Malaria in India

Malaria
Dr. Pallaavi Goel
JR1 Medicine

Introduction
• Malaria is a protozoan disease, caused by various species of genus Plasmodium, and
transmitted by the bite of infected female Anopheles mosquito.
• It is transmitted in 91 countries containing approx 3 billion people and causes ~1200
deaths each day.
• Many countries are now targeting malaria elimination. This ambitious goal is threatened
by increasing resistance to antimalarial drugs and insecticides.

Malaria remains today, as it has been for
centuries:
a heavy burden on tropical communities
a threat to nonendemic countries
a danger to travelers

Etiology
• The species of the genus Plasmodium that cause nearly all malarial infections in
humans are:
I. P. falciparum
II. P. vivax
III. P. ovale (curtisi and wallikeri- two morphologically identical sympatric
species)
IV. P. malariae
V. P. knowlesi - the monkey malaria parasite in Southeast Asia.
• While almost all deaths are caused by falciparum malaria, P. knowlesi and
occasionally P. vivax can also cause severe illness.

• Malaria occurs throughout most of the tropical regions of the world.
• P. falciparum predominates in Africa, New Guinea, The Dominican Republic and Haiti.
• P. vivax is more common in Central and South America.
• The prevalence of these two species is approximately equal on the Indian subcontinent and in
eastern Asia.
• P. malariae is found in most endemic areas, especially throughout sub-Saharan Africa, but is much
less common.
• P. ovale is relatively unusual outside of Africa and, where it is found, comprises <1% of isolates.
• P. knowlesi causes human infections commonly on the island of Borneo in Southeast Asia, where the
main hosts, long-tailed and pig-tailed macaques, are found.
Epidemiology

• The epidemiology of malaria is complex and may vary considerably even within a
relatively small geographic areas.
• Endemicity traditionally has been defined in terms of rates of microscopy-detected
parasitemia or palpable spleens in children 2–9 years of age and has been
classified as :
Hypo-endemic (<10%)
Meso-endemic (11–50%)
Hyper-endemic (51–75%)
Holo-endemic (>75%)

• In holo- and hyperendemic areas where there is intense P.
falciparum transmission, people may sustain as much as one
infectious mosquito bite per day and are infected repeatedly
throughout their lives.
• Hence malaria morbidity and mortality are substantial during early
childhood.
• Immunity against disease is hard won in these areas following
repeated symptomatic infections in childhood, but, if the child
survives, infections are likely to be asymptomatic.
• These asymptomatic older children and adults are a major source of
malaria transmission.
• As control measures progress and urbanization expands,
environmental conditions become less conducive to malaria
transmission, and all age groups may lose protective immunity
and become susceptible to illness.

VectorsofMalariainIndia
• ANOPHELES ANNULARIS
• ANOPHELES BALABACENSIS
(DIRUS)
• ANOPHELES CULICIFACIES
• ANOPHELES FLUVIATALIS
• ANOPHELES MINIMUS
• ANOPHELES PHILLIPENSIS
• ANOPHELES STEPHENSI
• ANOPHELES SUNDIACUS
• ANOPHELES TESELATUS
• ANOPHELES VARUNA

• A. CULICIFACIES
• A. STEPHENSI
• A.FLUVIATALIS
VectorsofMalariainRajasthan

• In areas where transmission is low and erratic, full
protective immunity is not acquired, and
symptomatic disease may occur at all ages is
termed as unstable transmission.
• It is common in hypo-endemic areas.
• The constant, frequent, year-round
infection is termed as stable
transmission.

• The principal determinants of the epidemiology of malaria are:
 the number (density)
 the human-biting habits
 the longevity of the anopheline mosquito vectors
• The transmission of malaria is directly proportional to:
∞ the density of the vector
∞ the square of the number of human bites per day per mosquito
∞ the tenth power of the probability of the mosquito’s surviving for 1
day.

