Clinical Aspects of MalariaHUMAN MALARIA PARASITESREVISION OF LIFE CYCLE • Characteristic of Plasmodium Species Infecting Humans.THE INFECTION • Susceptibility for infection.PATHOPHYSIOLOGY• Toxicity cytokines:• Sequestration• Rosetting:• Pathogenesis of Coma• Anaemia• Blackwater fever:• The spleen• Hypoglycemia
PATHOLOGY CLINICAL FEATURES• Brain • Severity and immune status• Heart and lungs • Incubation period• Liver and spleen • Uncomplicated Malaria: (UCM)• Kidneys • Cerebral Malaria:• Alimentary Tract • Relapse & recrudescence.• Bone marrow: • Severe Malaria:• Placenta: • Anaemia( Optional reading) • Acute renal Failure • Metabolic Acidosis. • Black water fever. • Acute Pulmonary oedema. • Algid Malaria (Hypotension). • Hypoglycemia • Malaria In Children • Malaria in Pregnancy
DIAGNOSIS • Blood smear • Other TechniquesCHRONIC COMPLICATIONS OF MALARIA • Hyperactive Malarial splenomegally • Quartan Malarial Nephropathy • Burkitt’s Lymphoma TREATMENT ANTIMALARIAL DRUGS CHOICE OF DRUGS
Clinical Aspects of Malaria• Over 500 million people each year, debilitating attacks• About 1 - 3 millions are fatal.• Up to 2.7 million deaths occur each year ( WHO,1996) The disease in humans Caused by • Direct effects of red cells invasion and • Destruction By: 1. The asexual parasite and 2. The host’s reaction.
The Life Cycle of Malaria Parasite in the Mosquito and in the Human host
Characteristic of Plasmodium Species Infecting Humans. P. falciparum P. Vivax P. ovale P .malariaeExo-erythrocytic 5.5 8 9 15hepatic phase ofdevelopment (days)Erythrocytic cycle 2 2 2 3(days)Hypnozoites (relapses) No Yes Yes NoNo of merozoites per 30000 10000 15000 2000hepatic schizontErythrocyte Young RBCs but Reticulo- Reticulo- Old RBCspreference can invade all ages cytes cytesMaximum duration of 2 4 4 40untreated infection(years)
Susceptibility for infectionUniversal, except in persons with Certain genetic TraitsGlucose-6-Phosphate Dehydrogenase DeficiencyTrait: • Offers protection against P. falciparum infectionDuffy blood factor [ Fya or Fyb ] Go to slide 33 • Serve as a site for attachment or penetration on the surface of RBCs for P. vivax. • Negative Duffy factor offers protection against P. Vivax (West Africa) .
Sickle-cell anaemia trait:• Abnormal haemoglobin. Go to slide 34• P. falciparum schizonts have difficulty in utilizing this haemoglobin Other haemoglobins• Thalassemia haemoglobin and Haemoglobin E. (P. vivax)• Hb F do not support parasitic growth, protects against all human plasmodia
Melanesian ovalocytic erythrocytesResist invasion by malaria parasite .Melanesia This is a group of several hundred islands east of NewGuinea. The largest island is Guadalcanal. Certain human leucocyte antigens (HLAs) ATP deficiency Nutritional deficiencies Go to slide 36
Virulence factors 1. Multiplication capacity. 2. Cytoadherence. 3. Rosetting ability. 4. The potential to induce cytokine release. 5. Antigenicity. 6. Antimalarial drug resistance
PATHOPHYSIOLOGY Results from Destruction of erythrocytes. • Liberation of parasites and erythrocytes material • Host reaction to those events. P. falciparum malaria-infected erythrocytes • Sequester in the micro-circulation of vital organs, • Interfering with • Microcirculatory flow • Host tissues metabolism.
Toxicity Cytokines• Malaria parasites induce release of cytokines.• Cells of macrophage-monocyte series, and possibly endothelium are stimulated to release cytokines.• Initially TNF and IL-1 are produced and in turn induce release of other pro-inflammatory cytokines including IL-6 then IL-8.• Cytokines ( mainly TNF) are responsible for many of the symptoms and sign of the infection.• Cytokines may be an important mediator of parasite killing by activating leucocytes.
Sequestration Adherence of erythrocytes containing mature forms of P. falciparum to microvascular endothelium (Cytoadherence) and disappear from peripheral circulation Occurs predominantly in the veinules of vital organs. Enhanced by cytokines ( adhesion on parasitized RCBs [70%] and ligand on endothelial cells
Rosetting• Erythrocytes containing mature parasites also adhere to uninfected erythrocytes.• This process leads to the formation of rosettes.
Pathogenesis of Coma in cerebral malaria Is not known, may be due to:• Increase in cerebral anaerobic glycolysis (with blood flow of low arterial oxygen content)• Increased cerebral metabolic rate for lactate.• Increased CSF concentration of lactate.• Presumably the metabolic milieu created adjacent to the sequestrated and highly metabolic parasites interferes with neurotransmission.• Cytokines increase production of nitric acid, a potent inhibitor of neurotransmission
Usually normocytic AnaemiaThe pathogenesis is multifactorial and complex:1. Obligatory destruction of parasitized red cells.(a)2. Accelerated destruction of parasitized red cells. (immunopathological mechanisms)(b) Parasite antigens, or immune complexes containing parasite antigens, may bind to parasitized red and accelerate their clearance by the cells of macrophage3. Autoantibodies produced against normal red cells, again accelerate their removal.(c)4. TNF released in response to infection, inhibits redblood cells development from bone marrow stem cells. (d)
Blackwater FeverA condition in which there is massive intravascularhaemolysis with passage of Coca-cola-coloured urine.
