Hilary Pathology 2014 Notes

Pathology- Experimental and clinical evidence. Hilary term 2014

Malaria:

• It is caused by four different types of PLASMODIA: vivax, ovale, malariae, and falciparum. The first and last are the most common causes.

• The VECTOR for the plasmodia is the FEMALE ANOPHELES MOSQUITO.

• Clinical:

MOST infections with malaria-causing agents are CLINICALLY SILENT, reflecting the ability of adaptive immune mechanisms to prevent disease. In NON-IMMUNE individuals, however, infections are more clinically overt, and a minority of these can become SEVERE OR LIFE THREATENING, manifesting a range of discrete and overlapping disease syndromes of complex aetiologies. Those dying of malaria can have multiple-organ or systemic involvement. Overall patterns of disease depend markedly on the AGE and the PREVIOUS IMMUNOLOGICAL EXPERIENCE of the host, and TRANSMISSION DYNAMICS: in areas of high malaria transmission, the burden of disease is borne by YOUNG CHILDREN (who have NOT YET DEVELOPED IMMUNITY); life-threatening disease in this setting typically consists of metabolic acidosis (which leads to respiratory distress), cerebral malaria and severe malarial anaemia. However, in areas of lower transmission, primary infections might occur in ADULTHOOD. Moreover, HOST GENETICS and IMMUNOLOGICAL RESPONSES determine the individual OUTCOME.

• UNCOMPLICATED MALARIA symptoms can be non-specific and easily missed by clinicians. Fever (spike can reach 41C), chills headache, weakness, vomiting and diarrhoea. The FEVER, CHILLS and SWEATS are experienced PERIODICALLY in a sort of cyclical cycle.

• INCUBATION TIME is about 2 weeks.

• SPLENOMEGALY seen in most patients, HEPATOMEGALY in about a third, and ANAEMIA is common.

• If left UNTREATED, malaria caused by P. falciparum is potentially life-threatening as a result of extensive BRAIN (cerebral malaria) and KIDNEY damage, SEVERE ANAEMIA and ACUTE RESPIRATORY DISTRESS SYNDROME. Malaria caused by the OTHER 3 SPECIES is usually self-limited.

• People who are HETEROZYGOUS for SICKLE CELL ANAEMIA are PROTECTED because their RBCs have too little ATPase activity.

• Life-cycle: there are TWO PHASES. 1) The sexual cycle which occurs primarily in the MOSQUITOES and 2) the asexual cycle which occurs in HUMANS (these are the intermediate hosts). However, the sexual cycle is INITIATED in humans due to the formation of the gametocytes within the RBCs- however this is COMPLETED in the mosquitoes as this is the site where the two games FUSE. This INTERDEPENDENCE means that the mosquito is not a “flying syringe”; there is an OBLIGATORY LIFE-CYCLE within the vector. The parasite that goes in in the vector is NOT THE SAME as the one that come out.

• The parasite enters the BLOOD from a mosquito bite- it originates from the mosquitoes SALIVARY GLANDS. At this stage it is in a SPECIFICALLY DIFFERENTIATED FORM that is “injectable” – sporozoite; i.e. it has gone through the obligatory stage of the life-cycle WITHIN THE MOSQUITO.

• It then makes its way IMMEDIATELY to the liver. These liver-stage parasites, schizonts, then undergo a SERIES OF ASEXUAL MULTIPLICATIONS (extra-erythrocytic schizogony) over the next 14 days, resulting in thousands of merozoites which BURST from the hepatocyte.

• The released merozoites have an ACTIVE MECHANSIM for INJECTION into RBCs, and infect them. The organism then DIFFERENTIATES into a ring-shaped trophozoite; this grows into an AMEBOID FORM, and an EQUIVALENT series of ASEXUAL multiplication cycles (erythrocytic schizogony) are initiated within these cells, which produces a SCHIZONT filled with new INFECTIVE MEROZOITES, at which point the cells burst and the infective cycle begins anew.

• The PERIODIC RELEASE of merozoites from RBCs (the erythrocytic stage takes about 48 hours) in this way causes the typical RECURRENT symptoms of chills, fever and sweats described above. I.e. the blood-stage parasites are responsible for the CLINICAL MANIFESTATIONS of the disease.

• Some merozoites in RBCs then DIFFERENTIATE into MALE GAMETOCYTES and others into FEMALE GAMETOCYTES. These have no other function other than hanging around in the blood WAITING TO BE TAKEN UP in a MOSQUITO BITE.

• Once both the male and female gametocytes and INGESTED by the female anopheles mosquito, the male one undergoes a RAPID NUCLEAR DIVISION, producing 8 flagellated microgametocytes which PENETRATE the female gametocyte in the mosquito GUT, generating zygotes.

• The zygote (or once MOTILE and ELONGATED known as ookinetes) then ENCYSTS on the exterior of the gut wall, at this stage being known as an oocyst. It then RUPTURES, releasing hundreds of sporozoites into the mosquito body cavity, where they eventually migrate to the mosquito SALIVARY GLAND. This part of the life-cycle is called the sporogenic cycle.

• At some points during the life-cycle it’s ONLY A FEW CELLS that establish the next stage of the infection whereas at other points it’s MANY MORE. These “pinch points” are relevant for VACCINE DEVELOPMENT.

Pathogenesis and immune evasion:

• The HETEROGENEITY of the syndromes might arise from: the SITE-SPECIFIC LOCALIZATION of parasitized red blood cells among target organs; the local and systemic action of BIOACTIVE PARASITE PRODUCTS (e.g. toxins); the local and systemic production of PRO-INFLAMMATORY cytokines and chemokines by the innate and adaptive immune systems in response to PARASITE PRODUCTS; and the resultant activation and recruitment of INFLAMMATORY CELLS. According to this view, diverse organ-specific or systemic disease syndromes are end-stage processes of ATYPICAL INFLAMMATORY CASCADES that are initiated in target organs by pathogen products and are maintained by infiltrating cells through positive-feedback cycles. In most cases, immune homeostasis through Treg cells and antiinflammatory mediators corrects the cascade effect, and responses are adequately downregulated. Indeed, the CHRONIC TOLERANCE built up in areas of endemic exposure causes INCREASED SUSCEPTIBILITY to other parasites e.g. Salmonella...

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