Malaria Attitude of Fetus by mikeholy

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									             Malaria

Charis Segeritz and Jo-Ann Osei-Twum
           January 21, 2008
                         Overview
1.) Malaria: Pathology           2.) Malaria: Discussion

• Transmission                   • Malaria misdiagnosis
   – How and through what route? • Malaria eradication
   – Main reservoirs?
   – Prevention?
• Life cycle
   – Tissue schizogony
   – Erythrocytic schizogony
   – Sporogony
• Clinical manifestation
• High risk groups
• Diagnosis
• Treatment
• Use of genetically modified
  mosquitoes
                Transmission
•     How and through which route does Malaria infect
      humans?
    –    transmitted by the bite of an infected female
         Anopheles mosquito most frequently between dusk
         and dawn
    –    risk of transmission is increased through exposure
         between dusk and dawn
        • in rural areas
        • at the end of the rainy season
        • below 2000m
    –    rarely:
        • transmission by blood transfusion
        • Transmission by shared needle use
        • Congenital transmission from mother to fetus
                     Transmission
•     What are the main reservoirs for the disease?
    –    infection caused by eukaryotic single-celled microorganism of genus
         Plasmodium
        • four species infecting humans:
              Plasmodium falciparum (may be fatal, sub-Saharan Africa,
                 principal cause of malaria deaths in young children in Africa)
              Plasmodium vivax (most widespread, but rarely fatal, Indian
                 subcontinent)
              Plasmodium ovale (least common, West Africa)
              Plasmodium malariae (worldwide, but low frequency)
        • differences
              Morphology
              Immunology
              Geographical distribution
              Relapse pattern
              Drug response
                   Transmission
• What can be done in order to prevent transmission?
  – avoid mosquitoes and bites
      • physical barriers: mosquito nets, clothing
      • chemical barriers:
          – repellents: keep mosquitoes from biting
              » DEET
              » “natural based” repellents
              » other synthetic repellents
          – insecticides: kill mosquitoes
              » treated mosquito nets
              » treated clothing
              » DDT
  – chemoprophylactic drugs
                         Life cycle
• Extremely complex
• Involves various proteins that ensure intracellular and extra-cellular
  survival
• Invasion of different cell types
• Evasion of the host immune system

• Three stages
   – Tissue Schizogony
   – Erythrocyte Schizogony
   – Sporogony
           Tissue Schizogony [A]
• Mosquitoes inject the parasite (sporozoites) into the host
  bloodstream [1]
• Sporozoites travel to the liver and penetrate liver cells (hepatocytes)

• Invasion [2]
   – mediated by thrombospondin domains of the circumsporozoite
     protein and the thrombospondin-related adhesive protein on
     sporozoites
   – bind to heparin sulphate proteoglycans on hepatocytes

• Asexual replication [3]
   – 9-16 days
Tissue Schizogony [A]

             One sporozoite [2]




    Tens of thousands of merozoites [3]




 Merozoites released into blood stream [4]




One merozoite invades one red blood cell [5]
http://www.cdc.gov/malaria/biology/life_cycle.htm
     Erythrocytic Schizogony [B]
• Merozoites invade erythrocytes [5]
   – Apical reorientation
   – Junction formation
   – Signalling
• Recognition
   – Merozoite surface proteins interact with sialic acid residues
• Invasion
   – Erythrocyte binding antigen 175 interacts with glycophorin A
      on erythrocytes
• P. falciparum erythrocytes membrane protein 1 (PfEMP1)
   – Parasite protein
   – Expressed at the surface of infected RBC
   – Bind to various host cell receptors
        • Endothelium
        • Placenta
       Erythrocytic Schizogony [B]
•     In the RBC, merozoites undergo asexual division
    –     series of developmental stages
        • Early trophozoite
             – “ring form”
        • Trophozoite
             – Highly metabolic
                  » Glycolysis
                  » Ingestion of host cytoplasm
                  » Proteolysis of hemoglobin
             – Rounds of nuclear division without cytokinesis forming
                 schizonts
                  » schizonts contain 20 merozoites, these are released once
                      the RBC is lyzed [6]
             – Cycle of invasion-multiplication-release is repeated
             – Some merozoites differentiate into male and female
                 gametocytes [7]
                   Sporogony [C]
• Gametocytes are ingested into the midgut of feeding mosquitoes [8]

• Fertilization
   – Gametes fuse [9]
   – Zygote formation
   – Development of an oocyst [11]

