Malaria is a mosquito-borne disease caused by Plasmodium parasites. In 2018, 228 million people were infected globally resulting in over 400,000 deaths. India accounts for 3% of global malaria cases and deaths, with most cases concentrated in 7 states. Malaria is transmitted via the bites of infected female Anopheles mosquitoes. Symptoms include fever, chills, and flu-like illness, with P. falciparum infections potentially causing severe complications like cerebral malaria, severe anemia, or respiratory distress. Proper diagnosis and treatment are needed to prevent mortality from this widespread and potentially deadly disease.

1. MALARIA

2. INTRODUCTION
• Malaria is a mosquito borne disease caused by infection with parasitic protozoa
of genus Plasmodium.
• According to world malaria report 2019, 228 million were affected with malaria in
2018 with 4 lakh deaths globally.

3. BURDEN OF DISEASE IN INDIA
• According to world malaria report 2019, India accounts for 3 percent of the
total malaria cases and 2 percent of malaria deaths across the globe.
• Further, only seven states accounted for 90 percent of the estimated malaria
cases in 2018. These states included West Bengal, Jharkhand, Chhattisgarh,
Odisha, Madhya Pradesh, Uttar Pradesh and Gujarat.
• Malaria incidences from tribal districts of Telangana constituted 63 per cent of
total cases and the rest of cases were from Hyderabad and towns in 2018

4. AGENT - DISCOVERY OF
MALARIAN PARASITE
• The idea that bad air (“mal aria” in Italian) rising from swamps caused
malaria had a good run: at least two and a half millennia, from the time of
the ancient Greeks until the mid-19th century.
• But as Louis Pasteur and Robert Koch popularized the germ theory of
infection in the late 1870s, bacterial origin of malaria became
interestingly attractive.

5. HISTORY
• Two scientists even reported having found the culprit, dubbed Bacillus
malariae, in the Pontine Marshes near Rome.
• It was against this background that Alphonse Laveran, an unknown
French army officer working in Algeria, challenged the perceived
wisdom and began in his own words 'to follow the pigment'.

6. “NEW PARASITE FOUND IN THE BLOOD OF SEVERAL
PATIENTS SUFFERING FROM MARSH FEVER.”- LAVERAN

7. HISTORY
• Not all of Laveran’s views on malaria would catch on, however. He
continued to insist, for example, that the disease was caused by only one
protozoan species, long after evidence emerged that there were two, then
three, then four .
• It would ultimately turn out that there are five species of malaria
protozoa affecting humans.

8. THE BEGINNINGS OF A MOSQUITO-TRANSMITTED MALARIA
!!

9. HISTORY

10. • In August 1897, in India, British bacteriologist Ronald Ross discovered
parasites of a malaria of birds in the stomach of a Culex mosquito.Ross
surmised correctly that human malaria was probably transmitted in the
same way
• In 1898, in Rome, Giovanni Grassi and his colleagues produced the final
proof when they fed local Anopheles mosquitoes on infected patients and
subsequently transmitted the infection to uninfected individuals via the
bite of these mosquitoes

11. AGENTS
• Human malaria is caused by any of the following :
 Plamodium vivax
 Plasmodium ovale
 Plasmodium malariae
 Plasmodium falciparum
 Plasmodium knowlesi

12. VECTOR-FEMALE ANOPHELES
MOSQUITO
Anopheles culicifacies : rural ,
periurban areas
Anopheles fluviatilis : forest , hilly
areas
Anopheles stephensi : urban,
industrialised areas
Anopheles minimus : foot hills
BREEDING HABITS - CLEAN , UNPOLLUTED
WATER : freshwater or saltwater marshes, mangrove
swamps, rice fields, grassy ditches, the edges of
streams and rivers, and small, temporary rain pools
TIME OF BITING - NIGHT TIMING

13. LIFECYCLE

14. P.falciparum P.vivax P.ovale P.malariae
Erythrocyte
preference
All stages Reticulocytes Reticulocytes Old RBCs
Duration of
schizogony
(days)
2 days 2 days 2 days 3 days
Hypnozoites No Yes Yes No

15. PATHOGENESIS
Destruction of Infected RBCs
Splenic macrophages
Anemia
Pro inflammatory cytokines
TNF , IFN 1
Expression of adhesion
molecules
ICAM1, CD36 , CSA , CR1
Sequestration ,
Rosette
PAROXYSMS

16. PATHOGENESIS
PAMP :GPI
Parasitic DNA
DAMP : Heme
PAMP : Hemozoin
DAMP : Urate
TLR
NF kB
Transcription of Pro inflammatory cytokines
PROINFLAMMATORY CYTOKINES CYTOKINES
Caspase 1
PAROXYSMS

17. PATHOGENESIS
Knob protrusions on infected RBCs
Bind with endothelial adhesion
molecules
Sequestration
Partial blood flow obstruction
Endothelial barrier breakdown
Inflammation
Uninfected RBCs(CR-
1)
Rosetting
Block micro circulation
Micro vascular disease
Cerebral malaria , ARDS , Renal failure , Placental
malaria
PfEMP-1

18. CLINICAL FEATURES
• The initial symptoms of malaria are nonspecific and include tachypnea, chills,
malaise, fatigue, diaphoresis (sweating), headache, cough, anorexia, nausea,
vomiting, abdominal pain, diarrhea, arthralgias, and myalgias
• The classical malarial paroxysms comprises of 3 successive stages-
DURATION FEATURES
COLD STAGE lasts for 15-60 minutes feeling of intense cold,
shivering
HOT STAGE lasts for 2-6 hours intense heat,dry burning skin,
throbbing headache
SWEATING STAGE lasts for 2-4 hours profuse sweating, declining
temperature, exhausted and
weak