• The most effective mosquito vectors of malaria are those, such as the
Anopheles gambiae species complex in Africa, that are long-lived, occur in
high densities in tropical climates, breed readily, and bite humans in
preference to other animals.
• The entomologic inoculation rate (i.e., the number of sporozoite-
positive mosquito bites per person per year) is the most common
measure of malaria transmission and varies from <1 in some parts of
Latin America and Southeast Asia to >300 in parts of tropical Africa.
• Sporogony is not completed at cooler temperatures—i.e.,
<16°C for P. vivax and <21°C for P. falciparum; thus
transmission does not occur below these temperatures or at
high altitudes.

ERYTHROCYT
E
CHANGES
HOST
RESPONSE

After invading an erythrocyte, the growing malarial parasite progressively consumes and degrades
intracellular proteins, principally hemoglobin.
The potentially toxic heme is detoxified to biologically inert hemozoin i.e. malaria pigment.
The parasite also alters the RBC membrane by changing its transport properties, exposing cryptic
surface antigens, and inserting new parasite-derived proteins.
Hence the RBC becomes more irregular in shape, more antigenic, and less deformable.

• In P. falciparum infections, membrane protuberances appear on the erythrocyte’s surface
12–15 h after the cell’s invasion.
• These “knobs” extrude a strain-specific erythrocyte membrane adhesive protein
(PfEMP1) that mediates attachment to receptors on venular and capillary endothelium
(cytoadherance).
• Erythrocytes containing more mature parasites stick inside and eventually block
capillaries and venules.
• These infected RBCs may also adhere to uninfected RBCs (to form rosettes) and to other
parasitized erythrocytes (agglutination).
The processes of cytoadherence,
rosetting, and agglutination are central
to the pathogenesis of falciparum
malaria.

In other forms, significant sequestration does not occur, and all stages of the parasite’s
development are evident on peripheral-blood smears.
This results in the sequestration of infected RBCs in vital organs (particularly the brain), where they
interfere with microcirculatory flow and metabolism.
Sequestered parasites continue to develop out of reach of the principal host defense mechanism.
As a consequence, only the younger ring forms of the asexual parasites are seen circulating in the
peripheral blood in falciparum malaria.
The level of peripheral parasitemia underestimates the true number of parasites within the body.

Temperatures of ≥104°F damage mature parasites; in untreated infections, the effect of such
temperatures is to further synchronize the parasitic cycle, with eventual production of the regular fever
spikes and rigors that originally characterized the different malarias.
Initially, the host responds to malaria infection by activating nonspecific defense mechanisms.
Splenic immunologic and filtrative clearance functions are augmented, and the removal of both
parasitized and uninfected erythrocytes is accelerated.
The spleen also removes damaged ring-form parasites (a process known as “pitting”) and returns the
once-infected erythrocytes to the circulation, where their survival is shortened.
The parasitized cells escaping splenic removal are destroyed when the schizont ruptures.
The material released induces monocyte/ macrophage activation and the release of proinflammatory
cytokines, which cause fever and other pathologic effects.

• Nonspecific host defense mechanisms stop the infection’s expansion, and the subsequent strain-
specific immune response then controls the infection.
• Eventually, exposure to sufficient strains confers protection from high-level parasitemia and disease
but not from infection.
• As a result of this state of infection without illness (premunition), asymptomatic parasitemia is very
common among adults and older children living in regions with stable and intense transmission (i.e.,
holo- or hyperendemic areas).
• Passively transferred IgG from immune adults has been shown to reduce levels of parasitemia in
children.
• Passive transfer of maternal antibody contributes to the
partial protection of infants from severe malaria in 1st month.
Immunity is mainly specific for both the
species and the strain of infecting malarial parasite.

• Fever is the cardinal symptom of malaria. It can be intermittent with or without periodicity or
continuous.
• The classic malarial paroxysms, in which fever spikes, chills, and rigors occur at regular intervals,
are relatively unusual and suggest infection (often relapse) with P. vivax or P. ovale.
• The fever is usually irregular at first (that of falciparum malaria may never become regular).
• The temperature of nonimmune individuals and children often rises above 104°F, with
accompanying tachycardia and sometimes delirium.
• The fever is often accompanied by headache, myalgia, arthralgia, anorexia, nausea and vomiting.
• The symptoms of malaria can be non-specific and mimic other diseases like viral infections, enteric
fever.
• These regular fever patterns (quotidian, daily; tertian, every 2 days; quartan, every 3 days) are
seldom seen today due to prompt treatment.