• Sporogony in oocyst produces many sporozoites
   – oocyst raptures releasing sporozoites [12]
   – sporozoites migrate to salivary glands
      • cycle begins once a mosquito bites a host [1]
    Clinical manifestations in humans
•        develop 6 days - several months after infected mosquito bite
•        characterized by fever and “flu-like” symptoms:
     –       myalgias
     –       headache
     –       abdominal pain
     –       malaise
•        often rigors and chills
•        classically described alternate-day fevers or other periodic fevers are often not
         present
•        severe malaria (due to P.falciparum) may cause . . .
     –       seizures
     –       coma
     –       renal and respiratory failure
     –       anemia (= blood loss), even cerebral anemia (= infected erythrocytes obstruct small blood
             vessels in brain, often fatal, especially in infants)
     –       may lead to death
•        dormancy
     –       P. ovale and P. vivax: hyponozoites
            •    Dormant liver stages
            •    Remain in organ for weeks/years before onset of new round of pre-erythrocytic schizogony 
                 relapses of malaria infection
     –       P. malariae
            •    May have long-lasting blood-stage infections that persist in human asymptomatically for several
                 decades if left untreated
               High risk groups
•   overall case-fatality rate of P. falciparum malaria imported into
    Canada varies from approximately 1% to 5% and increases to 30%
    for those > 70 years of age
•   children
•   pregnant women

                      Diagnosis
•   Combination of clinical observations, case history and diagnostic
    tests (microscopic examination of blood or rapid “dipstick” tests)
•   the symptoms of malaria are non-specific and diagnosis is not
    possible without a blood film
•   the most important factors that determine patient survival are
    early diagnosis and appropriate therapy
•   the majority of infections and deaths due to malaria are
    preventable
                        Treatment
• Problems:
   – widespread resistance of P. falciparum to chloroquine 
     complicates prevention and treatment of malaria: drug-resistant
     strains of malaria are now common in much of the world




   – Insecticide-resistant strains of mosquito
   – Lack of licensed malaria vaccines of proven efficacy
                       Treatment
• Solution:
   – Combination therapy, e.g. Artemisinin +Fansidar/Mefloquine
   – Quinine
      • First widely used antimalarial treatment
      • From bark of Andean Cinchona tree
   – Fansidar and Chloroquine
      • Most commonly used
      • Most affordable antimalarial drugs
• Goals:
   – Reduce antimalarial resistance
   – Prolong useful life of current drugs
   – Three combined strategies to reduce malaria transmission:
      • Develop clinically approved malaria vaccines
      • Drug treatment
      • Vector control
Genetically Modified Mosquitoes
  Germ-line transformations           Identification of effector molecules




                    Transgenic mosquitoes




            Prevent the transmission of the parasite
Genetically Modified Mosquitoes

• Well studied in the laboratory

• Must survive in the wild

• Out-compete their wild-type counterparts

• Genetic modifications must be permanent
  Discussion: Malaria misdiagnosis
   “In a recent study of children reporting to health centres in Uganda,
   Karin Kallander and colleagues found that 30% had symptoms
   compatible with both pneumonia and malaria and required dual
   treatment. This report, and previous studies, have concluded that
   community treatment of all childhood fevers as malaria is likely to
   result in malaria over-diagnosis with consequent under-diagnosis of
   other fever-causing disorders such as pneumonia.”
   (Amexo et al. 2004. Malaria misdiagnosis: effects on the poor and
   vulnerable)

1.) Discuss the challenge and problems of this issue.
2.) What do you consider the most ethical and cost-effective policy?
  Discussion: Malaria misdiagnosis
     “In a recent study of children reporting to health centres in Uganda,
     Karin Kallander and colleagues found that 30% had symptoms
     compatible with both pneumonia and malaria and required dual
     treatment. This report, and previous studies, have concluded that
     community treatment of all childhood fevers as malaria is likely to result
     in malaria over-diagnosis with consequent under-diagnosis of other
     fever-causing disorders such as pneumonia.”
     (Amexo et al. 2004. Malaria misdiagnosis: effects on the poor and vulnerable)

Discuss the challenge and problems of this issue.
a)   rapid, simple, accurate, inexpensive malaria diagnosis methods are not
     widely available, particularly in poor communities where they are most
     needed and individuals are least able to withstand the consequences of
     the illness
b)   how can one ensure that the more expensive combination therapies reach
     most of those who truly have malarial illness and not just an elite
     minority?
What do you consider the most ethical and cost-effective policy?
a)   newer drug combinations used only for true cases of malaria
b)   requirement: accurate malaria diagnosis
                                             malaria
                                      ( = fever symptoms)