19. • The classical paroxysms are relatively unusual and suggest infection
with P.vivax or P.ovale and synchronises with Erythrocytic Schizogony.
• Periodicity is approximately
 24 hrs in quotidian malaria ( P.knowlesi)
48 hrs in tertian malaria ( P.vivax, P.ovale )
 72 hrs in quartan malaria ( P.malariae )
In P. Falciparum, fever may occur at 24 hr intervals or at
48 hr intervals
CLINICAL FEATURES

20. UNCOMPLICATED MALARIA
• Patients are considered to have uncomplicated malaria in the setting of
 a positive parasitological test in the absence of signs of severe malaria ;
• Patients with uncomplicated disease are generally able to swallow
antimalarial drugs
• Uncomplicated malaria can occur with any Plasmodium species.
• Although falciparum malaria is the most virulent, appropriately and promptly
treated, uncomplicated falciparum malaria carries a mortality rate of <0.1%.

21. SEVERE FALCIPARUM MALARIA
• Severe malaria is defined as presenceof P.falciparum parasitemia and one or
more of the manifestations described below.
Hypotension / Shock SBP < 80mmHg (adults), <50 mmHg(children); capillary
refill time > 2 sec
Bleeding / DIC Significant bleeding from nose,gums and GI tract and /or
evidence of DIC
Convulsions More than 2 generalised seizures in 24 hrs, signs of continued
seizure activity, sometimes subtle (eg.Tonic clonic eye
movements without limb or face movements )

22. Unarousable
coma /
Cerebral malaria
 Diffuse reversible symmetric
encephalopathy that presents with impaired
consciousness, delirium, abnormal
behaviour and/or seizures; focal neurologic
signs are unusual.
 The onset may be gradual or sudden
following a convulsion.
 COMA GCS<11 or Blantyre coma score <3 in
young children.
 Coma persisting for >30 min after
generalised convulsion; Failure to localise
or respond appropriately to noxious stimuli
;
 Some resistance to head flexion,No signs of
meningeal irritation.
 Fundoscopy: Retinal hemorraghes, retinal
whitening, cotton-wool spots, focal whitening of
vessels, papilloedema
 If untreated, cerebral malaria is almost
universally fatal; with treatment,
mortality is 15 to 20 percent .
 Among survivors , neurologic sequelae
are more common among children(15%)
than adults(3%) especially those with
hypoglycemia, acidosis, severe
anemia, repeated seizures, and deep
coma.
 Residual deficits -recover in 6 months,
children - persistent language deficit
?Postmalaria neurologic syndrome
Hemiparesis , sensory deficit
psychosis , parkinsons rigidity , tremor
,cerebellar dysfunction
Mefloquine(10-50times)

23. Acidosis Manifested as labored breathing.
Causes:
• Anaerobic glycolysis in host tissues where
sequestered parasites interfere with micro-
circulatory flow
• Parasite lactate production
• Insufficient hepatic and renal lactate
clearance
Plasma concentrations of
bicarbonate or lactate are the best
biochemical prognosticators in
severe malaria.
Poor prognosis -
Acidosis (Arterial pH < 7.25
BASE DEFICIT > 8 mEq/L
Plasma HCO3 < 15 mmol/L, )
Hyperlactemia> 5mmol/L
Acidotic breathing is a sign of poor
prognosis
Severe
normochromic
normocytic
anemia
ANEMIA results from
●Hemolysis of parasitized red cells
●Increased splenic sequestration and
clearance of erythrocytes with diminished
deformability
●Cytokine suppression of hematopoiesis
●Shortened erythrocyte survival
Hematocrit < 15 % OR
Hb < 5gm/dl with parasitemia
<10000/microL

24. Renal failure Clinically and pathologically , manifests as
ACUTE TUBULAR NECROSIS
Labaratory findings
Serum creatinine > 3mg/dl ;
24 hr urine output < 400ml (adults) ,<12ml/kg
in children;
no improvement with hydration
Early dialysis or hemofiltration
considerably enhances the likelihood of
a patient's survival , particularly in acute
hypercatabolic renal failure
Hypoglycemia In severe disease, clinical diagnosis of
hypoglycemia is difficult : the usual
physical signs( sweating,goose flesh,
tachycardia) are absent , and neurologic
impairment caused by hypoglycemia cannot
be distinguished from that caused by malaria
Qunine - Hypoglycemia
Plasma glucose < 40 mg/dl indicates
POOR PROGNOSIS
Non cardiogenic
Pulmonary
edema / Adult
ARDS
Non cardiogenic pulmonary edema,often
aggravated by overhydration
May develop even after several days of
antimalarial therapy
• Mortality rate > 80 %
• Can also develop in otherwise
uncomplicated vivax malaria , where
recovery is usual.

25. OTHER MANIFESTATIONS OF SEVERE
MALARIA
Hemoglobinuria Macroscopic black,brown or red urine ;
not associated with effects of oxidant
drugs and red blood cell enzyme (
such as G6PD deficiency )
Extreme weakness Prostration; inability to sit unaided ( in
children who are normally able to sit
unaided )
Hyperparasitemia Parasitemia level of >5% in non-
immune patients (>10% in any patient
)
Jaundice Severe bilirubin >3mg/dl if combined
with a parasite density of
100,000/microL or other evidence of
vital organ dysfunction

26. CLINICAL FEATURES INDICATING POOR
PROGNOSIS IN SEVERE FALCIPARUM
MALARIA
Marked agitation
Hyperventilation
Low core temperature (<97.7 F)
Bleeding
Deep coma
Repeated convulsions
Anuria
Shock

27. LIVER DYSFUNCTION
• Mild hemolytic jaundice is common in malaria.
• Severe jaundice is associated with P. falciparum infections; is
more common among adults and results from hemolysis,
hepatocyte injury, and cholestasis.
• When accompanied by other vital-organ dysfunction (often renal
impairment), liver dysfunction carries a poor prognosis.

