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  1. 1. Malaria Dr. Pendru Raghunath Reddy
  2. 2. What is malaria? A mosquito-borne infectious disease caused by protozoan parasites of the genus Plasmodium Phylum: Apicomplexa Class: Sporozoea Order: Eucoccidea Suborder: Haemosporina
  3. 3.  There are 156 species of Plasmodium which infect various species of vertebrates  Of these only 4 species can infect human beings 1. Plasmodium vivax 2. Plasmodium malariae 3. Plasmodium falciparum 4. Plasmodium ovale  Of these P. vivax and P. falciparum account for 95% of infections  Some estimates indicate P. vivax may account for 80% of the infections
  4. 4. The genus Plasmodium is divided into two subgenera  P. vivax, P. malariae and P. ovale belonging to subgenus Plasmodium while P. falciparum is allocated to the subgenus Laverania
  5. 5. Is malaria a common disease? Yes. The World Health Organization estimates that each year 300-500 million cases of malaria occur and more than 1 million people die of malaria.
  6. 6. Is malaria a serious disease? Yes. Malaria is a leading cause of death and disease worldwide, especially in developing countries Most deaths occur in young children. For example, in Africa, a child dies from malaria every 30 seconds
  7. 7. It’s especially hard on kids 75% of the deaths are among African children
  8. 8. 2.1 billion people live in MALARIOUS areas
  9. 9. 1907 Nobel Prize for Physiology or Medicine! French army doctor in Algeria observed parasites inside red blood cells of malaria patients and proposed for the first time that a protozoan caused disease Charles Louis Alphonse Laveran
  10. 10. Habitat After passing through the hepatic parenchymal cells, the parasites reside within RBCs and are carried by blood to various organs Life cycle All species of Plasmodium have a life cycle both in man and various species of anopheline mosquitoes 1. Human cycle (Schizogony) 2. Mosquito cycle (Sporogony)
  11. 11. 1. Human cycle  The parasites in the liver and RBCs multiply asexually  Man therefore represents the intermediate host  Human cycle can be divided into three phases a) Exo-erythrocytic (tissue) phase b) Erythrocytic phase c) Gametogony 2. Mosquito cycle  Sporogony takes place in female anopheline mosquitoes  Therefore represents the definitive host
  12. 12. Malaria Life Cycle Sporogony Oocyst Sporozoites Mosquito Salivary Gland Zygote Exoerythrocytic (hepatic) cycle Gametocytes Erythrocytic Cycle Schizogony Hypnozoites (for P. vivax and P. ovale)
  13. 13. Life cycle
  14. 14. Morphological features of P. vivax Early trophozoite (ring form) Red nucleus on the ring-like light blue cytoplasm (large, 2.5 µm)
  15. 15. Late trophozoite  It is irregular shape like ameboid form with pseudopodia; within cytoplasm ,brown pigment granules (malarial pigment--haemozoin) appear  Infected RBCs are pale in color,and have schuffner’s dots in it (fine red granules)
  16. 16. Immature schizont  Oval in shape , nucleus divided into 2-4 or more , malarial pigment begins to concentrate in a mass Mature schizont  Nucleus divided into 12-24 ;and cytoplasm also divided, each nucleus surrounded by a portion of cytoplasm to form merozoites, malarial pigment clumped.