                         70 %                         30 %



     home treatment:             health centres on               health centres on district level =
     -traditional               community level =                          district hospitals
     remedies               peripheral health facilities
     -drugs from local                                       Diagnosis:
     stores
                                       Diagnosis:            1) Microscopy
                                solely based on clinical     -    standard for malaria
                                  features (i.e. fever)           diagnosis (accuracy 70-75%)
                                                             -    challenge:
                                                                    o    well-maintained
                                bad quality diagnosis                    equipment
                                                                    o    constant supply of
                                                                         good-quality reagent
                           pro: can reduce morbidity                o    trained staff:
                           contra: over-                                 monitoring,
                           diagnosis/over-treatment of                   supervising
                           malaria as many infectious
                           diseases mimic malaria            2) Rapid Diagnostic Tests
                           pathology                         -      when microscopy unavailable
                                                             -      based on detection of
                                                                    Plasmodium specific proteins
Design an educational step-                                  -      challenge:
                                                                      o    cost
by-step plan for elucidating                                          o    not quantitative =
                                                                           inability to provide
locals about successful self-                                              information about
                                                                           density of infection
treatment.                                                            o    Not species specific:
                                                                           can only diagnose P.
                                                                           falciparum specifically
     Proposal for educational self-
           treatment plan
1)   Discuss common errors concerning malaria
     recognition
       •   i.e. false assumptions such as “malaria can be recognized from its
           symptoms”
2)   Advise that malaria presents in various ways
       •   i.e. differing malarial symptoms may mimic other diseases
3)   Indicate need to seek professional medical care as soon
     as possible
       •   i.e. self-treatment is a temporary, life-saving measure while
           seeking medical attention or if medical care is not available
           within 24h
4)   Select self-treatment drug with care
       •   i.e. consider drug’s safety, efficacy, individual’s drug tolerance,
           other medication etc.
5)   Educate about drugs to avoid
       •   i.e. potential severe adverse effects and/or poor efficacy
                Misdiagnosis of Malaria =
contribution to a vicious cycle of increasing ill-health and
                    deepening poverty
Poor and Vulnerable   less likely to seek modern medical care for treatment of fevers
                      - wait-and-see approach
                      - unaffordable fees
                      - long waiting lists
                      - unavailability of drugs
                      - poor attitude among staff
                Misdiagnosis of Malaria =
contribution to a vicious cycle of increasing ill-health and
                    deepening poverty

Poor and Vulnerable   less likely to seek modern medical care for treatment of fevers
                      - wait-and-see approach
                      - unaffordable fees
                      - long waiting lists
                      - unavailability of drugs
                      - poor attitude among staff



                      inaccurate diagnosis         delayed diagnosis & treatment
                Misdiagnosis of Malaria =
contribution to a vicious cycle of increasing ill-health and
                    deepening poverty

Poor and Vulnerable   less likely to seek modern medical care for treatment of fevers
                      - wait-and-see approach
                      - unaffordable fees
                      - long waiting lists
                      - unavailability of drugs
                      - poor attitude among staff



                      inaccurate diagnosis         delayed diagnosis & treatment


                           more prolonged and severe disease
                Misdiagnosis of Malaria =
contribution to a vicious cycle of increasing ill-health and
                    deepening poverty

Poor and Vulnerable          less likely to seek modern medical care for treatment of fevers
                             - wait-and-see approach
                             - unaffordable fees
                             - long waiting lists
                             - unavailability of drugs
                             - poor attitude among staff



                              inaccurate diagnosis        delayed diagnosis & treatment


                                  more prolonged and severe disease

           Misallocation of Resources:
           - underlying fatal conditions are masked
           - exposure to unnecessary side-effects
           - lost confidence in allopathic health services in favour of traditional healers
           - lost productive time through illness (no insurance or savings)
           - impacts on anyone: men, women, children (leave school to look after relatives  reduced
              employment prospects
    Discussion: The long road to
        malaria eradication
• We saw that poverty was a contributing factor to the misdiagnosis
  of malaria, Peter Russell in 1946 wrote:
  “but all the evidence we possess would seem to indicate not that
  poverty is responsible for malaria but that malaria maintains
  poverty” (Majori. 1999. The long road to malaria eradication)

  With this in mind consider the following:

  Three approaches have been identified in the fight against malaria:
   – drug administration,
   – vector control (insecticides or insecticide sprayed bed nets) and
   – vaccine development.

  Of these three which approach do you think is the most feasible?
  Which would you allocate funds to?
    Discussion: The long road to
        malaria eradication
• The Director General of the WHO wrote to the 8th World Health
  Assembly:

“... At present time there are no obvious technical or economic reasons
    why malaria could not be driven out of the Americas, Europe,
    Australia and much of Asia within the next quarter of a century. As
    regards tropical Africa the situation is not quite so promising…one
    cannot foresee the elimination of malaria from Africa in the near
    future”. (Majori. 1999. The long road to malaria eradication)

   Do you agree or disagree with the latter part of this statement?

   Why do you think the outcomes of malaria eradication differed
   between countries of tropical Asia and countries of sub-Saharan
   Africa?
Global distribution of malaria




                 Sachs and Malaney, 2002. The economic and social burden of malaria.
Global distribution of per capita
              GDP




                    Sachs and Malaney, 2002. The economic and social burden of malaria.

								
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