MALARIA UPDATED

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MALARIA

• BYDR TAPAN
• MODERATOR DR S.S.PATTANAYAK

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CONTENTS

• INTODUCTION
• ETIOLOGY PATHOGENESIS
• CLINICAL FEATURES
• COMPLICATIONS
• DIAGNOSIS
• TREATMENT
• PREVENTIONS

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INTRODUCTION

• From the Italian malaria - Bad Air
• Also known as ague, marsh disease
• Descriptions of malaria go as far back as 3550
  B.C.
• Malaria is a protozoan disease transmitted by
  bite of infected Anopheles mosquito caused by
  parasites of genus Plasmodium
• In Nov. 1880,Charles Louis Alphonse Laveran, was
  the first to notice parasites in the blood of a
  patient suffering from malaria.
• Ronald Ross was the first to demonstrate that a
  mosquito could transmit a malaria parasite.
• Chloroquine(Resochin) was discovered by a German,
  Hans Andersag, in 1934.

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• EPIDEMIOLOGY
• -In 106 countries
• around 3.2 billion people
• -approximately 2000 deaths each day.
• Eliminated from USA, Canada, Europe Russia.

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• Species of Plasmodium causing Malaria in India
  are
• Plasmodium vivax
• Plasmodium falciparum
• Plasmodium ovale
• Plasmodium malariae
• Plasmodium knowlesi
• Almost all deaths are by falciparum malaria, but
  P. knowlesi and P. vivax may also cause serious
  disease.

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CHARACTERISTICS OF DIFFERENT PLASMODIUM SPECIES
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ERYTHROCYTE CHANGES IN MALARIA

• Growing parasite progressively consumes and
  degrades intracellular proteins, majorly
  Hemoglobin.
• Degradation of Hemoglobin produces toxic Heme
  which is detoxified by lipid mediated
  crystallization to inert Hemozoin.
• Parasite alters the RBC membrane. So RBC becomes
  more irregular, more antigenic and less
  deformable.

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• In P.falciparum, membrane protuberances or
  Knobs appear in RBC which extrude a high
  molecular weight erythrocyte membrane adhesive
  protein (PfEMP1).
• PfEMP1 mediates attachment of RBC to various
  receptors like Intercellular adhesion molecule 1,
  CD 36 in vascular and capillary endothelium- A
  process known as Cytoadherence.
• Rosetting Infected RBCs bind to uninfected
  RBCS.
• Agglutination Infected RBCS bind to other
  infected RBCs.
• Cytoadherence, Rosetting and Agglutination are
  central to pathogenesis of falciparum malaria.
  This blocks microcirculatory flow and impairs
  metabolism.

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HOST RESPONSE

• Splenic filtrative mechanism accelerates removal
  of both infected and uninfected RBCs.
• RBCs escaping splenic removal are destroyed when
  the shizont ruptures.
• Materials released induce activation of
  macrophages and release of proinflammatory
  cytokines occurs which cause fever and other
  pathologic effects.

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CLINICAL FEATURES

• Malaria should be suspected in patients residing
  in endemic
• areas or who have recently visited endemic area
  and presenting
• with
• Fever Classical fever spikes at regular
  intervals with chills and rigors are unusual and
  may suggest P. vivax or P. ovale infection. Fever
  usually irregular at first.
• Lack of sense of well being
• Headache and muscle aches
• Fatigue
• Nausea
• Vomitting
• Generalized seizures may occur.
• The symptoms of malaria can be non-specific and
  mimic other diseases like viral
• infections, enteric fever etc.
• SIGNS mild Pallor, mild jaundice and a palpable
  spleen maybe seen.

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MANIFESTATIONS OF SEVERE FALCIPARUM MALARIA

• Unarousable Coma / Cerebral Malaria
• Acidosis
• Severe Normocytic Normochromic anemia
• Renal failure
• Pulmonary edema / ARDS
• Hypoglycemia
• Hypotension / Shock
• Bleeding / DIC
• Convulsions
• Others like Jaundice, Hemoglobinuria, Extreme
  weakness, Hyperparasitemia

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CEREBRAL MALARIA / UNAROUSABLE COMA

• Failure to localize or respond appropriately to
  noxious stimuli or coma persisting for gt 30 min
  after generalized convulsion.
• Manifests as diffuse symmetric encephalopathy.
  Focal signs are unusual.
• Convulsions usually generalized and often
  repeated.
• Signs of meningeal irritation are absent.
• Muscle tone may be increased or decreased.
• Tendon reflexes variable and plantar maybe flexor
  or extensor.
• 10 of children surviving cerebral malaria have
  neurologic sequele which resolve completely with
  in 6months
• Adults rarely have neurologic sequele.