  17. 17. Male gametocyte  Oval in shape; 1 loose nucleus in centre of it ; malarial pigments diffuse Female gametocyte  Oval in shape ; 1 compact nucleus not in centre of it
  18. 18. Morphological features of P. falciparum Early trophozoite (ring form)  1or 2 red nuclei on the ring-like light blue cytoplasm ; multiple infection in a cell P. falciparum: Only the early trophozoites and gametocytes can be seen in the peripheral blood
  19. 19. Male gametocyte  Sausage in shape; 1 loose nucleus in centre of it ; malarial pigment diffuse Female gametocyte  Crescentic in shape ; 1 compact nucleus in centre of it
  20. 20. Differential characters of malaria parasites P. vivax P. falciparum P. malariae P. ovale Hypnozoites Yes No No Yes Erythrocyte preference Reticulocytes Young erythrocytes Old erythrocytes Reticulocytes As in vivax As in vivax Stages found in blood Rings, Only rings trophozoites, and schizonts and gametocytes gametocytes Duration of erythrocytic schizogony 48 h 48 h 72 h 48 h Prepatent period (days) 8 5 13 9 Average incubation period (days) 14 12 30 14
  21. 21. Schizogenic periodicity and fever patterns Schizogonic periodicity is length of asexual erythrocytic phase – 48 hours in P. falciparum, P. vivax and P. ovale (tertian) – 72 hours in P. malariae (quartan) Initially may not see characteristic fever pattern if schizogony not synchronous With synchrony, periods of fever or febrile paroxsyms assume a more definite 3 (tertian)- or 4 (quartan)- day pattern
  22. 22. Extrinsic Incubation Period Time required for the development of sexual cycle in mosquitoes at a given temperature Pre-patent period It is the time required for the malaria parasite to appear in the blood after the bite of infective mosquito Incubation period This is an interval between the infective mosquito bite and the first appearance of clinical symptoms, of which fever is most common The incubation period varies usually from 8 – 40 days
  23. 23. Reservoirs of infection  Human species of malarial parasites are not harboured by any of the lower animals  Hence man, particularly the children in an endemic area act as the only reservoir of infection Method of transmission: Infected mosquito bite (Inoculative method) Transmitting agent: Female anopheles Infective forms: Sporozoites Portal of entry: Skin Site of localisation: First in liver cells, then in erythrocytes
  24. 24. Other methods of transmission 1. Trophozoite - induced malaria Injection of blood from malarial patient containing the asexual forms of erythrocytic schizogony will also induce malaria in man a) Transfusion malaria b) Congenital malaria c) Malaria in drug addicts 2. Therapeutic malaria
  25. 25. Pathogenesis Infection with Plasmodia causes intermittent fevers which are known as malaria Each of the four species causes a characteristic fever and the disease are designated as follows P. vivax – Benign tertian malaria (Vivax malaria) P. malariae – Quartan malaria (Malariae malaria) P. falciparum – Malignant tertian malaria (Falciparum malaria) P. ovlae – Ovale tertian malaria (Ovale malaria)
  26. 26. Clinical features The main clinical manifestations in a typical case, are a series of febrile paroxysms (periodic bouts of fever) with rigor followed by anaemia and splenic enlargement Febrile paroxysm  The malarial fever starts generally in the early afternoon  The febrile paroxysm comprises three successive stages 1. The cold stage 2. The hot stage 3. The sweating stage
  27. 27. 1. The cold stage  Lasts for 15 – 60 minutes  The patient experiences intense cold and uncontrollable shivering 2. The hot stage  Lasts for 2 to 6 hours  The fever mounts to 410C or higher and the patient feels intensely hot  Severe headache, nausea, and vomiting are common
  28. 28. 3. The sweating stage  The patient is drenched in profuse sweat  The temperature drops rapidly and the patient usually falls into deep sleep, to wake up refreshed  The total duration of the febrile cycle is from 8 to 12 hours
  29. 29. All clinical manifestations in malaria are due to the products of erythrocytic schizogony and the host’s reactions to them The exoerythrocytic liver cycle and gametogony do not appear to contribute to clinical illness At the end of erythrocytic schizogony, mature schizont ruptures and merozoites, malarial pigment and other parasitic debris will be released Macrophages and polymorphs phagocytose these and release large quantities of endogenous pyrogens, leading to elevation of temperature
  30. 30. Recrudescence  In P. falciparum and P. malariae infections, the parasites are not completely eliminated after recovery from primary infection  Erythrocytic schizogony continues in the body at low levels and gradually the numbers of parasites build up to cross the fever - threshold  These new malarial attacks that appear after a period of latency usually within 8 weeks after the culmination of the primary attack are called recrudescences
