MALARIA

MALARIA Presentation By:-Aaryan Tiwari

Introduction & epidemiologyTropical disease

350 500 million cases per year

Important cause for morbidity in south asia.

2 million cases & 1000 deaths annually in India

Majority Orissa , Chhattisgarh , West Bengal , Karnataka , Jharkhand , Madhya Pradesh , Uttar Pradesh , Assam , Gujarat , & Rajasthan.

National Health Policy (2002) & Millenium Development Goals Aim for reduction in malaria morbity by 50 % by 2010.

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prevalenceSplenic Index :S.I. < 10% : Low PrevalenceS.I. > 50% : HyperendemicS.I. > 75% : Holoendemic

Parasite Rate

Proportionate Case Rate

etiologyParasite :P. vivaxP. falciparum P. malariaeP. ovale

Vectors :A. culcifacies (rural)A. fluvitalisA. stephensi (urban)A. minimusA. philippinesisA. sundaicus

Life cycle of malarial parasiteHepatic phase / Tissue phase

Erythrocytic phase

Sexual reproduction

2 HOSTS DEFINITE HOST Anopheles Mosquito

INTERMEDIATE HOST Human

Modes Of Transmission

Sporozoite induced malaria bite of female anopheles

Trophozoite induced malaria Transfusional malariaCongenital malariaMalaria in drug addicts

Therapeutic malaria for the treatment of neurosyphilis (k/a Dementia Paralytica)- By Wagner(Noble Prize in Medicine/Physiology in 1927)By inoculating blood of an infected donorBy allowing laboratory bred infected mosquitoes to bite the recipientBy injecting emulsion of salivary glands containing sporozoites

pathophysiologyINNATE RESISTANCE : Natural capacity of host to resist infection from malaria. ( which is due to differences in surface receptors , intraerythrocytic factors or yet unknown causes. )

In Endemic zones repeated infection development of resistance.

Some individuals vulnerable to infection with one species due to difference in genetic constitution of species.

Differences in cell membrane decides attachment/penetration of merozoites to receptors/cells.

Sickle cell trait & G-6-PD deficiency IMMUNE

Contd

INTRAERYTHROCYTIC FACTORS :

Resist penetration of cell by merozoites

Impede their development

Assist their removal by RES.

ACQUIRED RESISTANCE :Sporozoites Liver cells No immunological response

Merozoites invade erythrocytes Immunological response

First response phagocytosis in spleen / hyperplastic RE cells.

Cell mediated immunity through activated macrophages

Host defence defervescence of fever.

ContdProtective antibodies against merozoites IgM

Complement system not involved

Schizont infested cells phagocytosed rapidly after OPSONISATION

Antibodies against toxins

Antibodies and antigens may be transmitted to fetus transplacentally

Antibodies protect while antigens / antigen-antibody complexes help to acquire immunity.

Immune Evasion By Parasite :

Reasons for survival of parasite :

Antibodies against parasite may promote their survival instead of destruction

Infection may impair antibody synthesis

Handling & processing of antigens by macrophages is impaired

Sporozoites , schizonts & gametocytes are not destroyed by immune system.

immunopathologyAnemia :

Disproportionate to the damage to RBCs by parasite.

Formation of autoantibodies to RBCs & immune binding or adherence of circulating Ag-Ab complexes to uninfected RBCs.

Hemolysis blackwater fever drug hypersensitivity

16ContdDamage to Kidneys :

Acute transient lesion

Development of proteinuria 1-2 wks.

Responds to treatment.

Chronic progressive nephritic syndrome

Secondary to P. malariae infections

Soluble immune complexes deposits in BM of Glomerular capillaries glomerular lesions.

Contd

SPLEEN

Splenomegaly elevated levels of IgM & Lymphocytosis in peripheral blood , bone marrow & liver sinusoids.

Splenectomy Relapse of latent infection.

