MALARIA

 Genus Plasmodium
 Pigment producers
 Ameboid in shape
 Asexual life cycle – man (vertebrate and intermediate host)
 Sexual life cycle - Anopheles mosquito (invertebrate, definitive host)

ETIOLOGY

Plasmodium falciparum Malignant tertian or subtertian malaria

Falciparum malaria
Plasmodium vivax Benign tertian malaria
Vivax malaria
Plasmodium malariae Quartan malaria
Malariae malaria
Plasmodium ovale Benign tertian malaria
Ovale malaria
 ASEXUAL
SCHIZOGONY - formation of merozoites
GAMETOGONY - formation of gametocytes
 SEXUAL
SPOROGONY - formation of sporozoites
DEVELOPMENTAL STAGES
1. Trophozoite - feeding stage in the asexual cycle, found in the tissue cells
2. Schizonts - the sporozoan’s body during schizogony which includes the period of initial
growth to the complete splitting up of the nucleus with merozoite production
3. Merozoites - formed in the pre-erythrocyctic stage, are released into the blood stream and
enter the RBC through the erythrocytic surface receptors and start the
erythrocytic schizogony
The release of merozoites in the blood stream causes the:
Typical intermittent chills
Fever
Sweating(malaria paroxysms)
4. Gametocytes - immature sexual form of the parasite; infective to the mosquito
Macrogametocytes- female gametocytes
Microgametocytes- male gametocytes
5. Gametesc- mature sexual forms
Macrogametes- female sex cell in sporozoa
Microgametes- male sex cell in sporozoa
6. Zygote - result of the union of the macrogamete and microgamete (fertilized ovum)
7. Oocyst - encysted zygote
8. Sporozoites - end product of sexual multiplication of malarial parasites in mosquito;
infective stage of man

• Length of the developmental cycle in the mosquito depends not only on the species of Plasmodium but on
the particular mosquito host and the ambient temperature
• 8 days (P. vivax) to 35 days (P. malariae)
• Asexual multiplication takes place within the liver cells
• A varying portion of the infecting sporozoites of P. vivax and P. ovale enter into a resting stage before
undergoing asexual multiplication  HYPNOZOITE
• Principal malaria vector is Anopheles minismus var flavirostris
night biter
prefers to breed in slow-flowing, partly shaded streams
has the ability to adapt to or utilize new habitats such as irrigation
ditches, rice fields, wells,pools
 horizontal flight range 1-2 km
Anopheles litoralis: assoc w/ malaria transmission in the coastal areas
of Mindanao (Sulu)
• Transmitted by the BITE of a Plasmodium- infected female Anopheles mosquito
• Malaria can also be transmitted through blood transfusion from infected donors and by contaminated
needles and syringes
• In congenital malaria, infected mothers transmit parasites to their child before or during birth
• 9th leading cause of morbidity in the Philippines
• 58 out of 81 provinces are malaria-endemic

Parameter P. falciparum P. vivax P. ovale P. malariae

Infected RBC Size is not Size is enlarged with Larger than normal, Same with P.vivax
enlarged pale color often with fringed or
irregular shape
Color is normal

Round shaped, Round shaped,

sometimes sometimes fimbriated
crenated and adopt bizarre shapes
due to spreading

Basophilic Stippling:
Basophilic SCHUFFNER’S Basophilic Stippling Basophilic Stippling:
stippling: DOTS SCHUFFNER’S ZIEMANN’S DOTS
MAURER’S (very fine reddish DOTS
DOTS granules)
Parameter P. falciparum P. vivax P. ovale P. malariae
Small Same as P. vivax Signet-ring form with Small, darker in color, Same as P. vivax but
trophozoite but with small heavy red dot (nucleus) and generally more solid with blue cytoplasmic
(early rings) threadlike blue and blue cytoplasmic than those of P. circle, smaller, thicker
cytolasmic circle ring falciparum; Schuffner’s and heavier
with 1 or 2 small dots regularly present in
red chromatin almost 100% of infected
dots; double cells
chromatin
common; marginal
forms are common

Trophozoite Remains in ring Like small trophozoite, Resembles closely same Chromatin rounded or
form but grows with increased stage of P. malariae but elongated; cytoplasm
resembling small cytoplasm and ameboid is considerably larger; compact or in narrow
trophozoite of P. activity; small yellowish pigment is lighter and band across cell; dark
vivax in size; brown pigment granules less conspicuous brown granules may
usually the oldest in cytoplasm, increasing have peripheral
asexual stage seen with age of parasite arrangement
in peripheral
blood