• In nonimmune individuals with acute malaria, the spleen takes several days to become
palpable.
• But splenic enlargement is found in a high proportion of otherwise healthy individuals in
malaria-endemic areas and reflects repeated infections.
• Slight enlargement of the liver is also common, particularly among young children.
• Mild jaundice is common among adults; it may develop in patients with otherwise
uncomplicated malaria and usually resolves over 1–3 weeks.
• Malaria is not associated with a rash.
• Petechial hemorrhages in the skin or mucous membranes—features of viral hemorrhagic
fevers develop very rarely in severe falciparum malaria .

Malaria should be suspected in patients residing in endemic
areas and presenting with above symptoms.
All clinically suspected malaria cases should be investigated
immediately by microscopy and/or Rapid Diagnostic Test
(RDT)
It should also be suspected in those patients who have
recently visited an endemic area.

Although malaria is known to mimic the signs and symptoms of many
common infectious diseases, the other causes should also be suspected
and investigated in the presence of following manifestations:
► Running nose, cough and other signs of respiratory infection
► Diarrhoea/dysentery
► Burning micturition and/or lower abdominal pain
► Skin rash
► Abscess
► Painful swelling of joints
► Ear discharge
► Lymphadenopathy

Cerebral Malaria
• Coma is a characteristic feature of falciparum malaria and, even with treatment,
has been associated with death rates of ~20% among adults and 15% among children.
• Any delirium, or abnormal behavior in falciparum malaria should be taken very seriously.
• Cerebral malaria manifests as diffuse symmetric encephalopathy. The eyes may be divergent, and
bruxism and a pout reflex are common, but other primitive reflexes are usually absent.
• The corneal reflexes are preserved. Muscle tone may be either increased or decreased.
• The tendon reflexes are variable, and the plantar reflexes may be flexor or extensor; the abdominal
and cremasteric reflexes are absent. Flexor or extensor posturing may be seen.
• Convulsions, which are usually generalized and often repeated, occur in ~10% of adults and up to
50% of children with cerebral malaria.

• Adults rarely (<3% of cases) suffer neurologic sequelae.
• Children surviving cerebral malaria—especially those
with hypoglycemia, severe anemia, repeated
seizures, and deep coma—have residual neurologic
deficits when they regain consciousness; hemiplegia,
cerebral palsy, cortical blindness, deafness, and impaired
cognition may all occur.
• The majority of these deficits improve markedly or resolve
completely within 6 months.
• 10% of children surviving cerebral malaria have a
persistent language deficit.
• There may also be deficits in learning, planning and
executive functions, attention, memory, and nonverbal
functioning.
• The incidence of epilepsy is increased and life
expectancy decreased among these children.

Malaria in Pregnancy
• Malaria in early pregnancy causes fetal loss.
• In areas of high malaria transmission, falciparum malaria in primi- and secundigravid women is associated with
low birth weight and consequently increased infant mortality rates.
• Fetal distress, premature labor, and stillbirth or low birth weight are common results.
• Fetal death is usual in severe malaria.
• Congenital malaria occurs in fewer than 5% of newborns whose mothers are infected.

Malaria in Children
• Most of the estimated ~5,00,000 deaths from falciparum
malaria each year are in young African children.
• Convulsions, coma, hypoglycemia, metabolic acidosis, and
severe anemia are relatively common among children with
severe malaria.
• Whereas deep jaundice, oliguric acute kidney injury, and
acute pulmonary edema are unusual.
• Severely anemic children may present with labored deep
breathing, that is usually caused by metabolic acidosis,
sometimes compounded by hypovolemia.

Transfusion Malaria
• Malaria can be transmitted by blood transfusion,
needlestick injury, or organ transplantation.
• The incubation period in these settings is often short
because there is no pre-erythrocytic stage of
development.
• The clinical features and management of these cases
are the same as for naturally acquired infections.
• Radical chemotherapy with primaquine is not
necessary for transfusion-transmitted P. vivax and P.
ovale infections.