  31. 31. Relapse  In P. vivax and P. ovale infections, the parasite may survive for long periods in a dormant exoerythrocytic phase as hypnozoites in liver cells  Reactivation of those hypnozoites leads to initiation of fresh erythrocytic cycles, and leads to new attacks of malarial fever known as relapses  Relapses occur after long periods, usually from 24 weeks to 5 years after the primary attack
  32. 32. Anaemia  Anaemia occurs in all types of malaria, but is most pronounced in falciparum infections  The type of anaemia is haemolytic, normocytic, normochromic  Anaemia occurs due to a variety of reasons such as 1. Destruction of parasitised RBCs 2. Hypersplenism 3. Autoimmune lysis of coated infected and uninfected RBCs 4. Decreased RBC production from bone-marrow supression
  33. 33. Splenomegaly  The spleen is invariably affected, being always enlarged in malaria  Spleen becomes palpable after the second week of fever  Accumulation of macrophages leads to enlargement of spleen, which becomes hard due to fibrosis Malaria in pregnancy  Malaria of any form may precipitate miscarriage or abortion  May complicate pregnancy by causing severe anaemia  Pregnancy also appears to impair immunity and may lead to a relapse
  34. 34. Malaria in children  Malaria usually does not occur in a classical way in children  Children commonly develop high fever even from relatively mild infections  They may develop convulsions during malarial attack  Anaemia in children is more marked than in adults  Dehydration in them develops with greater rapidity as a result of vomiting and sweating
  35. 35. Complications of malaria The complications are more common due to P. falciparum infection than due to other three species Complications of P. falciparum infection Blackwater fever  It is seen in patients who have experienced repeated falciparum malaria infections and inadequately treated with quinine  Clinical manifestations include bilious vomiting and prostration with passage of dark red or blackish urine (black water)  The pathogenesis is believed to be massive intravascular hemolysis caused by antierythrocyte autoantibodies, leading to haemoglobinaemia and haemoglobinuria
  36. 36. Malignant Tertian Malaria  The most serious and fatal type of malaria  Caused by P. falciparum  When not treated promptly and adequately, dangerous complications develop
  37. 37. Pernicious malaria  Refers to a complex of life-threatening complications that sometimes supervenes in acute falciparum malaria  It results from anoxia due to obstruction of capillaries in various organs followed by necrosis (death) of tissues  The symptoms appearing depend on the site where the injury occurs without immunity to the parasite  In endemic conditions it is always due to P. falciparum infection
  38. 38. Clinical types  According to the organs affected pernicious malaria may be broadly divided into three groups 1. Cerebral malaria  Manifested by hyperpyrexia, coma, paralysis 2. Algid malaria  Resembles surgical shock, characterised by cold and clammy skin with vascular collapse leading to peripheral circulatory failure and profound hypotension  Gastro-intestinal system may be involved leading to vomiting (gastric type) or watery diarrhoea (choleraic type) or passage of blood in faceces (dysenteric type)
  39. 39. 3. Septicaemic malaria  Characterised by high continued temperature (resembling typhoid -fever), high degree of prostration, bilious remittent fever, and pneumonia  Acute renal failure and acute pulmonary oedema are other serious complications
  40. 40. Tropical splenomegaly syndrome  Also known as hyper-reactive malarial splenomegaly (HMS) is a chronic benign condition seen in some adults in endemic areas  This results from an abnormal immunological response to malaria and is characterised by 1. Enormous splenomegaly 2. High titres of circulating antimalaria antibody 3. Absence of malaria parasites in peripheral blood smears 4. Reduced C3 and presence of rheumatoid factor without arthritis 5. Normocytic, normochromic anaemia is present, not responding to haematinics or anthelmentics
  41. 41. Immunity  Immunity in malaria may be classified into innate immunity and acquired immunity 1. Innate immunity 2. Acquired immunity Innate immunity  Only little is known about innate immunity in malaria
  42. 42. But a few naturally occuring examples illustrate its importance  Persons who lack the Duffy blood group antigen (Fya FyB) are refractory to infection by P. vivax  P. falciparum does not multiply properly in sickle red cells containing abnormal haemoglobin S  G6PDH deficiency and HLA-B53 is associated with protection from falciparum malaria  There is some evidence that severe malnutrition and iron deficiency may confer some protection against malaria