Gametocytes Present in Microgametocyte larger, round or oval round, occupies the

peripheral blood light red to pink bodies and occupy the whole RBC
stream; similar to chromatin, light to blue whole of the enlarged
P. vivax crescent cytolasm, yellowish infected RBC
or sausage shape brown pigment, usually
round resembling RBC

Macrogametocyte
small, compact, dark red
eccentric chromatin,
cytoplasm dark blue, no
vacuoles, abundant dark
brown pigment scattered
throughout the
cytoplasm
Parameter P. falciparum P. vivax P. ovale P. malariae

Stages in Ring forms and All stages are present All stages are present All stages are present
Peripheral gametocyte; other
blood stages are rare
Length of 48 hours or less 48 hours 48 hours 72 hours
asexual cycle
Disease -black water fever intermittent fever every intermittent fever every intermittent fever every
- intermittent fever 48 hours 48 hours 72 hours
every 36-48 hours
RBC affected All Stages of RBC Young RBC Young RBC Aging RBC

DIAGNOSIS

The signs and symptoms of malaria are nonspecific. Malaria is clinically suspected mostly on the basis of fever
or a history of fever.
Diagnosis based on clinical features alone has very low specificity and results in over-treatment. Other possible
causes of fever and the need for alternative or additional treatment must always be carefully considered.
The WHO recommendations for clinical diagnosis/suspicion of uncomplicated malaria in different
epidemiological settings are as follows:
■ in settings where the risk of malaria is low, clinical diagnosis of uncomplicated malaria should
be based on the possibility of exposure to malaria and a history of fever in the previous
three days with no features of other severe diseases;
■ in settings where the risk of malaria is high, clinical diagnosis should be based on a history of
fever in the previous 24 h and/or the presence of anemia, for which pallor of the palms
appears to be the most reliable sign in young children.

In all settings, clinical suspicion of malaria should be confirmed with a parasitological diagnosis.
However, in settings where parasitological diagnosis is not possible, the decision to provide
antimalarial treatment must be based on the prior probability of the illness being malaria. Other
possible causes of fever and need for alternative treatment must always be carefully considered.

PARASITOLOGICAL DIAGNOSIS
Parasitological diagnosis has the following advantages:
■ improved patient care in parasite-positive patients;
■ identification of parasite-negative patients in whom another diagnosis must be sought;
■ prevention of unnecessary use of antimalarials, reducing frequency of adverse effects,
especially in those who do not need the medicines, and drug pressure selecting for
resistant parasites;
■ improved malaria case detection and reporting;
■ confirmation of treatment failures.

The two methods in routine use for parasitological diagnosis are light microscopy and
rapid diagnostic tests (RDTs). The latter detect parasite-specific antigens or enzymes
and some have a certain ability to differentiate species. Deployment of microscopy and
RDTs must be accompanied by quality assurance.
Antimalarial treatment should be limited to test positive cases and negative cases should be
reassessed for other common causes of fever.
 The benefit of parasitological diagnosis depends entirely on health-care providers adhering to the
results in managing the patient, except where the severity of the disease justifies the use
of antimalarials in test negative cases, considering the possible small risk of false
negative tests. The risk of false negative microscopy is higher if the patient has received a
recent dose of an artemisinin derivative.

The results of parasitological diagnosis should be available within a short time (less than two
hours) of the patient presenting. In the absence or delay of parasitological diagnosis,
patients with suspected severe malaria, and other high risk groups, should be treated
immediately on clinical grounds.

• Thick and thin smears

timing of blood examination is important
immediately after a paroxysm, the merozoite-filled red cells have ruptured and free
merozoites are found in the bloodstream (difficult to locate and impossible to identify by species)
Gametocytes may be present and readily identifiable
If parasites are not found in the first blood films, thick and thin films are advised to be
taken every 6-12 hours

THICK films – screening; presumptive

THIN films – species identification

 Recombinant DNA probes – involves transfer of DNA-containing material of any sort (insect
salivary glands or gut, human serum or feces) to a nitrocellulose membrane, where it is
fixed; a DNA segment of known sequence, characteristic of the parasite DNA (produced
by a cloning technique by means of hybridomas and then radioactively labeled) is
hybridized to the DNA on the membrane; radioactivity remaining after the membrane is
washed signals the presence of the parasite
• Ribosomal RNA probes

• Detection of plasmodial antigens or enzymes (Immunodiagnosis)

Malaria antigen detection systems available:
1. ParaSight-F (Becton Dickinson) detect histidine-rich protein-2
2. ICT Malaria (Amrad ICT) (HRP-2)*
3. OptiMAL (Flow, Inc.) – detects plasmodial lactate dehydrogenase (pLDH)
*highest sensitivity and specificity

Additional recommendations in the diagnosis based on the second edition of the Guidelines for the Treatment
of Malaria(2010) by the WHO

Prompt parasitological confirmation by microscopy or alternatively by RDTs is recommended

in all patients suspected of malaria before treatment is started.