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Perimacular whitening and Pale-centered retinal
hemorrhages
The EYE in cerebral malaria -retinal
hemorrhages (3040) -discrete spots of retinal
opacification (3060), -papilledema (8 among
children, rare among adults), -cotton wool spots
(lt5) -decolorization of a retinal vessel or
segment of vessel (occasional cases).
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HYPOGLYCEMIA

• Plasma glucose level of lt 40 mg/dl is associated
  with poor prognosis particularly in children and
  pregnant women.
• Results from failure of hepatic gluconeogenesis
  and increase in consumption of glucose by both
  host and parasite.
• Quinine used in Falciparum malaria enhances
  insulin release and aggravates hypoglycemia.
• The usual physical signs (sweating, gooseflesh,
  tachycardia) are absent.
• The neurologic impairment caused by hypoglycemia
  cannot be distinguished from that caused by
  malaria.

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ACIDOSIS

• Plasma pH of lt 7.25 or plasma bicarbonate lt 15
  mmol/L Lactate level of gt 5 mmol/L.
• Results from-
• -accumulation of organic acids produced by
  anaerobic glycolysis in tissues due to impaired
  microcirculatory flow
• -lactate production by the parasites
• -failure of hepatic and renal lactate clearance.
• Manifests as laboured deep breathing or acidotic
  breathing a sign of poor prognosis.
• Is followed by circulatory failure and
  respiratory arrest.

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RENAL FAILURE

• Serum Creatinine level of gt 3mg/dL
• 24hr urine output lt 400 ml in adults or lt 12 ml/
  Kg in children
• No improvement with rehydration.
• Maybe due to impaired micro-circulatory flow and
  metabolism.
• Manifests as Acute tubular necrosis
• Urine flow resumes in a median of 4 days, and
  serum creatinine levels return to normal in
  arround 17 days
• Early dialysis or hemofiltration increase the
  chances of patient survival.

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NONCARDIOGENIC PULMONARY EDEMA

• Often aggravated by overhydration.
• Pathogenesis is unclear.
• May develop even after several days of
  antimalarial therapy in falciparum malaria.
• Mortality rate is gt 80 in severe Falciparum
  malaria and usual in vivax malaria

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HEMATOLOGIC ABNORMALITIES

• Severe normocytic normochromic anemia due to
  accelerated RBC destruction by spleen and
  parasite.
• Splenic clearance is increased as RBCs show
  reduced deformability.
• In areas of unstable transmission, anemia can
  progress rapidly and transfusion may be required.
• Slight coagulation abnormalities are common in
  falciparum malaria and mild thrombocytopenia is
  usual.
• DIC with significant bleeding occurs in lt 5 of
  patients.

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LIVER DYSFUNCTION

• Mild hemolytic jaundice is common in malaria but
  severe jaundice may occur in P.falciparum
  infections.
• Jaundice is more common in adults than in
  children and results from hemolysis, hepatocyte
  injury and cholestasis.
• Liver dysfunction leads to hypoglycemia, lactic
  acidosis and impaired drug metabolism.

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OTHER COMPLICATIONS

• HIV/AIDS predispose to more severe malaria.
• Septicemia may complicate severe malaria.
• Aspiration pneumonia may occur after generalized
  convulsions.
• Chest infection and catheter induced UTI may
  occur in unconscious patients.
• In endemic areas,Salmonella bacteremia has been
  associated specifically with P. falciparum
  infections.

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Malaria in Pregnancy

• In early pregnancy causes abortion.
• In high transmission areas associated with low
  birth weight and increased infant mortality rate.
• Infected mothers in areas of stable transmission
  remain asymptomatic despite intense accumulation
  of parasitized erythrocytes in the placental
  microcirculation.
• In areas of unstable transmission pregnant women
  are susceptible to more severe infections with
  high parasitemia, anemia, hypoglycemia and
  pulmonary edema. Fetal distress, stillbirth,
  premature labor and low birthweight are usual.

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• 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
• Usually children tolerate antimalarial drugs well
  and respond rapidly to treatment.
• TRANSFUSION MALARIA -
• By blood transfusion, needle-stick injury,
  sharing of needles by infected injection drug
  users, or organ transplantation.
• Primaquine is unnecessary for transfusion-transmit
  ted P. vivax and P. ovale infections.