Chronic Complications of Malaria
1. HYPERREACTIVE MALARIAL SPLEENOMEGALY :
• Chronic or repeated malarial infections produce hypergammaglobulinemia; normochromic,
normocytic anemia; and, in certain situations, splenomegaly.
2. QUARTAN MALARIAL NEPHROPATHY:
• Chronic or repeated infections with P. malariae may cause soluble immune complex injury to the
renal glomeruli, resulting in the nephrotic syndrome.
• The histologic appearance is that of focal or segmental glomerulonephritis with splitting of the
capillary basement membrane.
3. BURKITT’S LYMPHOMA AND EPSTEIN-BARR VIRUS INFECTION :
• It is possible that malaria-related immune dysregulation provokes infection with lymphoma
viruses.

LABORATORY FINDINGS IN ACUTE MALARIA
• Normochromic, normocytic anemia.
• Normal or raised TLC
• The platelet count is usually reduced.
• C-reactive protein, Lactate dehydrogenase and other acute-phase proteins are elevated.
• Deranged LFTS
• Severe infections may be accompanied by prolonged prothrombin and partial thromboplastin times
• In uncomplicated malaria, plasma concentrations of electrolytes, and creatinine are usually normal.
• Findings in severe malaria may include metabolic acidosis, with low plasma concentrations of
glucose, sodium, bicarbonate, phosphate, and albumin, together with elevations in lactate,
creatinine, liver enzymes, and Bilirubin.
• Urinalysis generally gives normal results.
• In adults and children with cerebral malaria, the mean cerebrospinal fluid (CSF) opening pressure at
lumbar puncture is ~160 mm H2O; usually the CSF content is normal or there is a slight elevation of
total protein level and cell count.

Appropriately and promptly treated, uncomplicated falciparum malaria
(i.e., that in which the patient can sit or stand unaided and can swallow
medicines and food)
carries a mortality rate of <0.1%.
However, once vital-organ dysfunction occurs or the total proportion of
erythrocytes infected increases to >2% , mortality risk rises steeply,
depending on the immunity of the host.

Early diagnosis and treatment of cases of malaria
aims at:
 Providingprompt and complete treatment to all suspected/ confirmed cases of
malaria.
 Prevention of progression of mild cases of malaria into severe or complicated
forms of malaria.
 Prevention of deaths from severe and complicated malaria.
 Prevention of transmission of malaria
 Minimization of risk of spread of drug resistant parasites by use of effective
drugs in appropriate dosage byeveryone.

Uncomplicated P.Vivax malaria
 Uncomplicated malaria is defined as symptomatic malaria withoutsigns of severity
or evidence (clinical/ laboratory) of vital organ dysfunction.
 Chloroquine:
o 25mg/kg (base) divided over 3days
 Day 1-10mg/kg
 Day 2- 10mg/kg
 Day 3- 5 mg/kg
 Primaquine 0.25 mg/kg for 14days along with food.

 Primaquine is contraindicated in:
× G6PD Deficiency
× Infants
× Children <4 yrs
× Pregnant women
Stop Primaquine if patient has:
≡ Dark coloured urine
≡ Yellow conjunctiva
≡ Blue discoloration of lips
≡ Abdominal pain
≡ Nausea / Vomiting

Uncomplicated P.Falciparum malaria
 Treatment can be divided on the basis of Chloroquine Resistance.
 Chloroquine can be used in Chloroquine sensitive areas.
 Whereas in Chloroquine resistant areas we use Artemisinin based
Combination Therapy (ACT).
 Chloroquine resistant areas: High Pf endemic districts in seven North-eastern
states, Andhra Pradesh, Chhattisgarh, Jharkhand, Madhya Pradesh and Orissa
 Primaquine single dose 0.75 mg/kg is administered along with the primary
treatment of ACT.