28. LIVER DYSFUNCTION
• Hepatic dysfunction contributes to hypoglycemia, lactic
acidosis,reduced clotting factor synthesis and impaired drug
metabolism.
• There is no residual liver damage following malaria.

29. BACTERIAL INFECTIONS
• There appears to be a biological association between malaria, and invasive
bacterial infections.
• Septicemia may complicate severe malaria, particularly in children.
• In endemic areas, Salmonella bacteremia has been associated with P.
falciparum infections.
• Chest infections and catheter-induced urinary tract infections are common
among patients who are unconscious for ≥3 days.
• Aspiration pneumonia may follow generalized seizures.

30. HIV INFECTION
• HIV and malaria often coexist.
• Both conditions induce cell-mediated immunodepression.
• HIV infection is associated with increased susceptibility to malaria, higher
parasitemia, and increased risk for recurrent malaria infection, particularly
in patients with CD4 counts <200 cells/microL.

31. HIV INFECTION
• In addition, malaria infection in HIV-infected patients has been associated
with CD4 cell decline relative to HIV-infected patients without malaria.
• Malaria infection has been associated with a transient increase in HIV
viral load in some circumstances; however, this does not appear to hasten
progression to AIDS .

32. ALGID MALARIA
• Cardiovascular abnormalities, shock (‘algid malaria’).
• The blood pressure of patients with malaria is usually at the lower end of
the normal range, although most patients are warm and well perfused.
• Severe sudden hypotension [systolic blood pressure less than 80 mmHg
in adults in the supine position] with features of circulatory failure (cold,
clammy, cyanotic skin, constricted peripheral veins, prolonged capillary
refill time)

33. RELATIVE INCIDENCE OF SEVERE
COMPLICATIONS IN FALCIPARUM
MALARIA
COMPLICATION NON PREGNANT
ADULTS
PREGNANT CHILDREN
Anemia + ++ +++
Convulsions + + +++
Hypoglycemia + +++ +++
Jaundice +++ +++ +
Renal failure +++ +++ -
Pulmonary edema ++ +++ +
- : rare ; + : infrequent ; ++ : frequent : +++ : very frequent

34. MALARIA IN CHILDREN
• Convulsions, coma, hypoglycemia, metabolic acidosis, and severe anemia
are relatively common among children with severe malaria.
• Deep jaundice, oliguric acute kidney injury, and acute pulmonary edema
are unusual.
• In general, children tolerate antimalarial drugs well and respond rapidly to
treatment.

35. TRANSFUSION MALARIA
• Malaria can be transmitted by blood transfusion, needlestick injury or
organ transplantation.
• The incubation period is such settings is short as there is no
preerythrocytic stage.
• C/F and management-same
• Radical treatment with Primaquine is unnecessary.

36. MALARIA IN PREGNANCY
• Malaria in early pregnancy causes abortion.
• Congenital malaria occurs in <5 % of newborns whose mothers are
infected - its frequency and level of parasitemia are related directly to the
parasite density in maternal blood and in placenta.
• Falciparum malaria in primi and secundigravid women is associated with
low birth weight in contrast to vivax, where this effect is more pronounced
in multigravid women.

37. MALARIA IN PREGNANCY
• Infected mothers in areas of stable transmission remain asymptomatic
despite intense accumulation of parasitised erythrocytes in placental
microcirculation.
• Pregnant women in areas of unstable transmission are prone to severe
infections and are particularly vulnerable to high parasitemias with anemia ,
hypoglycemia, and acute pulmonary edema.
• Fetal distess, premature labour and still birth or LBW are common results.

38. CHRONIC COMPLICATIONS OF
MALARIA
HYPER-REACTIVE MALARIAL
SPLENOMEGALY
(TROPICAL SPLENOMEGALY SYNDROME
)
 There is gross splenomegaly with
normal architecture and lymphocytic
infiltration of the hepatic sinusoids with
Kupffer cell hyperplasia.
 The massively enlarged spleen leads to
hypersplenism with anaemia, leukopenia
and thrombocytopenia.
 There is polyclonal
hypergammaglobulinaemia with high
serum concentrations of IgM.
 High titres of malaria antibodies and a
variety of autoantibodies (antinuclear
factor, rheumatoid factor) are usually
present
 The malaria blood slide is usually
negative.
 The enlarged spleen usually regresses

39. QUARTAN MALARIAL NEPHROPATHY  Soluble immune complex injury to the renal glomeruli,
resulting in the nephrotic syndrome.
 Focal or segmental glomerulonephritis with splitting
of the capillary basement membrane.
 Progress to renal failure in 3-5 yrs
 Poor response to antimalarial agents or
glucocorticoids and cytotoxic drugs.
BURKITT’S LYMPHOMA AND EPSTEIN-
BARR VIRUS INFECTION
 Malaria-related immune dysregulation provokes
infection with lymphoma viruses.