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LAB DIAGNOSIS OF MALARIA

• Common methods of diagnosis of malaria are
• Light Microscopy
• Antigen detection Rapid Diagnostic Tests
• QBC
• Microtube concentration methods with acridine
  orange staining.

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LIGHT MICROSCOPY

• Gold standard
• Based on demonstration of asexual forms of
  parasite in stained peripheral blood smears
• Giemsa at pH 7.2 is preferred stain. Fields ,
  Wrights , or Leishmans stain can also be used.
• At least 100 to 200 fields should be examined
  under oil immersion microscopy.
• After a negative smear, repeat blood smear should
  be made if there is high degree clinical
  suspicion.

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RAPID DIAGNOSTIC TEST

• Pf HRP-2 based kits may show positive result up
  to three weeks after successful treatment and
  parasite clearance.
• In these cases, results should be correlated with
  microscopic diagnosis.

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TREATMENT OF MALARIA

• All fever cases diagnosed as malaria by either
  RDT or microscopy should be promptly given
  effective treatment. The medicine chosen will
  depend upon whether the patient has vivax malaria
  or falciparum malaria or mixed infection as
  diagnosed by the blood test.
• If the malaria species is not known with
  certainty, treat as for uncomplicated
  P.falciparum malaria.

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• Early diagnosis and complete treatment of malaria
  aims at
• Complete cure
• Prevention of progression of uncomplicated
  malaria to severe disease
• Prevention of deaths
• Interruption of transmission
• Minimizing risk of selection and spread of drug
  resistant parasites

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DRUGS USED FOR TREATMENT OF MALARIA

• Chloroquine
• Quinine or Quinidine
• ACT regimens Five regimens recommended by WHO
  are Artesunate SP
• Artemether Lumefantrine
• Artesunate Mefloquin
• Artesunate Amodiaquin
• Dihydroartemisinine Piperaquin
• Primaquine
• Tetracycline / Doxycycline
• Proguanil

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• Choloroquine
• - Acts on trophozoite blood stages Kills
  gametocytes of P.vivax, P.ovale and P.malariae
  no action on liver stages.
• Minor adverse effects are nausea, pruritus,
  postural hypotension, rash.
• Major toxicites include cardiac arrythmia,
  hypotensive shock, retinopathy.
• Quinine, Quinidine
• Antimalarial action is as Chloroquine.
• - Common minor adverse effect is Cinchonism ,
  Q-T prolongation, diarrhoea.
• - Common major toxicity is hypoglycemia,
  hypotension, blindness, deafness, HUS ,
  thrombocytopenia.

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• ARTEMISININ and derivatives
• Rapid action, broader stage specificity, no
  action on liver stages.
• -Common adverse effect is reduction in
  reticulocyte count but anemia does not occur.
  Neutropenia may occur at high doses.
• -Anaphylaxis is major adverse effect.
• Primaquine
• Used for Radical cure i.e. eradicates hepatic
  forms of P.vivax and P.ovale, kills all stages of
  gemetocyte development of P.falciparum.
• -Common adverse effects are nausea, vomiting ,
  diarrhoea, abdominal pain.
• -Major adverse effect is massive hemolysis in
  severe G6PD deficiency.

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• TREATMENT OF UNCOMPLICATED
• MALARIA

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General recommendations for the management of
uncomplicated malaria

1. Avoid starting treatment on empty stomach.
2. The first dose is given under observation.
3. Dose repeated if vomiting within half hour of
   drug intake.
4. Patient asked to report back, if no improvement
   after 48 hours/deteriorates.
5. Investigate for concomittant illnesses

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Treating uncomplicated P.vivax, P.ovale,
P. malariae or P. knowlesi malaria
-In areas with chloroquine susceptible
infections,treat adults and children with with
either an ACT(Except pregnant women in their
first trimester) or chloroquine. -In areas with
chloroquine resistant infections,treat adults and
children with uncomplicated P.vivax,P.ovalae , P.
malariae or P. knowlesi malaria with an ACT
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TREATMENT OF UNCOMPLICATED MALARIA

• P. vivax
• chloroquine 25 mg/kg in divided doses over 3days
• In some patients ( 8 - 30) relapse due to
  hypnozoites in liver cells
• Relapse prevention, primaquine 0.25-0.5 mg/kg
  daily for 14 days under supervision

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Chloroquine Primaquine Regimen
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• Primaquine is contraindicated in pregnant women,
  infants and known G6PD deficient patients.
• Primaquine can lead to hemolysis in G6PD
  deficiency
• Patient should be advised to stop primaquine
  immediately if any of the following symptoms
  appear
• (i) dark coloured urine
• (ii) yellow conjunctiva
• (iii) bluish discolouration of lips
• (iv) abdominal pain
• (v) nausea
• (vi) vomiting
• (vii) breathlessness, etc.

