause relapsing episodes.
3) P. falciparum and P. vivax species have different drug resistance patterns in
different geographic regions of the world.
Clinical status of the patient: Patients diagnosed with malaria are generally
categorized as having either uncomplicated or severe malaria:
Patients diagnosed with uncomplicated malaria can be effectively treated
with oral antimalarials.
patients who have one or more of complications, are considered to have
manifestations of severe disease and should be treated aggressively with
intravenous antimalarial therapy
45. Antimalarial Therapy
Objective Explanation Drugs
Causal prophylaxis Tissue schizonticides:
eliminate developing or
dormant liver forms.
Primaquine, proguanil and
pyrimethamine
Clinical cure Blood schizonticides
act on erythrocytic parasite
Chloroquine, quinine,
tetracyclines, mefloquine,
pyrimethamine-sulfadoxine
and artemisinin
Radical cure Eliminate both hepatic &
erythrocytic stages
Primaquine
Tafenoquine
Prevent
transmission
Gametocytocidal: prevent
transmission of infection to
the mosquito
Primaquine, proguanil
pyrimethamine and quinine
Chemoprophylaxis Protection of non-infected
people traveling to an
endemic area
Chloroquine, doxycycline,
mefloquine and primaquine
46. chloroquine-sensitive malaria: Chloroquine phosphate; Dose: orally total dose 1.5
gm (10 tablets)
4 tablets [600 mg] initial dose.
2 tablets [300 mg] after 6 hours
2 tablets [300 mg] daily x 2 days
For prevention of relapses in vivax and ovale malaria, using primaquine 15mg /
day x 14 days to destroy hypnozoites in the liver.
Therapy of Uncomplicated malaria (P.
falciparum or species not identified):
chloroquine-resistant malaria:
A. Mefloquine: 15mg/kg in a single oral dose.
B. Combined chemotherapy is the best:
1) Quinine sulfate 650 mg tds x 3-7 days orally + one of the followings:
Doxycycline, Tetracycline or Clindamycin
2) Artemisinin-based combination therapy: Companion drugs with
Artemisinin in one tablet include lumefantrine, mefloquine, amodiaquine, or
sulfadoxine/pyrimethamine,
3) Atovaquone(250 mg )/ proguanil (100 mg) (Malarone®) 4 tabs qd x 3 days
47. Therapy of Uncomplicated P. malariae
Chloroquine as above
Therapy of Uncomplicated P. vivax or P. ovale
Chloroquine-sensitive:
Chloroquine plus primaquine: Chloroquine treatment as above, and
primaquine: 30 mg base qd x 14 days.
Chloroquine-resistant:
A. Quinine plus either doxycycline or tetracycline. For prevention
of relapses in vivax and ovale malaria. For radical cure
primaquine is using (15mg / day x 14 days) to destroy
hypnozoites in the liver.
B. Mefloquine plus primaquine for radical cure
48. Therapy of Complicated P. falciparum
(A) Quinine: 16.7 mg/kg loading diluted in 10 ml/ kg isotonic fluid by IV infusion
over 4 hrs, then 8.3 mg base/ kg by IV infusion over 4 hrs, repeated 8
hourly for up to 72 hrs or until can swallow, then quinine tablets to
complete 3-7 days of treatment
Or, Quinidine: 15 mg/kg loading diluted in 10 ml/ kg isotonic fluid by IV
infusion over 4 hrs, then 7.5 mg/kg by IV infusion over 4 hrs,
repeated 8 hourly for up to 72 hrs or until can swallow, then
Quinidine tablets to complete 3-7 days of treatment
Plus, Doxycycline, Tetracycline, or Clindamycin, (either concurrently with
quinine/ quinidine or immediately after)
(B) Alternative: Artimesinin or one of its derivatives as artemether (in a dose of 3.2
mg/ kg IM followed by 1.6mg/kg daily for one week) are used for
multi-resistant malaria or when quinine is contraindicated as in
black water fever.
49. Is essential for non-immune travelers to an endemic area.
Starts 2 weeks before exposure, during stay, and 1-4 weeks after
leaving the endemic area.
Chemoprophylaxis
Drug indication contraindication
Chloroquine, 300
mg/week
Chloroquine sensitive Chloroquine resistant
Mefloquine, 250 mg
once weekly
Can be used in
pregnancy
Mefloquine resistant
Doxycycline, 100 mg
daily
For last minute travelers Child and pregnant
Primaquine, 15 mg/ day Terminal prophylaxis: for
vivax and ovale malaria
on leaving
G-6-PD (Severe
Hemolysis)
50. Prevention and
control:
o Mass treatment of cases +
eradication of gametocytes by
giving a single dose of 4 tablets of
primaquine to prevent transmission
of infection to mosquito.
o Mosquito control.
o Personal protection by:
• Using repellants and
insecticides.
• Screening of doors and
windows.
• Chemoprophylaxis for non-
infected persons traveling to
an endemic area.
o Vaccination: still under trial.