Treatment solely on the basis of clinical suspicion should only be considered when a
parasitological diagnosis is not accessible.

SYMPTOMS

The first symptoms of malaria are nonspecific and similar to the symptoms of a minor systemic viral illness:
headache, lassitude, fatigue, abdominal discomfort, and muscle and joint aches, usually followed by fever, chills,
perspiration, anorexia, vomiting and worsening malaise
Severe malaria usually manifests with one or more of the following: coma (cerebral malaria), metabolic
acidosis, severe anemia, hypoglycemia, acute renal failure or acute pulmonary edema. By this stage of the disease,
the case fatality in people receiving treatment is typically 10–20%.

Feature Vivax Ovale Malariae Falciparum

Incubation Period 10-17 days 10-17 days 18-40 days 8-11 days

Prodromal Symptoms May be influenza-like in all four types

HA, photophobia, muscle aches & pains, anorexia, N/V

Severity ++ + ++ +

Initial Fever Pattern Irregular to Usually regular Continuous,

quotidian every 72hrs remittent or
quotidian
Periodicity 44-48 hrs 48-50 hrs 72 hrs 36-48 hrs
Anemia ++ + ++ ++++
CNS involvement +/- +/- +/- ++++

Nephrotic Syndrome +/- - +++ +

• Classical Malarial Paroxysm

1 Cold stage
sudden shaking chill or rigor
10-15 minutes or longer
patient complains of extreme cold, temperature is elevated
pale and cyanotic skin
2 Hot stage
flushed skin
lasts for 2-6 hrs (vivax & ovale), 6 hrs or more (quartan)
3 Sweating Stage
sweat profusely for several hours

COMPLICATIONS
• Vivax, ovale and quartan malaria are relatively benign
1. cerebral malaria
most serious complication of falciparum infection
frequent cause of death
severe headache, drowsiness, confusion, coma
suspicion requires prompt administration of quinine or quinidine; consider exchange
transfusion
sequelae: cortical blindness, hemiparesis, generalized spasticity, cerebellar ataxia,
severe hypotonia
2. anemia – consequence of heavy parasite load
3. renal disease
common in severe falciparum malaria and repeated malariae infections, esp. in children
4. Blackwater Fever
 - Syndrome that results from massive intravascular hemolysis and consequent
hemoglobinuria
- Cause unknown; speculated that it represents autoimmune phenomenon with the
development of antibodies to the infected erythrocyte
5. Dysenteric Malaria
- Uncommon
- Abdominal pain, nausea, vomiting, UGIB
- Liver maybe enlarged & tender, skin icteric, urine may contain bile (bilious
remittent fever)
6. Algid Malaria
- Falciparum malaria attacks characterized by rapid development of hypotension
and impairment of vascular perfusion
- Temp drops, delirium, symptoms of generalized vascular collapse, pulmonary
edema, massive GI haemorrhage, splenic rupture or uncorrected dehydration
7. Pulmonary Edema – maybe secondary to overzealous parenteral fluid administration or a
result of DIC or anoxia affecting the pulmonary microcirculation
8. Tropical Splenomegaly Syndrome
- Splenomegaly of unknown cause
- Chronic splenomegaly and marked elevation of the serum IgM
- Lymphocytic infiltration of hepatic sinusoids
- Occurs only in malarious areas
- Condition improves with administration of anti-malarials
- Overproduction of immunoglobulins esp IgM and reduction of T lymphocytes
9. Hyperparasitemia - >10-20% of RBCs
- Exchange blood transfusion may be life-saving
10. Hypoglycemia – hyperinsulinemia may result from treatment of falciparum malaria with
quinine and quinidine hypoglycemia
• The course and severity of the attack of malaria depend on the species and the strain of the infecting
parasite, and hence, geographical origin of the infection
They also depend on the :
Age
Genetic constitution
State of immunity
General health and nutritional status of the host
Chemopropylaxis or chemotherapy used

PATHOGENESIS (Refer to Markell and Voge’s Medical Parasitology Chapter 4 p93)