ACT
• ACT consists of an artemisinin derivative combined with a long acting antimalarial.
• The ACT used in the national programme in India is :
Artesunate + Sulfadoxine-Pyrimethamine
Artemether-lumefantrine
• Artemisinin derivatives must never be administered as monotherapy for uncomplicated malaria.
These rapidly acting drugs, if used alone, can lead to development of parasite resistance.
• The other fixed dose combinations registered for marketing in India are artesunate-amodiaquine,
artesunate-mefloquine and arterolane-piperaquine (for adults only) and can be used for treatment
of uncomplicated P. falciparum or mixed infections.

• The ACT recommended in the National Programme all over India:
 Artesunate 4 mg/kg body weight daily for 3days
 Sulfadoxine (25 mg/kg body weight) –Pyrimethamine (1.25 mg/kg
body weight) on first day
 Plus Primaquine: 0.75 mg/kg body weight single dose on day 2.
• In the north eastern states there have been recent reports of late
treatment failures to the current combination of AS+SP in P. falciparum
malaria, presently recommended ACT in national drug policy is fixed
dose combination (FDC) of Artemether-lumefantrine (AL) .

Treatment of Mixed Infections
 Mixed infections with P. falciparum should be treated as
falciparum malaria.
Since AS+SP is not effective in vivax malaria, other ACT
should be used.
However, anti-relapse treatment with primaquine can be
given for 14 days

Treatment based on clinical criteria without
laboratory confirmation
• If RDT for only P. falciparum is used, negative cases showing signs and
symptoms of malaria without any other obvious cause for fever should be
considered as ‘clinical malaria’ and treated with chloroquine in full
therapeutic dose of 25 mg/kg body weight over three days.
• If a slide result is obtained later, the treatment should be completed according to
species.
• Suspected malaria cases not confirmed by RDT or microscopy should be treated
with chloroquine in full therapeutic dose.

General recommendations for the
management of uncomplicated malaria:
Avoid starting treatment on an empty stomach.
The first dose should be given under observation.
Dose should be repeated if vomiting occurs within 30 minutes.
The patient should report back, if there is no improvement after 48 hours
or if the situation deteriorates.
The patient should also be examined for concomitant illnesses

Severe Malaria
• Severe manifestations can develop in P. falciparum infection over a span of time
as short as 12 – 24 hours and may lead to death, if not treated promptly and
adequately.
∆ Impaired consciousness/coma
∆ Repeated generalized convulsions
∆ Renal failure (Serum Creatinine >3 mg/dl)
∆ Jaundice (Serum Bilirubin >3 mg/dl)
∆ Severe anaemia (Hb <5 g/dl)
∆ Pulmonary oedema/acute respiratory distress syndrome
∆ Hypoglycaemia (Plasma Glucose <40 mg/dl)
∆ Metabolic acidosis
∆ Circulatory collapse/shock (Systolic BP <80 mm Hg, <70 mm Hg in children)
∆ Abnormal bleeding/ DIC/ Haemoglobinuria
∆ Hyperthermia (Temperature >104oF)
∆ Hyper-parasitaemia (>5% parasitized RBCs in low endemic and >10% in
hyperendemic areas)

Parenteral artemisinin derivatives or quinine should be used irrespective of
chloroquine sensitivity
• Artesunate:
2.4 mg/kg i.v. or i.m. given on admission (time=0), then at 12 hours and 24 hours,
then once a day.
(Care should be taken to dilute artesunate powder in 5% Sodium bi-carbonate
provided in the pack).
• Artemether: 3.2 mg/kg i.m. given on admission then 1.6 mg/kg per day.
• Arteether: 150 mg daily i.m. for 3 days in adults only (not recommended for
children).

Quinine:
• 20 mg quinine salt/kg on admission (i.v. infusion in 5% dextrose/dextrose
saline over a period of 4 hours)
• followed by maintenance dose of 10 mg/kg 8 hourly;
• infusion rate should not exceed 5 mg/kg per hour.
• Loading dose of 20 mg/kg should not be given, if the patient has already
received quinine.
• NEVER GIVE BOLUS INJECTION OF QUININE.
• If parenteral quinine therapy needs to be continued beyond 48 hours, dose
should be reduced to 7 mg/kg 8 hourly.