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TREATMENT OF UNCOMPLICATED MALARIA

• P. falciparum
• ACT
• Artemisinin derivative with long acting
  antimalarial
• (amodiaquine, lumefantrine, mefloquine,
  piperaquine or sulfadoxine-pyrimethamine).
• The ACT in the National Programme all over India
  except northeastern states is
• Artesunate (4 mg/kg body weight) daily for 3 days
• Sulfadoxine (25 mg/kg body weight)
• Pyrimethamine (1.25 mg/kg body weight) ASSP on
  Day 0.
• Primaquine (0.75 mg/kg) single dose on Day 2

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Northeastern states

• Arunachal Pradesh, Assam, Manipur, Meghalaya,
  Mizoram, Nagaland, Tripura
• due to late treatment failures to ASSP in
• P. falciparum, the presently recommended ACT in
  national drug policy is a FDC of
• Artemether-lumefantrine (AL)
• ACT used in the national programme
• NE states AL
• Rest of India ASSP

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NVBDCP,2013

• MONOTHERAPY OF ORAL ARTEMISININ DERIVATIVES IS
  BANNED IN INDIA
• Injectable artemisinin derivatives should be used
  only in severe malaria.

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Treatment of malaria in pregnancy

• The ACT should be given for treatment of P.
  falciparum malaria in second and third trimesters
  of pregnancy
• Quinine recommended in the first trimester.
• Plasmodium vivax malaria can be treated with
  chloroquine.

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Treatment of mixed infections

• Mixed infections with P. falciparum should be
  treated as falciparum malaria.
• Since ASSP is not effective in vivax malaria,
  other ACT should be used.
• Anti-relapse treatment with primaquine is used
  for for 14 days.

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Treatment based on clinical criteria without
laboratoryconfirmation

• If RDT for only P. falciparum is used, negative
  cases showing signs and symptoms of malaria
  without other obvious cause for fever called as
  clinical malaria.
• Treatment- chloroquine 25 mg/kg for 3 days

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SEVERE MALARIA TREATMENT

• Things Necessary In a care centre
• ? Parenteral antimalarials, antipyretics,
  antibiotics, anticonvulsants? Intravenous
  infusion facilities? Special nursing for coma
  patients ? Blood transfusion? Laboratory
  facilities? Facility for Oxygen, dialysis,
  ventilator, etc.

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TREATMENT FAILURE/DRUG RESISTANCE

• Patient is called cured, if no fever or
  parasitaemia till Day 28 after treatment.
• Patients may not respond to treatment due to
  1)drug resistance/ 2)treatment failure.
• Early treatment failure (ETF) Development of
  danger signs on Day 1, 2 or 3 parasitaemia
  higher on Day 2

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TREATMENT FAILURE/DRUg RESISTANCE

• Late clinical failure (LCF) Development of
  danger signs parasitaemia on Day 4 - 28
• Late parasitological failure (LPF) parasitaemia
  on Day 7 - 28 temperature lt37.5C did not
  meet criteria of early treatment failure or late
  clinical failure.
• TREATMENT -
• alternative ACT or quinine with Doxycycline.
• Doxycycline is contraindicated in pregnancy,
  lactation and in children up to 8 years.

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MANAGEMENT OF COMPLICATIONS

• ACUTE RENAL FAILURE Fluid administration to be
  restricted. Hemofiltration and hemodialysis are
  effective.
• ACUTE PULMONARY EDEMA Patient should be
  positioned with the head end of the bed elevated.
  Oxygen and diuretics to be given.
• HYPOGLYCEMIA Initial slow injection of 50
  dextrose and then an infusion of 10 dextrose to
  be given. Blood glucose should be monitored
  regularly.
• CONVULSIONS IV or rectal benzodiazepine
• IV antimicrobial agents and oxygen to be given in
  suspected aspiration pneumonia.

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PREVENTION OF MALARIA

• Avoidance of exposure to mosquitoes during their
  peek feeding times.
• Wearing long sleeve clothes.
• Insecticide Treated Bed nets with residual
  pyrethroids.
• Mosquito repellant creams containing 10 35
  DEET.
• RTS,S is the first malaria vaccine to have
  completed pivotal Phase 3 testing and obtained a
  positive scientific opinion by a stringent
  medicines regulatory authority.

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CHEMOPROPHYLAXIS OF MALARIA
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• THANK YOU