Contd

CEREBRAL MALARIAPre school children

Common in PEM

Plugging of cerebral capillaries with infected erythrocytes

Hemorrhages

Deposition of fibrin in vessels

Altered capillary permeability

Intravascular coagulation

Clinical features

Children > 2 months (non immune ) symptoms vary widely

Low grade fever to temp of 104 F with headache, drowsiness

Anorexia, nausea, vomitting, diarrhoea

Pallor, cyanosis

Splenomegaly

Hepatomegaly

Anaemia , Thrombocytopenia

High risk patients depressed level of consciousness

seizures

Irregular resp.

Hypoxia

Orthostatic Hypotension

Tachycardia

Dehydration

Hypoglycemia

Metabolic acidosis

Hyperkalemia

Incubation periodP. falciparum: 9 14 days

P. vivax: 12-17 days

P. ovale: 16 18 days

P. malariae: 18 40 days

Contd

Onset sudden with fever , headache , loss of appetite , lassitude , pain in limbs.

Initially continuous or remittent fever

Later stages classically remittent fever

FEBRILE PAROXYSMSCOLD STAGECHILLSRIGORSNAUSEAMALAISEANOREXIA20mins 1 hr.

HOT STAGEDRY & FLUSHED SKINRAPID RESPIRATIONMARKED THIRST1 4 hrs.

SWEATING STAGETEMPERATURE FALLS BY CRISIS

2 3 hrs.NO FEVER 24-48 HOURS

Fever alternate days P. falciparum & P. vivax Tertian typeFever fourth day P. malariae quartan type

Clinical pattern in endemic zonesAtypicalTolerance leading to less parastitemiaMild symptomsAfter sometime inherited immunity ( due to continuous heavy exposure leading to poor

immunological defence) severe form of disease. Cerebral malaria DeathRe-development of toleranceChronic malaria with marked HEPATOSPLENOMEGALY in highly endemic zones.

relapseecrudescence / eoccurance of fever after a period greater than egular / normal periodicity of malarial fever.

Note : Recrudescence occurs due to persistence of blood infection in which surviving population of erythrocyte forms is increased.

Recurrence/true relapse - persistence of hypnozoite forms in liver in which erythrocytic schizogony commences again.

Falciparum malaria rare relapse(since erythrocytic schizogony does not lead to exoerythrocytic phase.)

Vivax malaria frequent relapse(since erythrocytic schizogony can be started in these plasmodia)

complicationsCerebral malariaAnemiaGastrointestinal illnessAlgid malariaBlackwater feverRenal lesionsSplenic rupture

HypoglycemiaHyperpyrexiaConvulsionsSpontaneous bleeding & coagulopathyAspiration pneumonia

Cerebral malariaMost common non-traumatic encephalopathyAdhering of P. falciparum infected erythrocytes to brain capillaries causing coma & death.key events influencing the disease were identified as:

Pathophysiology :SequestrationHaemostasis dysfunctionSystemic inflammationNeuronal damage

PfEMP-1 presentation, platelet activation and astrocyte dysfunctionIt is manifested by coma or confusion.Cerebral malarial fever d/d: menigititis , encephalitis , head injury or tetatanus on investigation on examination CSF is normal. splenomegaly

anaemiaIt is common in severe malaria. Causes:Haemolysis of infected & uninfected erythrocytes.Dyserythropoiesis.Splenomegaly causing erythrocyte sequestration & hemodilution.Depletion of folate stores.

Gastrointestinal illnessMarked vomiting in infantsDiarrhoeaDehydrationDyselectrolytemiaDark green or brownish stools tinged with bloodSymptoms relieved on antmalarial therapy

Blackwater feverSudden severe hemolysis

Hemoglobinuria

Renal failure

Caused by hypersensitivity to antimalarial drugs.

Nowadays rare due to development of synthetic drugs.

