MALARIA Anemia by mikesanye

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									‫بسم اهلل الرحمن الرحيم‬
PATHOGENESIS OF
   MALARIA
           By
    Assistant lecturer
     DINA ISMAIL
              Host Factors

   Race:
    • All races are affected, with some
      exceptions.
    • People of West African origin who do not
      have the Duffy blood group are not
      susceptible to P vivax malaria.
   Sex: Malaria affects females and
    males equally.
                     Age
   In non-malarious:
     • Children of all ages are equally
       susceptible.
   In endemic areas:
     • Children younger than 5 years have
       repeated and often serious attacks of
       malaria and the survivors develop
       partial immunity.
     • Older children and adults often have
       asymptomatic parasitemia.
           Mortality/Morbidity
   Internationally:
    • 1.5-3.5 million deaths occur annually.
    • Of these deaths, the overwhelming majority is
      among children aged 5 years or younger.
    • 90% of the deaths each year are in rural sub-
      Saharan Africa.
    • These deaths are unnecessary, since malaria is
      preventable and treatable.
    • However, the lack of prevention and treatment
      due to poverty, war, and other economic and
      social instabilities in endemic areas results in
      millions of deaths each year.
                      Agent
   Is caused by Plasmodium genus.
   Intraerythrocytic parasite.
   Four species can infect humans.
    •P   vivax
    •P   falciparum
    •P   malariae
    •P   ovale
   P vivax is distributed more widely
    than P falciparum and dominates in
    Asia and the Americas and it causes
    less morbidity and mortality.
   P falciparum is found mostly in the
    tropics and causing most malaria
    acquired in Africa.
   Together falciparum and P vivax,
    accounts for 95% of malarial
    infections diagnosed worldwide.
       P VIVAX & P OVALE
• P vivax:
     If untreated, it usually lasts for 2-3 months
      with diminishing frequency and intensity of
      paroxysms.
     50% Of patients experience a relapse.


• P ovale:
     Similar to P vivax infections, although they
      are usually less severe.
     Often resolves without treatment.
          P MALARIAE
• Those infected remain asymptomatic for
  a much longer period of time than those
  infected with P vivax or P ovale.

• Recrudescence is common.

• It often is associated with a nephrotic
 syndrome, possibly resulting from
 deposition of antibody-antigen complex
 upon the glomeruli.
          P FALCIPARUM
• The most malignant form.
• Infection is not limited to RBCs of a
  particular age and, hence, represents the
  highest level of parasitemia.
• This species also causes vascular
  obstruction due to its ability to adhere to
  endothelial cell walls.
• This property leads to most complications
  as
     cerebral malaria,
     pulmonary edema,
     rapidly developing anemia,
     renal problems.
      Transmission of malaria
• The bite of an infected female
  Anopheles mosquito transmits malaria.
• Malaria can be transmitted through
  blood transfusion.
     Among people living in malarious areas,
      semi-immunity to malaria allows donors to
      have parasitemia without any fever or other
      clinical manifestations.
     The malaria transmitted is by the
      merozoites, which do not enter the liver
      cells.
     Because the liver stage is not present,
      curing the acute attack results in complete
      cure.
      Transmission of malaria
• Organ transplantation may transmit
  malaria.
• Transplacental malaria (ie, congenital
  malaria) can be significant in
  populations who are semi-immune to
  malaria.
     The mother may have placental parasitemia,
      peripheral parasitemia, or both, without any
      fever or other clinical manifestations.
     Vertical transmission may be as high as
      40% and is associated with anemia in the
      baby.
Malaria life cycle
         Aetiopathogenesis
   Rupture of a large number of
    erythrocytes at the same time
    releases a large amount of
    pyrogens, which causes the
    paroxysms of malarial fever.

   These symptoms include chills,
    headache, myalgias, and malaise,
    and they occur in a cyclic pattern.

   The parasite also may cause jaundice
    and anemia.
         Aetiopathogenesis
   The periodicity of malarial fever
    depends on the time required for the
    erythrocytic cycle and is definite for
    each species.
   Plasmodium malariae needs 72 hrs
    for each cycle, leading to the name
    quartan malaria.
   Vivax & Ovale each take 48 hrs for
    one cycle and cause fever on
    alternate days (tertian malaria).
          Aetiopathogenesis
   P falciparum typically have irregular fever
    and chills & rarely presents with 48hrs
    cycle of symptoms despite 48hrs
    erythrocytic cycle of asexual parasite.