40. RECRUDESCENCE VS RELAPSE
RECRUDESCENCE RELAPSE
Seen in P. falciparum and P. malariae Seen in P. vivax and P. ovale
Due to persistence of the parasite at a
subclinical level in circulation
Due to reactivation of hypnozoites
present in liver cells
Occurs within a few weeks or months of
previous attack
Occurs usually 24 weeks to 5 years
after a previous attack
Can be treated by adequate drug
therapy
Can be prevented by giving
hypnozoiticides

41. LABARATORY DIAGNOSIS OF
MALARIA

42. GENERAL PRINCIPLES
• Tools for diagnosis of malaria include
 Microscopy (visualization of parasites in stained blood smears)
 Rapid diagnostic tests (RDTs; which detect antigen or antibody).
 Molecular techniques for detection of genetic material are limited to research
settings

43. GENERAL PRINCIPLES
• Smear examination via light microscopy is the standard tool for
diagnosis of malaria
• RDTs should be used if microscopy is not readily available.
• The CDC advises that RDTs should be used with a positive control (stored
blood containing P. falciparum), and both negative and positive results
should be confirmed with microscopy .

44. GENERAL PRINCIPLES
• Molecular diagnosis by PCR amplification of parasite nucleic acid is more
sensitive than microscopy or rapid diagnostic tests for detecting malaria
parasites and defining malarial species.
• However, the infrastructure and training required for use of PCR limits its
utility for these applications.

45. LIGHT MICROSCOPY
• When a patient in or from a malarious area presents with fever, thick and
thin blood smears should be prepared and examined immediately to
confirm the diagnosis and identify the species of infecting parasite.
• Two types of smear prepared- thick and thin, can be made on
a single slide.

46. THICK AND THIN SMEARS
THICK SMEAR THIN SMEAR
Larger volume - increased sensitivity in
detection of malarial parasites
Smaller volume - less sensitive
especially where there is low paratemia
The blood film is dehemoglobinised so
that only WBCs,platelets and parasites
are visualised
The purpose is to allow malarial
parasites to be seen within the RBCs
and to assess the morphology of the
infected RBCs compared to uninfected
RBCs
Mainly used to detect infection and
quantify the parasite load.
Used for species identification
200 oil immersion fields should be seen before thick film is
declared negative.

47. RED CELL MORPHOLOGY IN VARIOUS
FORMS OF PLASMODIUM
INFECTIONS
P.falciparu
m
P.vivax P.ovale P.malaria
e
Stages in
PBS
Only rings
and
gametocyte
s
+Trophoz
oites,
Schizonts
Same
as vivax
Same as
vivax
Schizont not seen in
PBS
12-24
merozoite
s
irregularly
6-12
merozoi
tes
6-12
daisy
head
pattern
Gametocyt
es
Cresecent
shaped
spherical,
deep blue
cytoplasm
same
as vivax
same as
vivax
Ring stage Multiple
rings,doubl
e chromatin
usually
single
same
as vivax
but
same as
vivax but
thicker

48. LIGHT MICROSCOPY
• If malaria is suspected and the initial smear is negative, additional
smears should be prepared and examined over the subsequent 48 to 72
hours
• The CDC recommends repeating a thick and thin smear every 12 to 24
hours for a total of three sets before ruling out malaria.

49. DEFINITION OF SEVERE MALARIA
• The WHO definition of severe P. falciparum malaria includes
hyperparasitemia :
>2 percent or 100,000 parasites/microL in low-intensity transmission
areas or >5 percent or 250,000 parasites/microL in areas of high stable
malaria transmission intensity
• The CDC definition of severe malaria includes parasitemia of ≥5 percent.

50. RAPID DIAGNOSTIC TESTS
• RDTs based on antigen detection detect one or more of the following:
histidine-rich protein 2 (HRP2),Plasmodium lactate dehydrogenase (pLDH)
,aldolase.
• Based on immunochromatography methods, where the casette bears
monoclonal antibodies, which are directed against parasitic antigen.
• Depending on the target antigen(s), an RDT identify Plasmodium genus only or
may distinguish P. falciparum and/or P. vivax infections.

51. PARASITE -F-TEST
• This test is based on the detection of histidine rich protein-2 (HRP-2)
antigen produced by asexual stages of P.Falciparum expressed on surface
of RBCs
ADVANTAGES DISADVANTAGES
High sensitivity (96 %)
Can detect low asexual parasitemia
of more than 40 parasites/microL
Can be performed in 10 minutes
Cannot detect 3 species
More recently, reports have emerged
of pfhrp2 and pfhrp3 mutations or
deletions in Africa and India leading
to false-negative RDT results in
some cases

52. DUAL ANTIGEN TEST
• This test detects pLDH produced by trophozoites and gametocytes or Plasmodium
aldolase,an enzyme of the parasite glycolytic pathway expressed of all plasmodium
species and PF-HRP2 antigen
• Thus, one band (Pv band ) Plasmodium specific and other band is P.falciparum specific
ADVANTAGES DISADVANTAGES
Specific detection and differentiation
of P.falciparum AND P.vivax malaria in
areas of high rates of mixed infections
Expensive
Cannot differentiate between P.vivax ,
P.ovale , P.malariae

53. Comparison of Peripheral Blood Smear Examination and RDTs forMalaria
Peripheral smear RDT’s
Test duration 20-60 minutes or
more
5-30 minutes
Test result Direct visualization of
the parasites
Color changes on antibody
coated lines
Capability Detects and
differentiates all
plasmodia at
different stages
Detects malaria antigens (PfHRP2/
PMA/pLDH) from asexual and/or
sexual forms of the parasite
Detection
threshold
5-10 parasites/µL of
blood
100-500/µL for
P. falciparum, higher for
non-falciparum
Species
differentiation
Possible Cannot differentiate among non-
falciparum species; mixed
infections
of P.falciparum and non-
falciparum appear
as P. falciparum
Quantification Possible Not possible

54. MOLECULAR METHODS
Polymerase chain reaction :
• Primarily for research and epidemiologic purposes
• Typically used as a gold standard in efficacy studies for antimalarial
drugs, vaccines, and evaluation of other diagnostic agents.
• Target genus-specific and species-specific sequences of the 18S small-
subunit ribosomal RNA, circumsporozoite surface protein (a nuclear
gene encoding a cysteine protease), and the cytochrome b gene.