Repeated falciparum infection

Hypersensitivity

Anti erythrocyte antibodies

Intravascular haemolysis

RBCs destroyed rapidly

Haemoglobinaemia & haemoglobinuria

Algid feverIt is charectorised by pheripheral circulatory failure and shock.Usually occurs with falciparum inf in non immune childrenCirculatory collapse low BP , hypodermia , rapid thready pulse

Abdominal pain , vomitting , diarrhoea may be seen

Adrenal damage congested , necrotic , haemorrhagic on post mortem

Renal lesionsAcute transient nephritisChronic nephrotic syndrome

Renal failure results from acute tubular necrosis.The acute renal failure associated with malaria is usually reversible.Hypoglycaemia

It is a frequent complication of falciparum malaria. It can occur due to various mechanisms:Failure of hepatic gluconeogenesis.Increased consumption of glucose by host & parasite.Treatment with quinine results in stimulation of pancreas to secrete insulin. The resulting hyperinsulinaemia causes hypoglycaemia.

jaundiceIt occurs due to severe hemolysis & hepatic involvement.

Clinical manifestation include: haematemesis or malaenableeding gums epistaxis petechiae subconjuctival hages

Spontaneous bleeding &Disseminated intravascular coagulation

referencesGhai Essential PediatricsProtozoology By K.D.ChaterjeeDavidsons Principles & Practice Of MedicineInternetMALARIA( Contd)BYAaryan Tiwari

INVESTIGATIONS

Investigations Blood Film ExaminationThick and thin blood films (or smears) have remained the gold standard for the diagnosis of malaria. The films are stained and examined by microscopy.

Thick blood film - Used for detecting malaria: a larger volume of blood is examined allowing detection of even low levels of parasitaemia. Also used for determining parasite density and monitoring the response to treatment.

Thin blood film Gives more information about the parasite morphology and, therefore, is used to identify the particular infecting species of Plasmodium.

45THICK BLOOD FILMA drop of blood is spread over a small area. When dry, the slide is stained with Romanowsky stains (Fields , Giemsa ,Wrights ,Leishmans stains). The red cells lyse leaving behind the parasites.

Used to detect parasites, even if parasitaemia is low

THIN BLOOD FILMA small drop of blood is spread across a microscope slide, fixed in methanol and stained with Giemsa stain.

The microscopist finds the area of the film where red cells are lying next to each other. The fine details of the parasites can be examined to determine the species.

Used for speciationDoes not detect low parasitaemia

Ring forms or trophozoites; many red cells infected some with more than one parasiteGametocytes (sexual stages); After a blood meal, these forms will develop in the mosquito gut

Appearance of P. falciparum in thin blood films

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Other methods of diagnosis of malariaQuantitative Buffy coat test:- It involves staining of the centrifuged & compressed red cell layer with acridine orange & its examination under UV light source.Fast, easy & more sensitive than thick smear examination, abt 60microlitres of blood from a finger, ear, or heel puncture is sufficient.Key feature is centrifugation & thereby concentration of red blood cells in the predictable area of the QBC tube making detection easy and fast.Red cells containing plasmodia are less dense than normal ones and concentrate just below the leucocytes , at the top of the erythrocyte column.The parasites contain DNA which takes up acridine orange stain, fluorescing parasites can be observed at the RBC/WBC interface using standard white light microscope

Rapid diagnostic tests:-

Detects malarial antigens (PfHRP2/PMA/pLDH) from asexual &/or sexual forms of the parasite.Detected by colour changes on the antibody coated lines on the strip test such as optiMAL assay and para sight F test are being increasingly employed.optiMAL:- immunochromographic test that can be performed with a drop of finger stick blood,Detects LDH (parasite glycolytic enzyme) produced by all species of metabolizing plasmodium parasitesThe detection limit of test is >100-200 parasites/ microL for P.falciparum & P.vivaxPositive test indicates presence of viable parasitemia.Two other RDTs are available :- these are based on histidine rich protein 2 of P.falciparum(PfHRP2), a water soluble protein expressed on RBC membrane of P.falciparum & panspecific plasmodium aldolase(PMA),

One test utilizes PfHRP2 alone, while another test uses both PfHRP2 & PMA,

Polymerase chain reaction:-

Highly sensitive and specific test for detecting all species of malaria, particularly in cases of low level parasitemia and mixed infections10 fold more sensitive than microscopyOther investigations:-

Complete blood countsBlood levels of glucoseBilirubinUreaCreatinineTransaminasesprothrombin timeurine analysis may be done as required.