   However, this periodicity requires all
    the parasites to be developing and
    releasing simultaneously; if this
    synchronization is absent, periodicity
    is not observed.
    Relapses and recrudescences
   Depending on the species of
    Plasmodium involved, relapses and
    recrudescences vary in their effects.
   P vivax and P ovale both give rise to
    hypnozoites in the liver.
   P vivax malaria may relapse from
    few weeks up to 5 years and P ovale
    for 1-1.5 years.
    Relapses and recrudescences
   P falciparum and P malariae do not
    form hypnozoites, so they do not
    have true relapses.
    • However, the disease recrudesces
      because of surviving erythrocytic forms.
    • While P falciparum can recrudesce for
      up to 1 year, P malariae may continue
      to cause clinical malarial attacks even
      20 years after the original infection.
    Relapses and recrudescences
   Only the sporozoites (introduced by
    the mosquitoes themselves) can
    penetrate the liver cells.
    Thus, if malaria is acquired by blood
    transfusion or transplacentally, no
    infection of the liver occurs and
    relapses do not occur
            Pathophysiology
   The vector, the Anopheles mosquito,
    passes plasmodia that
    • Enter circulating erythrocytes (RBCs)
    • Feed on the hemoglobin and other
      proteins within the cells
    • Replicates inside the cell
    • Create a toxic pigment termed
      hemozoin.
                     Hemozoin and
                   other toxic factors




                    Macrophage
                   And other cells



             Cytokines and other
                soluble factors




Fever and rigors                       Sever
                                   pathophysiology
            Pathophysiology
   The parasites derive their energy solely
    from glucose, and they metabolize it 70
    times faster than the RBCs they inhabit,
    thereby causing hypoglycemia and
    lactic acidosis.
   The plasmodia also cause lysis of
    infected and uninfected RBCs, suppression
    of hematopoiesis, and increased clearance
    of RBCs by the spleen, which leads to
    anemia.
   Over time, malaria infection also causes
    thrombocytopenia and
    hepatosplenomegaly.
             Pathophysiology
   Anemia
    • is frequently severe in children and pregnant
      women infected with P. falciparum.
    • Can be severe with P. vivax infections.
    • Macrophages not only clear infected
      erythrocytes but also phagocytoze and destroy
      uninfected RBCs.
    • Active infections also through unknown
      mechanisms induce BM dyscrasias and
      suppress normal development.
    • Intravascular hemolysis does not appear to be
      a major contributor to malarial anemia except
      in the pathological state known as
      blackwater fever.
                 Pathophysiology
   The morbidity and mortality caused by P
    falciparum are increased greatly
    • because of the increased parasitemia of P
      falciparum
    • its ability to cytoadhere.
   When RBCs become infected with P
    falciparum
    • With maturation, they develop knobs that
      contain histidine-rich proteins.
    • These knobs adhere to endothelial cells in
      peripheral microvasculature by means of
      receptors e.g (ICAM-1), thrombopodin or
      CD36, resulting in;
          Exacerbation of the microvascular pathology
           produced by the parasite
          Removal of mature P falciparum from circulation
           leaving only early asexual stages in peripheral blood.
             Pathophysiology
   The adherence of these infected RBCs
    causes them to clump together in the
    blood vessels in many areas of the body,
    leading to much of the damage incurred
    by the parasite.

   When this sequestration of infected
    erythrocytes occurs in the vessels of the
    brain it is believed to be a factor in
    causing the severe disease syndrome
    known as cerebral malaria, which is
    associated with high mortality.
    Genetic Factors That Influence
               Malaria
   Several innate influence malaria infection.
   Persons who carry the sickle cell trait
    will be relatively protected against severe
    disease and death caused by Plasmodium
    falciparum malaria.
   In general, the prevalence of hemoglobin-
    related disorders and other blood cell
    dyscrasias, such as Hemoglobin C, the
    thalassemias and G6PD deficiency, are
    more prevalent in malaria endemic areas
    and are thought to provide protection
    from malarial disease.
    Genetic Factors That Influence
               Malaria
   Persons who do not have the Duffy blood
    receptors on their erythrocytes, have red
    blood cells that are refractory to infection
    by P. vivax.

   Most of the people in West Africa and
    much of East Africa do not have this
    receptor and they are protected from P.
    vivax infection.
    Immune Responses to Malaria
   People residing in malaria-endemic regions
    acquire immunity to malaria through natural
    exposure to malaria parasites (semi-immunity).

   This results only after continued exposure from
    multiple infections with malaria parasites over
    time.

   It provides protection against severe effects of
    malaria but fails to provide strong protection
    against infection with malaria parasites, and
    generally develops first.