55. LOOP-MEDIATED ISOTHERMAL
AMPLIFICATION
• LAMP assays for detection of malaria parasite DNA are being developed
to facilitate use of molecular technology in endemic areas
• Use of LAMP for amplification of DNA occurs at a single temperature so
does not require the thermocycler instrumentation necessary for PCR.

56. LOOP-MEDIATED ISOTHERMAL
AMPLIFICATION
• LAMP generates 109 to 1010 replicates in 15 to 60 minutes, and the
resultant turbidity can be detected visually or by turbidimetry, without
need for further manipulation.
• Use of LAMP assays with a variety of target sequences and
processing methods has demonstrated variable sensitivity and
specificity

57. SEROLOGICAL DIAGNOSIS
• Serologic diagnosis with either indirect fluorescent antibody or enzyme-
linked immunosorbent assays is useful for screening of prospective blood
donors and may prove useful as a measure of transmission intensity in
future epidemiologic studies.
• It has no place in the diagnosis of acute illness.

58. LABORATORY FINDINGS IN ACUTE
MALARIA
• Normochromic, normocytic anemia is usual.
• The leukocyte count is generally normal, although it may be raised in
very severe infections.
• There is slight monocytosis, lymphopenia, and eosinopenia, with
reactive
lymphocytosis and eosinophilia in the weeks after acute infection.

59. LABORATORY FINDINGS IN ACUTE
MALARIA
• The erythrocyte sedimentation rate, plasma viscosity, and levels of C-reactive
protein and other acute-phase proteins are elevated.
• Severe infections may be accompanied by prolonged prothrombin and partial
thromboplastin times and by more severe thrombocytopenia.
• Antithrombin III levels are reduced even in mild infection.
• In uncomplicated malaria, plasma concentrations of electrolytes, blood urea
nitrogen (BUN), and creatinine are usually normal

60. LABORATORY FINDINGS
• Findings in severe malaria may include
 Metabolic acidosis,
 Low plasma concentrations of glucose, sodium, bicarbonate, phosphate,
and albumin,
Elevations in lactate, BUN, creatinine, urate, muscle and liver enzymes,
and conjugated and unconjugated bilirubin.

61. LABORATORY FINDINGS
• In adults and children with cerebral malaria, CSF findings
 Opening pressure at lumbar puncture is ~160mm H2O;
 Slight elevation of total protein level (<200 mg/dL])
 Cell count (<10/μL).
Lactate is raised
Glucose is low

62. LABORATORY FEATURES INDICATING
POOR PROGNOSIS IN SEVERE
FALCIPARUM MALARIA
Biochemistry  Hypoglycemia(<40mg/dL),
 Acidosis(pH<7.3, serum HCO3<15 mmol/L),
 Serum Creatinine(>3mg/dL),
 Total Bilirubin(>3mg/dL),
 Elevated Liver Enzymes(AST/ALT>3 times the upper limit of normal),
 Elevated Muscle Enzymes(CPK, Myoglobin),
 High CSF Lactate>6 mmol/L, low CSF Glucose,
 Venous Lactate >5 mmol/L,
 Elevated plasma 5’ Nucleotidase, TNF
 Low Antithrombin III levels

63. Haematology  Leucocytosis(>12,000/microLitre),
 Severe Anemia(PCV<15%, Hb<5gm/dL)
 Coagulopathy:decreased Platelets(<50,000), prolonged PT(>3
sec),APTT, decreased Fibrinogen(<200mg/dL)
Parasitology
(Hyperparasitae
mia)
 100,000/microLitre- increased mortality
 500,000/microLitre- high mortality
 20% of parasites are pigment containing trophozoites and schizonts
 5% of neutrophils contain visible malaria pigment
LABORATORY FEATURES INDICATING POOR
PROGNOSIS IN SEVERE FALCIPARUM
MALARIA

64. TREATMENT

65. OBJECTIVES OF TREATMENT OF
MALARIA
• Of uncomplicated malaria
• To cure the infection as rapidly
as possible.
• Prevention of progression to
severe disease, and additional
morbidity associated with
treatment failure.
• Of severe malaria
• To prevent death.
• In treating cerebral malaria,
prevention of neurological
deficit is also an important
objective.

66. CLINICAL CLASSIFICATION OF ANTIMALARIAL DRUGS
CAUSAL
PROPHYLAXIS
( tissue schizonticides )
Prevent the maturation of or destroy the
sporozoites within infected liver cells and
thus prevent erythrocytic invasion
Pyrimethamine and Primaquine
HYPNOZOITICIDES act on the hypnozoites of P. vivax and P.
ovale in the liver that cause relapse of
symptoms on reactivation.
Primaquine is the prototype drug.
BLOOD
SCHIZONTICIDES
Inhibiterythrocyticschizogonyandpreventthe
ruptureoftheinfectederythrocytes.Leadsto
freedomfromrigorsandpyrexia butdonot
eradicateinfection
Rapid acting : chloroquine, quinine,
mefloquine,atovaquone, artemisinin
Slowacting : pyrimethamine,
sulfadoxine, sulfones, tetracyclines
GAMETOCYTOCIDES Destroy the gametocytes in the blood and
thereby prevent transmission of the
infection to the mosquito.
Chloroquine , Artesunate and
quinine : against P.vivax and P.
malariae.
Primaquine :against all plasmodia,
including P.falciparum.

