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Malaria

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    • Malaria is the most important parasitic disease of human beings.
    • Malaria is a protozoan disease transmitted by Anopheles mosquitoes.
    • Five species of the genus Plasmodium cause all malarial infections in human beings.
    • Most cases are caused by either Plasmodium falciparum (SSA) or Plasmodium vivax (Other regions), but human infections can also be caused by Plasmodium ovale, Plasmodium malariae, and, in parts of southeast Asia, the monkey malaria Plasmodium knowlesi.

    What is Malaria?

    • Malaria is caused by the parasite of the genus Plasmodium.
    • Five species of plasmodium cause infection in humans:
      • P. falciparum - Most common/deadly
      • P. vivax
      • P. ovale
      • P. malariae
      • P. knowlesi

    Plasmodium Species
    Falciparum

    Commonest in Africa (98% of malaria)

    Main cause of severe malaria

    Rapidly fatal
    Vivax

    Responsible for half of malaria cases outside Africa

    Contributes to malaria in horn of Africa

    Can cause severe malaria

    Relapse occurs
    Ovale

    Mostly occurs in sub-Sahara Africa

    Incidence relatively low

    Not associated with fatal disease

    Relapse occurs
    Malariae

    Distribution is everywhere

    Tends to occur as mixed infection

    Replication is slow

    Hence parasitaemia is very low
    Knowlesi

    Occurs as a zoonotic infection

    Difficult to differentiate from trophozoites of P. malariae

    Causes severe malaria and rapidly fatal

    As rule consider P. knowlesi if there is microscopic suggestion of P. malariae with high parasitaemia

    • Bites from infected female Anopheles mosquito
      • The main method of transmission
      • Bites occur between dusk and dawn
    • Accidental
      • Blood transfusion, needle stick injury
    • Mother to Child
      • 1 in 20 mothers could infect their babies if they have malaria close to delivery
    • Animal to Man
      • From close interaction with the Macaques

    • 91 countries and territories
    • Half world at risk (3.4 billion)
    • According to the latest WHO estimates, released in December 2017, there were 216 million cases of malaria in 2016 and 445,000 deaths
    • The malaria mortality rate, which takes into account population growth, is estimated to have decreased by 60% globally between 2000 and 2015

    Classification on Transmission Rates

    • High transmission (>1 case per 1000 pop)
      • Transmission is all year round, but there may be seasonal variation.
      • Partial immunity in older children and adults.
      • May be less likely to get severe disease.
    • Low transmission (<1 case per 1000 population)
      • Intermittent transmission that may be annual, bi-annual, or variable.
      • Prone to occurrence of malaria epidemics.
    • Malaria Free (Zero cases)
      • Usually the population has no immunity whatsoever against malaria and
      • therefore prone to severe malaria if they travel to high transmission areas.

    Classification based on Spleen and Parasite Rates

    • The spleen rate % enlarged spleens in a sample of the population, usually children aged 2–10 years.
    • The parasite rate is the proportion of a given population with malaria parasites in the blood.
    • According to the classification using these two indices, regions may be described as:
      • Hypoendemic: Spleen and parasite rates 1–10%
      • Mesoendemic: Spleen and parasite rates 11–50%
      • Hyperendemic: Spleen and parasite rates constantly > 50%
      • Holoendemic: Spleen and parasite rates constantly > 75% (for parasite rate this applies to infants only)

    Determinants of Endemicity

    • Presence of competent Anopheles mosquitoes
    • Human factors, especially socio-economic factors, and control measures
    • Temperature:
      • Sporogony phase requires temperature between 16°C and 33°C and mean relative humidity of 60%

    Malaria Life Cycle
    Malaria Life Cycle (3-sites, 3-steps, 1 or 2-exit)
    P. falciparum – asexual stages

    • Uncomplicated Malaria:
      • Symptomatic infection with malaria parasitaemia without evidence of vital organ dysfunction
      • Symptoms:
        • The main manifestation is FEVER
        • Cold Chills / Rigor
        • Headaches and other body aches
        • Malaise
        • Nausea / Vomiting
        • Joint weakness / pains
      • Signs:
        • Fever
        • Hepatosplenomegaly
        • Pallor (Children / pregnant women)
    • Severe Malaria
      • Acute falciparum malaria with evidence of vital organ dysfunction. Or,
      • Patient with P. falciparum asexual parasitaemia and presence of one or more of the clinical or laboratory features listed.