  43. 43. Acquired immunity  Infection with malaria parasites induces specific immunity which can bring about clinical cure but cannot lead to complete elimination of parasites from the body  It can prevent superinfection. This state of resistance in an infected host, which is associated with continued asymptomatic parasitic infection is called premunition Protective immunity against malaria includes 1. Humoral immunity (IgM, IgG and IgA antibodies) 2. Cell Mediated Immunity (CMI)
  44. 44.  The immunity produced is species-specific, stage-specific and strain-specific  The mechanisms employed by the malarial parasite to persist in the host are not known but may include 1. Antigenic variation 2. Sequestration in a protected site such as liver and/ or 3. Supression of host immune responses
  45. 45. Laboratory diagnosis of malaria  Clinical diagnosis of malaria can be made with considerable confidence in residents of endemic areas and recent visitors but confirmation requires the finding of parasites in blood smear The most important method for the diagnosis of malaria is the demonstration of the parasite in blood Site of sampling  The concentration of malarial parasites is fairly homogenous throughout circulatory system, so the sample can be taken either from peripheral blood or internal blood
  46. 46. Two kinds of smears are prepared from the peripheral blood 1. Thin smear 2. Thick smear
  47. 47. Time of collection Parasites are abundant in peripheral blood late in the febrile paroxysm, a few hours after the peak of the fever Fixation of the smear Thin film is fixed in methanol for 30 seconds Thick film is not fixed as it is to be dehaemoglobinised
  48. 48. Staining The smears are stained by JSB stain, Field’s or Giemsa stain Why make thin and thick smears?  Thick smears have more quantity of blood in a smaller area, so that the parasites are concentrated in this area, hence chances of detection of malaria parasite are more in a thick smear  But one disadvantage is that morphology of the parasite is not clear  Thin smears are less sensitive for detection of malaria parasites but better for species identification
  49. 49. Morphological features in thin films  The cytoplasm of the parasite stained blue  The nucleus, known as chromatin is stained red  There is central unstained portion called vacuole in the early stages  Pigment granules of different colours are found on the cytoplasm and vacuole  Stippling appears as pink dots. These are inside the RBC but lie on the outside of the parasite
  50. 50. Some notable features in malaria morphology include:  Enlargement of RBCs in P. vivax infection  Multiple invasion of RBCs by ring forms is more common in P. falciparum infection  In P. falciparum, only ring stages and gametocytes are seen in the peripheral blood  Gametocytes of all other species are round except that of P. falciparum where these are crescent shaped  The pigment is black in P. malariae infection
  51. 51. P. vivax P. ovale
  52. 52. P. malariae P. falciparum
  53. 53.  It is recommended that 200 oil immersion fields should be examined before a thick film is declared negative  When parasites are found, an approximate quantitative estimate may be given as follows + = 1-10 parasites per 100 thick film fields ++ = 11-100 parasites per 100 thick film fields +++ = 1-10 parasites per each thick film field ++++ = More than 10 parasites per each thick film field
  54. 54. QBC (Quantitative Buffy Coat) technique
  55. 55. Immunodiagnosis  Detection of parasite-specific antigens using monoclonal antibodies  The Para Sight –F test (BD) is a dip-stick antigen capture test targeting the “histidine-rich protein-2” (HRP-2), specific for P. falciparum  Dipstick tests are also available for vivax malaria  Various serological tests such as IHA, IFA, ELISA, RIA and agar gel -diffusion have been investigated or applied for the diagnosis of malaria  However, serological tests are not employed for routine diagnosis
  56. 56. Treatment The various antimalarial drugs are grouped as follows 1. Essentially therapeutic (Clinical cure)  Chloroquine, quinine, mefloquine  To destroy exoerythrocytic parasites, a tissue schizonticidal drug such as primaquine should be administered 2. Protective or prophylactic  Proguanil, pyrimethamine and trimethoprim
  57. 57. Prophylaxis 1. Personal prophylaxis 2. Chemoprophylaxis  The drugs recommended for chemoprophylaxis are chloroquine, amodiaquin and fansidar in weekly doses or doxycycline daily  No vaccine is now available Control