- The pathogenic effects of a malarial infection are related to:
1. Hemolysis of infected and uninfected RBCs
2. Liberation of the metabolites of the parasite
3. Immunologic response of the host to this antigenic material
4. Formation of malarial pigment

TREATMENT
 SUPPRESSIVE THERAPY (Chemoprophylaxis)
 Attempts to destroy the parasites as they enter the bloodstream with small doses of drugs effective
against the erythrocytic stages
 RADICAL CURE
 Elimination of not only the bloodstream infection but the tissue stages in the liver as well

BLOOD SCHIZONTICIDAL DRUGS

  Suppression or treatment of an acute attack of malaria
 Most have no effect on either the exo-erythrocytic stages of the parasites or gametocytes
 Quinine, Quinidine
 Chloroquine- mainstay of blood schizonticidal therapy for all species of malaria except chloroquine-
resistant Plasmodium falciparum (CRPF)
 Hydrochloroquine, amodiaquine. Pyrimethamine, Mefloquine, Halofantrine, Artemisin

TISSUE SCHIZONTICIDES
 Causal prophylaxis
 Destroy the developmental stages in the liver
 Primaquine

GAMETOCYTICIDES
 Destroy the sexual forms (gametocytes) of the parasite in the blood (vivax, ovale, malariae, immature
gametocytes of falciparum)
 Do not affect the mature gametocytes of falciparum
 Primaquine

DRUGS USED IN SINGLE DRUG THERAPY

1. QUININE
 Only effective drug for chemoprophylaxis or tx of malaria
 Potent blood schizonticide
 DOC for severe falciparum malaria
 DOC for malaria in pregnancy
 Prophylaxis: 325mg twice daily with meals; continued for 4 weeks after leaving the endemic area
 Tx: 650 mg every 8hrs for 3-7 or 10 days (A); 10-25mg/kg every 8hrs for 3-7 or 10 days (P)
2. QUINIDINE
 Anti-malarial activity slightly superior to quinine
 Cardiotoxicity more pronounced
 Ready accessibility when IV tx is indicated
3. CHLOROQUINE
 Mainstay of anti-malarial treatment
 Treatment of choice for P.vivax, P. ovale, P. malariae and uncomplicated P. falciparum
 No other antimalarial has a safety profile similar to this drug
4. AMODIAQUINE
5. PYRIMETHAMINE
6. MEFLOQUINE
7. DOXYCYCLINE
8. PROGUANIL
9. HALOFANTRINE
10. ARTEMISININ
11. NORFLOXACIN/CIPROFLOXACIN

MULTIPLE DRUG PROPHYLAXIS & TX OF RESISTANT FALCIPARUM MALARIA

1. QUININE or MEFLOQUINE and DOXYCYCLINE
2. PYRIMETHAMINE-SULFADOXINE (FANSIDAR)
3. PYRIMETHAMINE-SULFADOXINE-MEFLOQUINE (FANSIMEF)
4. PYRIMETHAMINE-DAPSONE (MALOPRIM)
5. ATOVAQUONE-PROGUANIL (MALARONE)

TREATMENT OF TISSUE SCHIZONTS, HYPNOZOITES AND GAMETOCYTES

 1. PRIMAQUINE – effective against the hypnozoites of P. vivax & P. ovale; gametocyticidal to all 4
species of malaria

WHO UPDATES

The Global Malaria Programme (GMP) is responsible for malaria surveillance, monitoring and evaluation,
policy and strategy formulation, technical assistance, and coordination of WHO's global efforts to fight malaria.

24 April, 2012

On World Malaria Day 2012, WHO hails global progress in combating malaria but highlights the need to further
reinforce the fight. The Global Malaria Programme’s new initiative, T3: Test. Treat. Track, urges malaria-
endemic countries and donors to move towards universal access to diagnostic testing and antimalarial treatment,
and to build stronger malaria surveillance systems.

The initiative seeks to focus the attention of policy-makers and donors on the importance of adopting WHO’s latest
evidence-based recommendations on diagnostic testing, treatment and surveillance, and updating existing malaria
control and elimination strategies, as well as country-specific operational plans.

Malaria-endemic countries should ensure that every suspected malaria case is tested, that every confirmed case is
treated with a quality-assured antimalarial medicine, and that the disease is tracked through timely and accurate
surveillance systems to guide policy and operational decisions. The initiative is built on a foundation of the
following core WHO documents:

 Universal Access to Malaria Diagnostic Testing: an Operational Manual (2011)

 Guidelines for the Treatment of Malaria, Second Edition (2010)
 Disease Surveillance for Malaria Control, and Disease Surveillance for Malaria Elimination (2012)