    Severe Malaria- WHO 2015
    Impaired consciousness A Glasgow coma score < 11 in adults or a Blantyre coma score < 3 in children
    Prostration Generalized weakness so that the person is unable to sit, stand or walk without assistance
    Multiple convulsions More than two episodes within 24 h
    Acidosis A base deficit of > 8 mEq/L or, if not available, a plasma bicarbonate level of < 15 mmol/L or venous plasma lactate ≥ 5 mmol/L. Severe acidosis manifests clinically as respiratory distress (rapid, deep, laboured breathing).
    Hypoglycaemia Blood or plasma glucose < 2.2 mmol/L (< 40 mg/dL)
    Severe malarial anaemia Haemoglobin concentration ≤ 5 g/dL or a haematocrit of ≤ 15% in children < 12 years of age (< 7 g/dL and < 20%, respectively, in adults) with a parasite count > 10,000/µl
    Renal impairment Plasma or serum creatinine > 265 μmol/L (3 mg/dL) or blood urea > 20 mmol/L
    Jaundice Plasma or serum bilirubin > 50 μmol/L (3 mg/dL) with a parasite count > 100,000/µL
    Pulmonary oedema Radiologically confirmed or oxygen saturation < 92% on room air with a respiratory rate > 30/min, often with chest in-drawing and crepitation on auscultation
    Significant bleeding Including recurrent or prolonged bleeding from the nose, gums or venepuncture sites; haematemesis or melena
    Shock Compensated shock is defined as capillary refill ≥ 3 s or temperature gradient on leg (mid to proximal limb), but no hypotension. Decompensated shock is defined as systolic blood pressure < 70 mm Hg in children or < 80 mmHg in adults, with evidence of impaired perfusion (cool peripheries or prolonged capillary refill).
    Hyperparasitaemia P. falciparum parasitaemia > 10%

    • Children
    • Pregnant Women
    • Adults
    • Everyone

    Groups at Special Risk

    • People who are heavily exposed to the bites of mosquitoes infected with P. falciparum.
    • People who have little or no immunity to malaria, such as young children and pregnant women.
    • Travelers coming from areas with no malaria are more likely to become very sick and die.

    Groups at Special Risk

    • Poor people living in rural areas who lack access to health care are at greater risk for this disease.
    • People suffering from Sickle Cell Anaemia (Not SCD)
    • Refugees or Internally Displaced Persons
    • Those who have had their spleens removed

    History

    General Information

    • Age, place of residence, and travel.

    Specific Features of Uncomplicated Disease

    • Fever, chills / rigor,
    • Headaches and other aches in the older patient

    Ask About

    • Features of severe disease
    • Previous treatment with antimalarial drug

    Physical Examination

    • Check body temperature.
    • Pallor (children/pregnant women)
    • Check state of hydration
    • Pulse and BP
    • Enlarged spleen or liver, especially in children

    Exclude Signs of Severe Disease:

    • Central nervous system:
      • Assess the level of consciousness using an objective coma scale
      • Evidence of Seizure
      • Posturing
      • Fundoscopy
    • Respiratory system: check for respiratory distress
    • Cardiovascular: rate, volume of pulse, BP
    • Abdomen: Feel for the spleen and liver
    • Identifying other possible causes of disease.

    Diagnosis

    • Clinical
      • Fever + other symptoms
      • Exclusion of focal point of disease
      • Endemicity
    • Parasitological
      • Required to confirm diagnosis in all patients
      • To monitor response to treatment/treatment failure
    • Other Tests
      • HCT, Blood glucose,
      • Lumbar Puncture

    Laboratory Diagnosis- Microscopy

    • Involves staining and direct visualization of the parasite under the microscope.
    • Peripheral smear study on light microscopy using various stains
      • Thick blood film
      • Thin blood films
      Thin and thick smear
    • Quantitative Buffy Coat test (QBC)

    Light Microscopy – Thick Blood Film

    • Parasite identification
    • Parasite density
    Light Microscopy – Thick Blood Film

    Light Microscopy – Thin Blood Film

    • Speciation
    • Parasite Density
    Light Microscopy – Thin Blood Film

    Quantitative Buffy Coat test (QBC)

    • Blood is mixed with acridine orange
    • Centrifuge in a capillary tube
    • Read directly with a fluorescent microscope
    QBC
    QBC

    Non-Microscopic Tests

    • Involves identification of the parasitic antigen or the anti-plasmodial antibodies or the parasitic metabolic products.
    • RDTs
    • PfHRPII antigens
    • pLDH enzyme
    • Other Tests
      • Polymerase Chain Reaction
      • Detection of antibodies by Radioimmunoassay, immunofluorescence, or enzyme immunoassay.