DIFFERENTIAL DIAGNOSISEARLY PHASE :Typhoid feverNon icteric hepatitisSepticemia

PAROXYSMAL PHASE :U.T.I.Gm. Ve SepticemiaLiver abscess

ContdCEREBRAL MALARIA:MeningitisEncephalitisLead encephalopathyHeat strokeGASTROINTESTINAL ILLNESS:Non specific gastroenteritisCholeraE. coli diarrhoeaAbdominal emergenciesContdALGID MALARIA:Shock due to septicaemia

CHRONIC MALARIAL FEVER WITH SPLENOMEGALY:TuberculosisKala azarLeukemia

TREATMENT

TREATMENTANTI-MALARIAL THERAPY:-Cinchona alkaloids:- Quinine 1st line of treatmentActs on mature trophozoite stages only85% bioavailability on IM, but avoided because of painA loading dose of IV quinine(20mg salt/kg over4hr ) allows for parasiticidal conc to be achieved quicklyQuinidineD-isomer of quinineMore effective than quinine as antimalarial but also more cardiotoxicArtemisinin derivatives:- Artemether & ArtesunateTreatment is initiated with a loading dose that is followed by a once-daily dose regimen. ( Artesunate -2.3mg/kg IV, 1.2mg/kg/d. Artemether-3.2mg/kg IM 1.6mg/kg/d) Advantage of clearing the parasitemia at a faster rate than that seen with quinineFatal for all stages of parasiteShould be used in combination with other anti-malarials to prevent resistance

Other antimalarials:- halofantrine, Mefloquine, atavaquone, doxycycline and tetracyclinenot recommended in severe and complicated malaria as primary treatmentThese antimalarials may be used in latter stages of management of severe malaria to reduce the development of resistance

Supportive therapiesAntibiotics:- tetracycline, doxycycline etc..,

Anticonvulsants:- should be administered for seizures lasting more than 5mins, benzodiazepines-mostly used,other anticonvulsants-paraldehyde, phenytoin, phenobarbitone, fosphenytoin, etc,

Blood transfusions is life saving in severe malarial anemia

Exchange transfusions has thought to benefit patients with high parasite count rationale is to remove parasite burden, to reduce antigen load, to remove parasite derived toxins and metabolites and to correct anemia.Dialysis:- indicated in case of acute renal failure due to severe falciparum malaria,Rapidly raise of creatinine level-most sensitive indicator.

Inotropic support:- shock- algid malaria, Dopamine is used

Hypoglycemia:-any blood sugar 40kg4adult tabs PO qd*3days

13.7mg base/kg (15mg salt/kg) PO as initial dose followed by 9.1mg base/kg (10mg salt/kg) PO given 6-12hr after initial dose total dose25mg salt/kgClinical diagnosis/ plasmodium speciesRecommended drugs

Uncomplicated malaria/ p.malariae

Chloroquine phosphate-10mg base/kg PO immediately followed by 5mg base/kg PO at 6,24, & 48 hrs, total dose 25mg base/kg

Uncomplicated malaria/ p.vivax or p.ovaleChloroquine phosphate + primaquine phosphate

0.5mg base/kg PO qd * 14 daysUncomplicated malaria/ p.vivax chloroquine resistantA). Quinine sulphate + (doxycycline or tatracycline) + primaquine phosphate

B). Mefloquine + primaquine sulphateSEVERE MALARIAArtesunate IV or IMQuinine IV Artemether IM give parenteral antimalarial for min of 24hrs once started & there after complete treatment by giving a complete course of artesunate + clindamycin or doxycyclinequinine + clindamycin or doxycyclineWHO GUIDELINES FOR THE TREATMENT OF MALARIA-2010

1. MALARIAL DIAGNOSIS

2. TREATMENT OF UNCOMPLICATED FALCIPARUM MALARIA

3. TREATMENT OF SEVERE MALARIA

4. TREATMENT OF VIVAX MALARIA

CRITERIA FOR ADMISSION OF PATIENTS TO I.C.U.Acidosis Base excess < - 8Parasitemia endemic areas : > 20% non endemic areas : >10%Coma : Glassgow coma scale 8Hypoglycemia : blood glucose level