67. DRUG MINOR TOXICITY MAJOR TOXICITY
QUININE Common- Cinchonism , ECG QT
interval prolongation
Common - Hypoglycemia
CHLOROQUINE Common - Pruritis in dark skinned
indviduals, Postural
hypotension,ECG QT interval
prolongation
Acute -Hypotensive shock (IV),
cardiac arrythmias
Chronic - Retinopathy ( RA)
AMODIAQUINE Common -Nausea ( tastes better
than Chloroquine), ECG QT
interval prolongation
Chronic therapy - Hepatitis,
Agranulocytosis
PRIMAQUINE Common - Epigastric distress,
abdominal cramps
Serious hemolytic anemia, severe
G6PD deficiency
MEFLOQUINE Common- Nausea, fuzzy thinking,
sleeplessness
Neuropsychiatric reactions,
convulsions and encephalopathy

68. DRUG MINOR TOXICITY MAJOR TOXICITY
Artemesinin and derivatives Reduction in reticulocyte count but
not anemia ; in some cases
delayed anemia after treatment of
severe malaria with high
parasitemia
Contraindicated in 1st trimester of
pregnacy
Rare- Anaphylaxis , Utricaria
Pyrimethamine Megaloblastic anemia
Proguanil mouth ulcers and rare alopecia Megaloblastic anemia in Renal
failure
Doxycycline, Tetracycline Gastrointestinal intolerance,
deposition in growing bones and
teeth, benign intracranial
hypertension
Renal failure in patients with
impaired renal function (
tetracycline )

69. GENERAL RECOMMENDATIONS FOR THE
MANAGEMENT OF UNCOMPLICATED
MALARIA
• Avoid starting treatment on empty stomach
• 1st dose- under supervision
• If vomiting occurs within ½ hour- dose is repeated
• Patient should report after 48 hours if- no improvement
- situation deteriorates
• Other illnesses should be ruled out.

70. TREATMENT OF UNCOMPLICATED MALARIA
FIRST-LINE DRUGS FOR ENDEMIC AREAS
MALARIA DRUG TREATMENT
Known chloroquine sensitive
p.vivax, p.malariae, p.ovale,
p.falciparum
• Chloroquine 10mg base/kg stat. f/b 5mg/kg at 12,24 and 36
h OR
10mg/kg at 24h, 5mg/kg at 48h OR
• Amodiaqione 10-12mg base/kg qd for 3d
Sensitive p.falciparum malaria
(Other than north eastern states)
• Artesunate 4mg/kg/d for 3 days + sulfadoxine 25mg/kg+
pyrimethamine 1.25mg/kg single dose OR
• Artesunate 4mg/kg/d for 3d+amodiaquine 10mg base/kg/d
for 3d as FCT
Multi drug resistant
p.falciparum
(In north eastern states)
• Artemether-lumefantrine 1.5/9 mg/kg BD for 3d with food
OR
• Artesunate 4mg/kg/d+ mefloquine 8mg/kg/d for 3d in FCT
OR
• Dihydroartemisinin-piperaquine 4/18mg/kg/d for 3d

71. Radical treatment
Patients with p.vivax and p.ovale infections should also be given
primaquine 0.25 mg base/kg daily with food for 14 days to prevent
relapse.
In mild G6PD deficiency 0.75 mg base/kg should be given once
weekly for 6 weeks.
Primaquine should not be given in severe G6PDdeficiency, young
infants or pregnant women.
In low transmission settings, a single dose of primaquine 0.25 mg base/kg should
be added as a gametocide to all falciparum malaria treatments and given with first
dose of ACT, except in infants and pregnant women.

72. • Patient should be advised to stop primaquine if he/she develops any of
the following symptoms:
 Dark coloured urine
 Yellow conjunctiva
 Bluish discoloration of lips
 Abdominal pain
 Breathlessness
 Vomiting

73. SECOND LINE OF TREATMENT
• Artesunate 2-4 mg/kg daily + either tetracycline 4mg/kg QID for 7d
OR doxycycline 3mg/kg OD for 7d
OR clindamycin 10mg/kg BD for 7d
• Quinine10mg salt/kg TID + either tetracycline 4mg/kg QID for 7d
OR doxycycline 3mg/kg OD for 7d
OR clindamycin 10mg/kg BD for 7d
• Atovaquone-proguanil 20/8 mg/kg OD for 3d with food

74. MANAGEMENT OF SEVERE MALARIA
Initial parenteral treatment for
atleast 48 hours
(Chloroquine resistant )
Follow up treatment when the patient can take
oralmedication following parenteral
Quinine: 20mg quinine salt/kg body wgt
on admission(IV infusion or IM divided doses
) followed by maintainence dose of 10mg/kg
8th hourly.(infusion rate must not exceed
5mg salt/kg body wt/hr.)
Full course of area specific ACT: In north
eastern states:
Artemether-lumefantrine 1.5/9 mg/kg twice
daily for three days.i.e adult dose is 4tabs b.d for
3 days (ACT-AL) for 3 days+ PQ single dose on
second day.
In other states:
Artesunate 4mg/kg per day for 3 days+
sulphadoxine 25mg/kg + pyrimethamine
1.25mg/kg single dose. (ACT-SP) for 3 days+ PQ
single dose on second day.
Artesunate : 2.4mg/kg IV on admission(time
=0) , then at 12and 24hrs, then oncedaily.
Artemether : 3.2mg/kg body wgt IM given
on admission then 1.6mg/kgper day.