    Rapid Diagnostic Tests

    • Detects specific antigens (proteins) produced by malaria parasites
    • These antigens are present in the blood of infected or recently infected people.
    • The RDT signifies their presence by a colour change on nitrocellulose strip
      • RDTs Detects specific antigens (proteins) produced by malaria parasites

      RDT: PfHRP-2 Based Test

      • This is a dip stick antigen capture assay, using a monoclonal antibody against P. falciparum histidine-rich protein-2 (PfHRP-2)
      RDT: PfHRP-2 Based Test

      RDTs: pLDH Based Test

      • Dip stick coated with monoclonal antibodies against the intracellular metabolic enzyme parasite lactate dehydrogenase (pLDH)
      • Allows for speciation between the pLDH isoforms.
      • pLDH is produced only by live parasites,
      • Hence the ability to differentiate live from dead organisms
    RDTs: pLDH Based Test
    Malaria Diagnosis -

    Treatment of Malaria


    Principles of Antimalarial Treatment
    Aims Causation Therapy Drugs
    To alleviate symptoms Symptoms are caused by blood forms of the parasite Blood schizonticidal drugs Chloroquine, quinine, pyrimethamine/sulphadoxine, artemisinin and its derivatives
    To prevent relapse Relapses due to hypnozoites of P. vivax/P. ovale Tissue schizonticidal drugs Primaquine
    To prevent spread Spread is through the gametocytes Gametocytocidal drugs Primaquine for P. falciparum, Chloroquine for all others

    Uncomplicated Malaria

    • Artemether-lumefantrine
      • 1.5/9 mg/kg twice daily for three days
    • Artesunate-Amodiaquine
      • Artesunate 4 mg/kg + Amodiaquine 10mg base/kg once daily for 3 days
    • Artesunate+Mefloquine
      • Artesunate 4 mg/kg once daily for 3 days + mefloquine 25 mg base/kg (mefloquine 8.3mg/kg daily for 3 days)
    • Artesunate+Sulfadoxine/pyrimethamine
      • Artesunate 4mg/kg once daily for 3 days + SP 25/1.25mg/kg once
    • Dihydroartemisinin+piperaquine
      • In children <25kg 2.5mg/kg DHA and 20mg/kg PPQ once daily for 3 days
    • New
      • Pyronaridine-Artesunate
        • Granules and Tablets

    What is Antimalarial Combination Therapy

    • Simultaneous use of two or more blood schizonticidal drugs with
      • Independent modes of action and
      • Different biochemical targets in the parasite
    • Fixed-dose formulations or co-administrated therapy

    Management of Severe Malaria

    • This comprises of four main steps:
      • Clinical assessment of the patient,
      • Specific anti-malarial treatment,
      • Treatment of complications, and
      • Supportive care.

    Clinical Assessment

    • Rapid evaluation
    • To make a clinical diagnosis of severe malaria
    • Identify life-threatening complications

    Treatment of Severe Malaria

    • For children ≤20kg, artesunate 3 mg/kg BW IV or IM given on admission (time = 0), then at 12 h and 24 h, then once a day is the recommended treatment.
    • For adults and children >20kg, artesunate 2.4 mg/kg Body Weight (BW) IV or IM given on admission (time = 0), then at 12 h and 24 h, then once a day is the recommended treatment.
    • There is no upper limit to the total dose of artesunate.
    • Artemether, or quinine, is an acceptable alternative if parenteral artesunate is not available:
      • Artemether 3.2 mg/kg BW IM given on admission then 1.6mg/kg BW per day; or
      • Quinine 20 mg salt/kg BW on admission (IV infusion or divided IM injection), then 10 mg/kg BW every 8 hrs;
    • Parenteral antimalarials used in the treatment of severe malaria should be given for a minimum of 24 hours, once started (irrespective of the patient's ability to tolerate oral medication earlier), and, thereafter, complete treatment a full course of the recommended ACT.

    At community or health facility levels where complete management of severe malaria is not possible, patients with severe malaria should be given pre-referral treatment and referred immediately to an appropriate facility for further treatment.

