| Malaria is an acute febrile illness characterized | | | | Thisadhesion phenomenon explains why mature |
| clinically by paroxysms of fever, the consequence | | | | trophozoitesand schizonts are usually absent from |
| of rupture of infected red cells due to asexual | | | | peripheral bloodfilms. Maximum numbers of |
| reproduction by species of Plasmodium | | | | adherent RBCs are found invenules in brain, liver, |
| (schizogony). Plasmodium vivax, P. ovale and P. | | | | spleen, kidney and lung. The placentais heavily |
| malariae are associated with morbidity but no | | | | parasitized with chondroitin sulphate Aserving as a |
| major mortality, but P. falciparum causes both | | | | specific receptor for adhesion of infectedRBCs. |
| morbidity and considerable mortality. | | | | The trophozoite matures into the schizont and |
| Malaria is an acute febrile illness characterized | | | | atschizogony the RBC membrane bursts, releasing |
| clinically by paroxysms of fever, the consequence | | | | merozoites,malaria antigen, malaria pigment and |
| of rupture ofinfected red cells due to asexual | | | | RBC cytoplasmicconstituents.The cycle continues, |
| reproduction by species of Plasmodium | | | | progressivelybuilding up the numbers of parasitized |
| (schizogony). Plasmodium vivax, P. ovaleand P. | | | | RBCs.How these changes lead to altered |
| malariae are associated with morbidity but no | | | | consciousness in cerebralmalaria is not clear. CT of |
| majormortality, but P. falciparum causes both | | | | the brain in patients withcerebral malaria has not |
| morbidity andconsiderable mortality. The infection | | | | shown oedema, although amongchildren in Kenya |
| is transmitted bythe bite of the female anopheline | | | | intracranial pressure recording hasshown raised |
| mosquito. Distribution and incidence Malaria occurs | | | | pressure. Diffuse irreversible vascularobstruction is |
| widely throughout the tropical areas of the world, | | | | also an unlikely cause, in view of the |
| in the Americas, Africa, Asia and the Pacific area. | | | | normalcerebral flow and complete recovery |
| Falciparum malaria is particularly common in | | | | without neurologicaldeficit in most survivors. CSF |
| tropical Africa, where it causes at least 1000000 | | | | lactate levels are increasedin cerebral malaria, |
| deaths per year, mainly in children. The | | | | which may indicate some degree ofanaerobic |
| resurgence of malaria in the Indian subcontinent | | | | cerebral glycolysis. At the molecular level, |
| was led by a rising incidence of vivax malaria in | | | | highlevels of TNF and other cytokines are found in |
| the 1970s, and now falciparum infection is more | | | | theblood of patients with the most severe forms |
| widespread in the region. Ovale malaria is | | | | of malaria,especially cerebral malaria. The extent |
| predominantlya west African disease. Malariae | | | | to which thesemolecules cause severe malaria is |
| malaria is the least common form .Malaria is | | | | not yet known. It isrecognized that quantitative |
| imported into temperate regions by tourists, | | | | differences in cytokine production,particularly TNF, |
| people employed overseas, business travellers and | | | | are genetically determined, indicatingpossible |
| immigrants. The numbers of cases have risen | | | | inherent predisposition to severe disease.Renal |
| progressively over the past 20 years. Vivax and | | | | damage occurs because of prerenal and |
| ovale life cycles are similar, with primary | | | | renalfactors. Acute tubular necrosis is the usual |
| exoerythrocyticschizogony (EES) in hepatocytes | | | | effect of severemalaria on the kidney. This may |
| leading to infection of the peripheral blood with | | | | occur both with andwithout severe intravascular |
| merozoites. These enter red blood cells (RBCs) | | | | haemolysis. Vessels in theheart are parasitized but |
| and undergo erythrocytic schizogony(ES) every | | | | cardiac function is well preserved.Reduced |
| 48 hours; this is benign tertian and ovale | | | | peripheral vascular resistance and dehydrationfrom |
| tertianmalaria. Some of the sporozoites produce | | | | sweating, vomiting and reduced fluid intake may |
| latent forms, the hypnozoites, within liver cells, | | | | contributeto hypotension.In cerebral malaria post |
| which produce EES and then ES up to 2 or 3 | | | | mortem the brain showsswelling with |
| years after infection, i.e. relapsing | | | | smallhaemorrhages throughout the whitematter. |
| malaria.Falciparum malaria has no hypnozoite form, | | | | The spleen is enlarged and has a slate-grey |
| and so the infection is cured when parasites are | | | | hueover the normal red colour. Centrilobular |
| cleared from the blood by treatment. ES has a | | | | necrosis is seenin the liver with the accumulation |
| periodicity of less than 48hours ('sub tertian'). | | | | of malaria pigmentin Kiipffer cells. The pulmonary |
| Malariae parasites also lack the hypnozoite stage | | | | venules contain largenumbers of parasitized RBCs. |
| but can cause reappearance of | | | | Pulmonary oedema of theARDS type occurs but |