The spleen• Considerable splenic enlargement with increased capacity to clear red cells from the circulation both by: - Fc receptor-mediated ( immune ) mechanism. - Recognition of reduced deformability (filtration).• Plays a central role in limiting the expansion of malaria by removing parasitized erythrocytesPlasmodiumfalciparum:enlarged, heavilypigmented spleenis seen in grosssection.
HypoglycemiaPathophysiological etiology 1. Increased peripheral requirement for glucose upon anaerobic glycolysis. 2. Increased metabolic demand of the febrile illness. 3. The obligatory demands of the parasite, which use glucose as their major fuel. 4. Failure of hepatic gluconeogenesis and glycogenolysis. 5. Quinine-induced (hyperinsulinaemic), occur 24 hours after treatment.
CLINICAL FEATURES OF MALARIAThe severity and course of an attack ofmalaria depends on:1. Species and strain of parasite ( geographical origin).2. Age of host.3. Genetic constitution.4. State of immunity.5. General health and nutritional status of pt.6. Chemoprophylaxis or chemotherapy used.
Depend on the previous immune status of the host. Intense P. falciparum malaria transmission Asymptomatic parasitaemia in adults ( premunition ) No severe malaria in this age group. Severe malaria in the first year of life, decline with increasing age. Severe anaemia is the most common presentation of severe falciparum malaria in infancy. Spleen rates will be high(>50%) in children between 2 - 9 years. With unstable transmission The age distribution of severe malaria shifts upwards, Older children as well, Cerebral malaria is most prominent. Spleen rates in children is lower than 50%. With lower or sporadic pattern of transmission, and non-immune travelers to endemic areas, symptomatic disease is seen in all ages.
Incubation periodThe prepatent period (time from sporozoite inoculation until demonstrating parasites in blood film).The incubation period Go to slide 32 (time from sporozoite inoculation to fever).
Uncomplicated Malaria: (UCM) The clinical features of UCM are common to all four species. First symptoms are non-specific, resemble influenza. 1. Lack of sense of well-being. 2. Headache. 3. Fatigue. 4. Abdominal discomfort. 5. Muscle aches followed by fever. The temperature rises erratically at first, with shivering, mild chills, worsening headache and malaise, and loss of appetite. If the infection is left untreated, the fever:- in P. vivax and P. ovale regularize to a 2-day cycle (tertian) P. malariae fever spikes occur 3 days(quartan) pattern. P. falciparum remains erratic for longer, and may never regularize to a pattern (Quotidian).
In a true paroxysm 1. The temperature rises steeply to exceed 39 C. 2. Intense headache and muscular discomfort. 3. The patient feels cold, clutches at blankets, and curls up shivering, uncommunicative (the chill). 4. There is vasoconstriction, within minutes the limbs begin to shake and the teeth chatter. 5. The temperature climbs rapidly to a peak ( 39 -41.5 C). 6. The rigors lasts 10 - 30 minutes and may be up to 90 minutes. 7. By the end of rigors, there is vasodilatation , the skin feels hot, then a profuse sweating breaks out. 8. The blood pressure is relatively low & may be symptoms of orthostatic hypotension. 9. The patient feels exhausted and may sleep. 10. Defervescence takes 4 - 8 hours
As the infection continue the spleen and liver enlarge and anaemia develops, and patient loss weight. If no treatment is given the natural infection stabilizes for several weeks or months then gradually resolves. Mild abdominal pain is common in malaria, constipation or diarrhea may occur In the tropics malaria is so common that it must be excluded in any febrile patient.
Low activity of this enzyme results insubnormal concentration of reducedglutathione in red cells and also in thelimitation of the hexose monophosphateshunt pathway ( e.g. production ofessential ribose phosphate ). P. falciparumuse this pathway in their metabolism. Go back to slide 7
Haemoglobin Molecules is tetramer:Adult normal HbA = 2 α chains + 2 β chainsHbS : there is amino acid substitution ( valine for glutathione at position 17) in the β chainHeterozygotes for HbS have one normal and one defective β gene &are said to have sickle triat and are designated AS, their RBCscontain mixture of HbA and HbS and function fairly normalRBCs of homozygos (SS) contain mainly HbS (2 abnormal β genes),at low Oxygen tension their cell form abnormal shape (sickle) Next
Go Back to slide 8 Figure 2. Schematic representation of the effect of the sickle cell hemoglobin gene on survival in endemic malarial areas.People with normal hemoglobin (left of the diagram) are susceptible to death from malaria.People with sickle cell disease (right of the diagram) are susceptible to death from the complications of sickle cell disease.People with sickle cell trait, who have one gene for hemoglobin A and one gene for hemoglobin S, have a greater chance of surviving malaria and do not suffer adverse consequences from the hemoglobin S gene.
Table 1: Red Cell Defenses Against MalariaCell Component Alteration Global DistributionMembrane Duffy antigen null Africa Melanesian Melanesia ElliptocytosisHemoglobin Hemoglobin S Africa, Middle East, India Hemoglobin C Africa Hemoglobin E S.E. Asia ß-thalassemia Africa, Mediterranean, India, S.E. Asia, Melanesia -thalassemia Africa, India, S.E. Asia Africa, Mediterranean,Red cell enzymes G-6-PD deficiency India, S.E. Asia Go back to slide 9