   After several years of continued exposure, people
    develop immunity that limits high-density
    parasitemia; however it does not lead to sterile
    protection.
    Immune Responses to Malaria
   The transmission intensity influences the
    course of development of both clinical and
    parasitic immunity.
   Where malaria transmission is intense,
    young children bear the brunt of the
    disease, but as they grow older, they build
    up an acquired immunity and are
    relatively protected against disease and
    blood stage parasites.
   In areas of low malaria endemicity both
    children and adults suffer disease and high
    parasitemia since exposure is less.
    Immune Responses to Malaria
   Two characteristics of the immunity
    acquired against malaria is that
    • The maintenance of this non-sterile state of
      immune protection requires continued
      exposure to malaria infection and a
      functioning spleen.
    • Splenectomy makes an otherwise immune
      protected animal or human fully susceptible
      again to infection and disease.
    • Likewise, when immune individuals leave a
      malaria endemic area and reside for several
      years in a malaria-free area often become
      susceptible to infection and clinical symptoms
      if they return to a malarious area.
    Immune Responses to Malaria
   Malaria parasites infect different targets such as
    liver and responses are elicited by infection with
    malaria parasites.

   These immune responses include antibodies,
    lymphocytes, monocytes, macrophages, natural
    killer (NK) cells, and neutrophils.

   Experimental studies have shown that both
    antibodies, cells and cellular factors can mediate
    protection in malaria as well as disease.
    Immune Responses to Malaria
   Antibodies can mediate their protective effect by
    multiple mechanisms.
    •   neutralize the parasites
    •   retard parasite development
    •   prevent them from entering target cells
    •   help macrophages to efficiently engulf the parasites and
        infected cells.
   Antibodies developed against gametocytes
    (sexual stage parasites) can:
    • prevent development of sexual stage parasites in
      mosquitoes when taken up along with the blood meal.
   This type of immune protection is often referred
    to as transmission-blocking immunity.
    Immune Responses to Malaria
   NK cells and neutrophils are first line
    defenses against malaria and they
    can attack malaria parasites in
    several ways.
   Macrophages are responsible for
    eventual clearance of parasites from
    the blood.
   These cells engulf malaria parasites
    and parasitized erythrocytes and kill
    them.
    Immune Responses to Malaria
   Cellular immunity involving cytotoxic T
    cells are particularly effective in attacking
    malaria parasites during the liver stage
    development.
   Cytokines released from lymphocytes
    enhance this process.
   Cytokines secreted by different leukocyte
    populations may also play a direct role in
    protection.
    • For example, interferon-gamma has been
      shown to work against liver stage parasite
      development and activate macrophages to
      attack blood stage parasites.
     Immune Responses to Malaria
   Cytokines are also responsible for
    the severity of disease.
   A cytokine known as tumor necrosis
    factor (TNF)-alpha is one factor
    responsible for inducing high fever
    observed in malaria patients.
   The severity of disease may vary
    depending upon the level and the
    type of cytokines produced after
    malaria parasite infection.
     Immune Responses to Malaria
   Only about 2/3 of the patients who
    develop the clinical syndrome known
    as cerebral malaria survive after
    curative and supportive treatment.
    • It is not known, though, why still about
      20 to 30% of patients die despite
      treatment.
   some women deliver prematurely
    after malaria and some women
    deliver low birth weight babies.
     Immune Responses to Malaria
   Each of the developmental forms (liver
    stages, asexual blood stages,
    gametocytes, sporozoites) of the malaria
    parasites presents a different group of
    targets (antigens) to the immune system of
    the infected host.

   Malaria parasites mutate rapidly
    generating different variant forms such
    that individual antigens may differ within
    the same species of parasite.
    Immune Responses to Malaria
   This ability to generate different forms and
    a diversity of polymorphism within the
    antigenic targets of the host's immune
    system help the parasites to evade
    malarial immunity.

   Characterization of parasite diversity is
    critical for developing suitable targets for
    vaccine development
             Cerebral malaria
   The histopathologic hallmark of cerebral
    malaria is engorgement of cerebral
    capillaries and venules with parasitized
    and non-parasitized red blood cells and
    hypoglycemia.

   Current understanding of the pathogenesis
    of cerebral malaria implicates parasitized
    red blood cell sequestration in the brain,
    leading to localized ischemia, hypoxia, and
    the release of nitric oxide and cytokines,
    notably tumor necrosis factor a (TNF-a),
    in these areas of sequestration.
               Cerebral malaria
   It remains unclear whether measures to decrease
    or neutralize TNF-a will improve outcomes in
    cerebral malaria.

   The use of anti-TNF-a monoclonal antibodies in
    African children with cerebral malaria did not
    result in a decrease in mortality and children who
    received antibodies were more likely to have
    neurological sequelae at 6-month follow-up.

   The precise role of nitric oxide in cerebral malaria
    remains poorly characterized.
          Malaria in pregnancy
   Pregnant women are particularly
    vulnerable to malaria as pregnancy
    reduces a woman’s immunity to malaria,
    making her more susceptible to malaria
    infection and increasing the risk of illness,
    severe anaemia and death.

   For the unborn child, maternal malaria
    increases the risk of spontaneous
    abortion, stillbirth, premature delivery and
    low birth weight - a leading cause of child
    mortality

								
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