75. ADJUVANT TREATMENT IN SEVERE
FALCIPARUM MALARIA
CEREBRAL
MALARIA/
UNAROUSABLE
COMA
 Maintain airway, place patient on his or her side, exclude
other treatable causes of coma (e.g. hypoglycaemia,
bacterial meningitis);
 avoid harmful ancillary treatment, such as corticosteroids,
heparin and adrenaline;
 intubate if necessary.
ACIDOSIS  Exclude or treat hypoglycaemia, hypovolaemia and
septicaemia.
 If severe (pH<7.15) , add haemofiltration or haemodialysis.
HYPOGYCEMIA  Check blood glucose(4th hourly), correct hypoglycaemia and
maintain with glucose containing infusion.
HYPERPARASITEMI
A
Consider exchange transfusion (>10% circulating parasitized
erythrocytes)

76. ADJUVANT TREATMENT IN SEVERE
FALCIPARUM MALARIA
SHOCK/ ALGID MALARIA  Suspect septicaemia, take blood for cultures;
 Give parenteral broad-spectrum antimicrobials,
 Correct haemodynamic disturbances
CONVULSIONS  Maintain airways; treat promptly with intravenous or rectal diazepam
or intramuscular paraldehyde.
 Check blood glucose.
BLEEDING / DIC  Transfuse with screened fresh whole blood (cryoprecipitate, fresh
frozen plasma and platelets, if available);
 Give vitamin K injection.
SEVERE ANEMIA Transfuse with screened fresh whole blood.

77. ADJUVANT TREATMENT IN SEVERE
FALCIPARUM MALARIA
HYPERPYREXIA
 Administer tepid sponging, fanning, a cooling blanket and antipyretic
drugs.
 Paracetamol is preferred over more nephrotoxic drugs (e.g. NSAIDs
).
RENAL FAILURE  Exclude pre-renal causes,
 Check fluid balance and urinary sodium;
 If in established renal failure add haemofiltration or haemodialysis,
or if unavailable, peritoneal dialysis.
ACUTE PULMONARY
EDEMA
 Prop patient up at an angle of 45°
 Give oxygen,
 Give a diuretic,
 Stop intravenous fluids,
 Intubate and add positive end-expiratory pressure/ continuous

78. MIXED INFECTIONS
• ACTs are effective against all malaria species, and they are the treatment of choice.
• Radical treatment with primaquine should be given to patients with confirmed P. vivax and
P. ovale infections, except in high transmission settings where the risk of re-infection is
high.
Mixed infections (p.vivax +p.falciparum)
In north eastern states Artemether-lumefantrine 1.5/9 mg/kg twice daily
for three days.i.e adult dose is 4tabs b.d for 3
days.(ACT-AL )+ primaquine 0.25mg/kg body wgt
dailyfor 14 days.
In other states Artesunate 4mg/kg per day for 3 days+
sulphadoxine 25mg/kg + pyrimethamine
1.25mg/kg single dose. (ACT-SP) + primaquine
0.25mg/kg body wgt daily for 14days.

79. MALARIA IN PREGNANCY
Treatment of uncomplicated malaria (P. falciparum)
1st trimester Quinine salt 10mg/kg 3 times daily for 7
days. Combined with clindamycin
10mg/kg twice daily.
If Quinine is unavailable ACT therapy is
used.
2nd and 3rd trimester In north eastern
states
Artemether-lumefantrine 1.5/9 mg/kg
twice daily for three days.i.e adult dose is
4tabs b.d for 3 days.(ACT-AL )
In other states Artesunate 4mg/kg per day for 3 days+
sulphadoxine 25mg/kg +
pyrimethamine 1.25mg/kg single dose.

80. TREATMENT OF UNCOMPLICATED VIVAX MALARIA IN
PREGNANCY
• Oral Chloroquine 600mg followed by 300mg 6 hours later, then 300mg on
day 2 and again on day 3.
• 300mg weekly until delivery and 3 months after delivery/breast feeding to
prevent relapse.
• Radical treatment with Primaquine 15mg OD for 14 days can be initiated after
that.

81. TREATMENT OF SEVERE MALARIA IN PREGNANCY
(NATIONAL DRUG POLICY ON MALARIA, 2015)
Trimester Drugs
1st •Quinine 20mg of salt/kg on admission f/b maintenance dose of 10mg/kg 8th
hourly (iv infusion in 5% D or DNS over 4 hours)
Note- Quinine dosing should be reduced to 12th hourly if iv therapy extends more
than 48 hours or if the patient has renal or hepatic dysfunction.
•Switch to oral once the patient is better- oral Quinine 10mg/kg 12th hourly for 7
days
+
•Clindamycin 10mg/kg 12th hourly for 7 days
2nd and 3rd •Artesunate 2.4 mg/kg iv given on admission, then at 12 and 24 hours and later
once a day till the patient resumes oral feeds
Or
•Artemether 3.2mg/kg im on admission f/b 1.6mg/kg per day till patient resumes
oral feeds.
•Followed by ACT therapy

82. DRUG SAFETY PROFILE IN
PREGNANCY
Chloroquine Well tolerated and safe throughout pregnancy
Mefloquine Less well tolerated. No increased adverse events noted
Artemisinin derivatives •To be avoided during 1st trimester(Indian guidelines 2015)
•Used safely n 2nd and 3rd trimester as parental as well as
combination therapy.
Quinine Safe and effective n 1st trimester. When used as iv infusion, risk of
hypoglycemia and cardiac arrhythmia is high.
Sulphadoxine and
pyrimethamine
Seemed safe and well tolerated as part of ACT and IPTp
Lumefantrine As part of ACT- well tolerated
Clindamycin Relatively safe and well tolerated
Tetracycline,
doxycycline and
primaquine
Strictly contraindicated in pregnancy

83. CO EXISTING MORBIDITIES
HIV
• Patients with HIV infection who develop malaria should receive prompt,
effective antimalarial treatment regimens as recommended in the relevant
sections of these guidelines.
• Treatment or intermittent preventive treatment with sulfadoxine-
pyrimethamine should not be given to HIV-infected patients receiving
cotrimoxazole (trimethoprim plus sulfamethoxazole) prophylaxis.
• Treatment in HIV-infected patients on zidovudine or efavirenz should, if
possible, avoid amodiaquine-containing ACT regimens.