| parasitaemia(parasites in peripheral RBCs) up to | | | | the cause is not understood. Theplacenta is usually |
| 20 or more years afterinfection. Small numbers of | | | | heavily parasitized.The anaemia of malaria has |
| parasites persist in RBCs to cause this. The | | | | several causes, which includerupture of parasitized |
| periodicity of ES is 72 hours (quartanmalaria). | | | | RBCs in schizogony; sequestrationof RBCs in |
| Vivax, ovale and malariae parasites invade 1-2% | | | | tissue venules; destruction of parasitized |
| ofRBCs at most. Falciparum parasites invade any | | | | andnon-parasitized RBCs in the reticuloendothelial |
| proportionof RBCs, accounting for the severity of | | | | system(especially the spleen); haemolysis due to |
| disease and the high mortality. Host A baby born | | | | the presence ofmalaria antigen, antibodies and |
| of an indigenous mother in an endemic falciparum | | | | complement on RBCs;and marrow suppression. |
| area will be protected against infection during the | | | | Abnormalities of coagulation are usual, with low |
| first year of life by maternal antimalaria IgG | | | | platelet counts due to peripheralconsumption and |
| crossing the placenta in the last trimester of | | | | consumption of clotting factors.Disseminated |
| pregnancy. After the first year the child is fully | | | | intravascular coagulation does occur in afew |
| susceptible. Without chemoprophylax is the child | | | | patients with severe malaria but is probably not a |
| experiences repeated attacks of malaria, and by | | | | major factor in pathogenesis in most severely ill |
| the age of 4 or 5 years will have acquired | | | | patients. Clinical features Vivax and ovale• |
| protective immunity, which persists as long as | | | | After an incubation period of about 13 days |
| they remain in the endemic area. Parasites are | | | | (vivax) or18 days (ovale), prodromal symptoms |
| often found in the peripheralblood of an | | | | begin with headache, fever, shivering without |
| asymptomatic child ,so that there is disease | | | | rigors, and generalaches. These last for up to 3 |
| immunity without immunity to reinfection; indeed, | | | | days before the first paroxysm of coldness, then |
| reinfectionis necessary to maintain antigenic | | | | extreme heat, then defervescence with a |
| challenge and the immune status. The immunity | | | | profuse sweat.• Forty-eight hours later the full |
| declines if an individual leaves the endemic area. | | | | paroxysm occurs, with a feeling of extreme |
| Maternal immunity declines during pregnancy, | | | | coldness and a rigor beginning inthe late afternoon. |
| particularly in primiparae, with transplacental | | | | Headache, nausea and vomiting areusually present. |
| transfer of IgG. Anaemia, fever and intense | | | | The temperature is high, the pulse rapidand low in |
| parasitizationof the placenta make miscarriage, | | | | volume, and the skin is cold. This phase lasts for |
| prematurelabour and low birthweight common, | | | | 45 minutes to 1 hour. When the rigor ceases, |
| especially in areassuch as West Africa, where | | | | peripheral dilatation occurs; the patient feels very |
| there is heavy seasonal transmission with a high | | | | hot andt hirsty. The pulse is rapid and of full |
| risk of infection. Where transmissionis not so | | | | volume. The skin is hot and dry. This lasts about 1 |
| intense, effective immunity is not built up and all | | | | hour and defervescence follows, with a profuse |
| ages in the exposed population are at risk. Any | | | | sweat. The symptoms settle completely and the |
| individual, of any age, from a malaria-free area | | | | patient will usually sleep. The following day there |
| maycontract severe malaria. Splenectomy | | | | may be a little weakness. One day later the |
| enhances susceptibilityto maleria to a considerable | | | | malaria paroxysm recurs. Daily paroxysms occur |
| degree. Sickle cell trait haemoglobin C trait, and | | | | when parasite broods are undergoing schizogony |
| the heterozygous state forglucose-6-phosphate | | | | on successive days.• Untreated, the |
| dehydrogenase (G6PD) deficiencyprotect against | | | | paroxysms continue for 6 weeks and die out |
| severe malaria. Vector Climatic factors have a | | | | spontaneously, only to recur 2-3 months later. By |
| profound influence on the transmission of malaria | | | | the time symptoms have been present for a |
| through effects on survival and reproduction of | | | | week the spleen is usually palpable and there may |
| the mosquito population, and on the development | | | | be mild anaemia. Rupture of the enlarged spleen is |
| of the parasite in the vector. Mosquito survive up | | | | reported in vivax malaria. incubation period is |
| to several months and theirlifespan is not affected | | | | usually about 28 days. Nonspecific prodromal |
| by malaria parasites. Ambient temperatures in the | | | | symptoms last for 2-3 days before the onset of |
| range 20-30°C, with a relative humidity of 60% | | | | the first paroxysm, which is accompanied by |