    The following options for pre-referral treatment are recommended in a ranked order:

    • For children: artesunate IM; rectal artesunate; artemether IM; quinine IM
    • For adults: artesunate IM, artemether IM; quinine IM

    Treatment of Complications & Supportive Care

    • Coma (cerebral malaria):
      • Standard care for the unconscious patient
      • Avoid harmful ancillary treatment such as corticosteroids, heparin, and adrenaline; intubate if necessary
    • Hyperpyrexia:
      • Tepid sponging, fanning, cooling blanket, and antipyretic drugs
    • Convulsions:
      • Maintain airways; treat promptly with intravenous or rectal benzodiazepine or intramuscular paraldehyde
    • Hypoglycaemia:
      • Correct hypoglycaemia and maintain with glucose-containing infusion
    • Severe anaemia:
      • (Hb <5g%, or PCV <15%) Transfuse
    • Acute pulmonary oedema:
      • Prop up at 45°, give oxygen, give diuretic, stop intravenous fluids, intubate and add PEEP/CPAP in life-threatening hypoxaemia; haemofilter
    • Acute renal failure:
      • Exclude pre-renal causes, check fluid balance, urinary sodium; if in established renal failure; haemofilter or haemodialysis, or if unavailable, peritoneal dialysis.
    • Spontaneous bleeding and coagulopathy:
      • Transfuse screened fresh whole blood (cryoprecipitate, /fresh frozen plasma and platelets if available; vitamin K injection
    • Metabolic acidosis:
      • Exclude or treat hypoglycaemia, hypovolaemia and septicaemia.
    • Shock:
      • Suspect septicaemia, make blood cultures; give parenteral antimicrobials, correct haemodynamic disturbances.
    • Hyperparasitaemia:
      • >250,000 parasites per μl of blood.

    WHAT IS RBM?

    • A global movement mobilizing support for local initiative
    • A coordinated approach to strengthen public and private health care.
    • Multiple strategies targeted to meet local malaria control needs.
    • A diverse partnership acting in concert to achieve common goals.
    • Established 31st July 1998

    Six Principles of RBM

    • Early detection
    • Rapid diagnosis and Effective Treatment
    • Multiple prevention
    • Focused research
    • Well coordinated actions
    • Dynamic movement

    1. Early Detection

    • Community Awareness
      • Grassroots education and training to facilitate early detection of illness
    • Surveillance
      • And climate studies to detect at-risk groups.
    • Resistance Alert
      • Drug resistance pattern will guide prescription to ensure effective treatment.

    2. Rapid Diagnosis And Effective Treatment

    • Home is the First Hospital
      • A simple packet of fast-acting drugs made widely available to parents can rescue children before it is too late.
    • Bringing Treatment to the People
      • People with fever often seek help from friends or local healers. Communities must become knowledgeable in treating malaria quickly.

    3. Multiple Prevention

    1. Integrated Vector Management (IVM)
      1. The use of Long Lasting Insecticidal Nets (LLINs)
      2. Indoor Residual Spraying (IRS)
      3. Larval Source Management (Larviciding and Environmental Management)
      4. Personal protective measures such as house screening, durable linings and the use of repellents
    2. Malaria Chemoprevention
      1. Chemoprophylaxis for non-immune immigrants & at risk groups
      2. Intermittent Preventive Treatment
      3. Seasonal Malaria Chemoprevention
      4. ?Vaccine

    Intermittent Preventive Treatment (IPT)

    • All pregnant women should receive two doses of IPT after quickening, during routinely scheduled ANC visits but no more frequently than monthly (as Directly observed Treatment)
    • Presently, the most effective drug for IPT is sulfadoxine-pyrimethamine (SP)

    Timing Of IPT And Fetal Growth Velocity

    IPT is best given when the fetal growth velocity is at its highest, in order to reduce placental parasitaemia and resultant fetal growth retardation

    4. Focused Research

    • Drive to discover new tools
    • A new medicine has to be discovered every 5 years
    • Existing ones can be more user-friendly
    • An effective vaccine will be a powerful tool
    • New ecologically safe insecticides are needed to protect homes and treat bed nets

    5. Well-coordinated Strategy

    • Situation Assessment
      • Community prevention and treatment practices will be reviewed and a common strategy built
    • Structured Technical Support Networks
      • A network of resource people will be created to provide consistent and harmonized expert advice

    6. Dynamic Movement

    • A Coalition of Stakeholders
    • Community Participation
      • The private sector foundations and trusts
      • NGOs Civil societies, Associations, and media
      • UNDP, WB, UNICEF, and key UN Partners
      • Research and Academic institutions
    • Involvement of many sectors

    Targets

    • RBM: To reduce by Half malaria morbidity and mortality by the year 2010
    • SUFI: Scale-up for Impact (at least 80% coverage for key interventions)
    • Universal Coverage: All households and all susceptible population
    • Elimination:
    • Eradication:
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