84. TREATMENT BASED ON CLINICAL
CRITERIA WITHOUT LABARATORY
CONFIRMATION
• If RDT for P. falciparum is used- negative cases with signs and symptoms
of malaria without any other obvious cause for fever should be considered
as Clinical malaria.
• Treated with chloroquine (25mg/kg over 3 days)
• Treatment should be completed according to species after slide result is
obtained.
• If RDT and microscopy are negative- treat with chloroquine

85. TREATMENT FAILURE/DRUG
RESISTANCE
• No fever/parasitaemia till day 28- patient cured
• In treatment failure cases alternative ACT or Quinine with Doxycycline is given.
• Early treatment failure-
• Danger signs or severe malaria on day 1,2, or 3, in the presence of parasitaemia
• Parasitaemia on day 2> day 0 ( irrespective of axillary temp)
• Parasitaemia on day 3 with temp>37.5 degree C
• Parasitaemia on day 3- >25% count on day 0

86. • Late clinical failure:
• Development of danger signs or severe malaria In the presence of parasitaemia on
any day between day 4 and 28 in patients who did not previously meet any of the
criteria of ETF.
• Presence of parasitaemia on any day between day 4 and 28 with axillary temp>37
degree C in patients who did not previously meet the criteria of ETF.
• Late parasitological failure:
• Presence of parasitaemia on any day between day 7 and 28 with axillary temp <37
degree C in patients who did not previously meet any of the criteria of ETF or LCF.

87. ASSESMENT OF THERAPEUTIC
RESPONSE
 Parasite clearance time(PCT)
This is the interval between beginning of antimalarial treatment and the
firstnegative blood slide.
 Fever clearance time(FCT)
- This is the time from beginning of the antimalarial treatment until
the patient is apyrexial.
- Approach is to record when temp first falls below 37.5c and then when
temperature falls and remains below 37.5c for 24 hours

89. MONOTHERAPY OF ORAL ARTEMISININ DERIVATIVES
IS BANNED IN INDIA
Artemisinin derivatives are the only rapidly acting antimalarials as of date and if
used alone, can lead to the development of artemisinin resistance. Hence, they
should not be administered as monotherapy for uncomplicated malaria except
for specific studies on artemisinin resistance after consultation with NVBDCP
and NIMR or as injectables
for severe malaria.
Injectable artemisinin derivatives should be used only in severe malaria.

90. CHEMOPROPHYLAXIS
 The National Vector Borne Disease Control Programme
(NVBDCP) recommends chemoprophylaxis for selective
groups in high P. falciparum endemic areas
 Chemoprophylaxis is recommended for travellers from non-
endemic areas and pregnant women in endemic areas.

91. CHEMOPROPHYLAXIS
 For longer stay of Military and Para-military forces in high P.
falciparum endemic areas, the practice of chemoprophylaxis should
be followed wherever appropriate, e.g. troops on night patrolduty.
 For pregnant women living in endemic areas(pf % >30)
IPTp(intermittent preventing therapy in pregnant women) with
sulphadoxine-pyrimethamine is recommended.

92. Drug Dosage Comments
Atovaquone/ proguanil
Only in areas with
chloroquine or
mefloquine resistant P.f
250mg of atovaquone and
100 mg of proguanil OD
Begin 1-2 days beforeand for 7 days
after leaving such areas.
Chloroquine phosphate
(Sensitive p.f strains)
300mg base once aweek on
the same day each week
Begin 1-2 weeks beforeand for 4
weeks after leaving such areas.
Doxycycline(chloroquine
or mefloquine resistant
P.f)- short term(<6 weeks)
100mg PO OD Begin 1-2 days beforeand for 4 weeks
after leaving such areas.
Mefloquine (Chloroquine
resistant areas)- long term (>6
weeks)
228mg base=250mg tablet 1
tablet once a week on the
same day each week.
Begin 1-2 weeks beforeand for 4
weeks after leaving such areas.
National Drug Policy on Malaria – 2015. Directorate of National Vector Borne Disease Control Programme. Govt. of India. New
Delhi. 2015
CHEMOPROPHYLAXIS

93. •In July 2018, the FDA approved tafenoquine, an antiplasmodial 8-aminoquinoline
derivative indicated for the radical cure .
•The drug is active against all stages of the P vivax life cycle.
•Tafenoquine is administered as a single oral dose (300mg) on the first or second
day of appropriate antimalarial therapy for acute P vivax malaria.
•In August 2018, tafenoquine gained a second indication- PROPHYLAXIS.
•Contraindicated in pregnancy and G6PD deficiency .
TAFENOQUIN
E

94. PREVENTION AND CONTROL
REDUCING
HUMAN-
MOSQUITO
CONTACT

96. MALARIA VACCINE
• Malaria vaccine production and distribution continues to be in the research and
development stage.
• The RTS, S/AS01 (commercial name, Mosquirix ) was engineered using genes
from outer protein of P.falciparum and a portion of Hep.B virus plus a chemical
adjuvant.
• Interim phase 3 trial results were reported in 2011 for the malaria vaccine
RTS,S/AS01. The vaccine efficacy rate was calculated to be 55.8%.

97. REFERENCES
• Harrison’s- Principles of INTERNAL MEDICINE, 20th Edition
• Uptodate
• Manson’s Tropical Diseases 23rd Edition
• National Guidelines for Diagnosis and Treatment of Malaria in
India(NVBDCP)
• Satoskar textbook of Pharmacology
• Panikers textbook of Medical Parasitology