| or more,are ideal. In most areas of tropical Africa | | | | arigor. The periodicity of symptoms is every 72 |
| malaria is transmittedall year round, with upsurges | | | | hours. The spleen is enlarged when symptoms |
| of incidence with thedramatic increase of | | | | have been present for7-10 days. Falciparum |
| anopheline numbers during rainyseasons. In Asia | | | | malaria• The incubation period is about 12 days, |
| transmission is seasonal with the rains.Sporogony | | | | range 9-17 days.• Headache, anorexia, nausea, |
| will not occur below 16° or above 33°C. | | | | vomiting, weakness and fever are prominent |
| Thevector species vary considerably in different | | | | symptoms.• The periodicity of symptoms is |
| localities.Anopheles gambiae is one of the most | | | | less than 48 hours, andperiodicity is an unreliable |
| efficient vectorsbecause of its long lifespan and | | | | clinical feature, being present in only 30% of |
| preference for bitinghumans rather than other | | | | cases.• The patient feels ill all the time, with |
| animals.Additional routes for transmission of | | | | exacerbation ofsymptoms at the time of |
| malaria are:• Transplacental, which is | | | | paroxysms, which are similar to those described |
| uncommon• Transfusion associated, which is | | | | above but usually more severe.• Convulsions |
| uncommon in Europeand North America but | | | | occur in children. Vomiting and diarrhea are |
| common in endemic areas• Syringe | | | | sometimes prominent features in the history. |
| transmitted, among intravenous drug | | | | Herpes simplex vesicles may appear on the lips |
| abusers.Mention should be made of 'airport | | | | during the illness. Complications Complicated |
| malaria', which hasbeen documented in a range of | | | | malaria occurs in falciparum infections.• Altered |
| temperate countries,including the UK and France. | | | | consciousness in the presence of falciparum |
| Malaria can occur in peoplewho have never been | | | | malaria must be taken as a clinical indication of |
| to an endemic area and who are notat risk as a | | | | cerebral malaria. Neck rigidity is not a feature, |
| result of transfusion, shared syringes etc. | | | | although mild neck stiffness may be present. |
| Suchcases have occurred around airports, and it is | | | | Raised intracranial pressure is not seen and focal |
| thought thatmalarious mosquitoes that have been | | | | neurological signs are uncommon. Generalized |
| carried on internationalflights survive in the | | | | convulsions occur in children and adults.• |
| temperate country and biteindividuals there, | | | | Hypoglycaemia occurs in children, pregnant |
| infecting them and causing disease.Pathogenesis | | | | women with severe malaria and, less often, in |
| and pathologyThe pathogenesis of falciparum | | | | adults with severe infection.• Jaundice may be |
| malaria is complex andincompletely understood. | | | | a prominent physical sign in some patients with |
| The initial step is adhesion of themerozoite to the | | | | severe malaria. Haemolysis can cause this, but |
| erythrocyte membrane. Glycophorin A,the major | | | | tender hepatomegaly and abnormalities of liver |
| glycoprotein on erythrocyte membranes, is | | | | function suggest liver involvement.• Some |
| areceptor for binding specific surface proteins of | | | | degree of uraemia is common, but this resolves |
| falciparummerozoites. RBCs deficient in glycophorin | | | | after treatment. Uraemia with oliguria indicates |
| A are resistantto invasion. The Duffy blood group | | | | renal involvement.• Pulmonary oedema can |
| antigen is a specificreceptor for invasion by P. | | | | result from over hydration, but can also occur in |
| vivax merozoites, and theabsence of this antigen | | | | the patient whose infection is coming under |
| among populations from westAfrica explains the | | | | control.• Blackwater fever, due to acute |
| absence of vivax infections there.Changes in the | | | | massive intravascular haemolysis, became less |
| parasitized RBC result in sequestrationof RBCs | | | | common after chloroquine replaced quinine for |
| containing mature falciparum trophozoites in | | | | prophylaxis and treatment of malaria, suggesting |
| thepostcapillary venules. 1 Parasitized cells are less | | | | that quinine itself contributed to pathogenesis. It |
| flexiblethan normal cells. In addition, as the parasite | | | | does, however, occur in people who have not |
| matures theRBC becomes deformed and knobs | | | | taken quinine. The urine is black, the |
| develop on its surface.These knobs are an | | | | haemoglobin falls rapidly and jaundice appears. |
| expression of a parasite-derived | | | | Hypotension and tachycardia are usual, and renal |
| adhesion-promoting molecule which binds to | | | | failure may follow.• Gram-negative septicaemia |
| molecules such asICAM-1, VCAM-1 and | | | | has been reported in patients with severe malaria |
| thrombospondin expressed on thevascular | | | | and may be responsible for hypotension. |
| endothelium of the postcapillary venule. | | | | |