Once the patient can take oral therapy, the further follow-up treatment
should be as below:
• Patients receiving parenteral quinine should be treated with oral quinine
10 mg/kg three times a day to complete a course of 7 days.
• Along with doxycycline 3 mg/kg per day for 7 days. (Doxycycline is
contraindicated in pregnant women and children under 8 years of age;
instead, Clindamycin 10 mg/kg bw 12 hourly for 7 days should be used).
• Patients receiving artemisinin derivatives should get full course of oral
ACT.
• However, ACT containing mefloquine should be avoided in cerebral
malaria due to neuropsychiatric complications.

Management of Complications
 Coma:
Maintain airway
exclude other treatable causes of coma(e.g. hypoglycaemia, bacterial meningitis)
 Convulsions:
Maintain airway
Treat promptly with intravenous or rectal diazepam
Check blood glucose
Respiratory support if needed

 Hyperpyrexia:
Administer tepid sponging, fanning, a cooling blanket
and antipyretic drugs.
Paracetamol is preferred over more nephrotoxic drugs.
 Hypoglycemia:
Check blood glucose every 4-6 hrly
Glucose level should be >100mg/dL
An initial slow injection of 20% dextrose (2 mL/kg over 10 min) should be followed by
an infusion of 10% dextrose (0.10 g/kg per hour)

 Acute pulmonary oedema:
Prop patient up at an angle of 45°
give oxygen
give diuretic
stop intravenous fluids
intubate and add positive end-expiratory pressure
 Acute renal failure:
Exclude pre-renal causes
fluid administration should be restricted to prevent volume overload
Renal replacement therapy best performed early

 Spontaneous bleeding and coagulopathy:
Transfuse with screened fresh whole blood (cryoprecipitate, fresh frozen plasma
and platelets, if available)
Vitamin K
 Sepsis:
Broad spectrum antibiotics along with Antimalarials
Antibiotics should be considered for severely ill patients of any age who are
not responding to antimalarial treatment.

Treatment in specific populations and
situations:
• Treatment of uncomplicated P.falciparum cases in pregnancy:
 1st Trimester : Quinine salt 10mg/kg 3times daily for 7 days.
 2nd and 3rd trimester: ACT as per dosage schedule.
 Primaquine is contraindicated.
• Lactating women: recommended antimalarial treatment (including ACT),
except for primaquine and tetracyclines.

Treatment Failure
• After treatment patient is considered cured if he/she does not have fever or
parasitemia till Day 28.
• Some patients may not respond to treatment which may be due to drug
resistance or treatment failure, especially in falciparum malaria.
• Such cases of falciparum malaria should be given alternative ACT or
quinine with Doxycycline.
• Treatment failure with chloroquine in P. vivax malaria is rare in India.

Chemoprophylaxis
• Chemoprophylaxis is recommended for:
Travellers
Migrant laborer’s
Military personnel
Others visiting a highly endemic area

• For short-term chemoprophylaxis (less than 6 weeks):
• Doxycycline: 100 mg daily in adults and 1.5 mg/kg for children more than 8 years old.
• The drug should be started 2 days before travel and continued for 4 weeks after leaving the
area.
• Note: Doxycycline is contraindicated in pregnant women and children less than 8 years.
• For long-term chemoprophylaxis (more than 6 weeks):
• Mefloquine: 5 mg/kg bw (up to 250 mg) weekly
• Should be administered two weeks before, during and four weeks after leaving the area.
• Note: Mefloquine is contraindicated in cases with history of convulsions, neuropsychiatric
problems and cardiac conditions.

Prevention of malaria
• Apply insect repellent to exposed skin. The
recommended repellent contains 20-35%
percent N,N-Diethyl-meta-toluamide
(DEET).
• Wear long-sleeved clothing and long pants
if you are outdoors at night.
• Use a mosquito net over the bed and For
additional protection, treat the mosquito net
with the insecticide permethrin.
• Spray an insecticide or repellent on
clothing, as mosquitoes may bite through
thin clothing

Malaria in India

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