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Plasmodium falciparum
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== Pathogenicity == {{Main|Malaria}} The clinical symptoms of falciparum malaria are produced by the rupture and destruction of erythrocytes by the merozoites. High fever, called paroxysm, is the most basic indication. The fever has a characteristic cycle of hot stage, cold stage, and sweating stages.<ref name=":1">{{Citation|last1=Crutcher|first1=James M.|title=Malaria|date=1996|url=http://www.ncbi.nlm.nih.gov/books/NBK8584/|work=Medical Microbiology|editor-last=Baron|editor-first=Samuel|edition=4th|place=Galveston (TX)|publisher=University of Texas Medical Branch at Galveston|isbn=978-0-9631172-1-2|pmid=21413352|access-date=2022-02-01|last2=Hoffman|first2=Stephen L.}}</ref> Since each erythrocytic schizogony takes a cycle of 48 hours, i.e., two days, the febrile symptom appears every third day. This is the reason the infection is classically named tertian malignant fever (tertian, a derivative of a Latin word that means "third").<ref>{{Cite journal|last=Buchanan|first=Andrew|date=1901|title=Malignant Tertian Fever|journal=The Indian Medical Gazette|volume=36|issue=7|pages=256–258|issn=0019-5863|pmc=5164271|pmid=29004267}}</ref><ref>{{Cite journal|last1=Hemmer|first1=C. J.|last2=Loebermann|first2=M.|last3=Reisinger|first3=E. C.|date=2016|title=Fever after travel to tropical regions: Malaria and other emergencies|journal=Notfall & Rettungsmedizin|volume=19|issue=4|pages=263–268|doi=10.1007/s10049-016-0176-3|issn=1434-6222|pmc=7101662|pmid=32288635}}</ref> The most common symptoms are [[fever]] (>92% of cases), [[chills]] (79%), [[headaches]] (70%), and [[sweating]] (64%). [[Dizziness]], [[malaise]], [[myalgia|muscle pain]], [[abdominal pain]], [[nausea]], [[vomiting]], mild [[diarrhea]], and [[dry cough]] are also generally associated. [[Tachycardia|High heartrate]], [[jaundice]], [[pallor]], [[orthostatic hypotension]], [[hepatomegaly|enlarged liver]], and [[splenomegaly|enlarged spleen]] are also diagnosed.<ref name="trampuz03" /> The insoluble β-hematin crystal, [[Hemozoin|haemozoin]], produced from the digestion of haemoglobin of the RBCs is the main agent that affects body organs. Acting as a blood toxin, haemozoin-containing RBCs cannot be attacked by phagocytes during the immune response to malaria.<ref>{{Cite journal|last1=Corbett|first1=Yolanda|last2=Parapini|first2=Silvia|last3=Perego|first3=Federica|last4=Messina|first4=Valeria|last5=Delbue|first5=Serena|last6=Misiano|first6=Paola|last7=Falchi|first7=Mario|last8=Silvestrini|first8=Francesco|last9=Taramelli|first9=Donatella|last10=Basilico|first10=Nicoletta|last11=D'Alessandro|first11=Sarah|date=2021|title=Phagocytosis and activation of bone marrow-derived macrophages by ''Plasmodium falciparum'' gametocytes|journal=Malaria Journal|volume=20|issue=1|pages=81|doi=10.1186/s12936-021-03589-2|issn=1475-2875|pmc=7874634|pmid=33568138 |doi-access=free }}</ref> The phagocytes can ingest free haemozoins liberated after the rupture of RBCs by which they are induced to initiate chains of [[inflammatory reaction]] that results in increased fever.<ref>{{Cite journal|last1=Coronado|first1=Lorena M.|last2=Nadovich|first2=Christopher T.|last3=Spadafora|first3=Carmenza|date=2014|title=Malarial Hemozoin: From target to tool|journal=Biochimica et Biophysica Acta (BBA) - General Subjects|volume=1840|issue=6|pages=2032–2041|doi=10.1016/j.bbagen.2014.02.009|issn=0006-3002|pmc=4049529|pmid=24556123}}</ref><ref>{{Cite journal|last1=Tyberghein|first1=Ariane|last2=Deroost|first2=Katrien|last3=Schwarzer|first3=Evelin|last4=Arese|first4=Paolo|last5=Van den Steen|first5=Philippe E.|date=2014|title=Immunopathological effects of malaria pigment or hemozoin and other crystals|journal=BioFactors|volume=40|issue=1|pages=59–78|doi=10.1002/biof.1119|issn=1872-8081|pmid=23907956|s2cid=45386035|doi-access=free}}</ref> It is the haemozoin that is deposited in body organs such as the spleen and liver, as well as in kidneys and lungs, to cause their enlargement and discolouration.<ref>{{Cite journal|last1=Deroost|first1=Katrien|last2=Lays|first2=Natacha|last3=Noppen|first3=Sam|last4=Martens|first4=Erik|last5=Opdenakker|first5=Ghislain|last6=Van den Steen|first6=Philippe E.|date=2012|title=Improved methods for haemozoin quantification in tissues yield organ-and parasite-specific information in malaria-infected mice|journal=Malaria Journal|volume=11|pages=166|doi=10.1186/1475-2875-11-166|issn=1475-2875|pmc=3473299|pmid=22583751 |doi-access=free }}</ref><ref>{{Cite journal|last1=Pek|first1=Rini H.|last2=Yuan|first2=Xiaojing|last3=Rietzschel|first3=Nicole|last4=Zhang|first4=Jianbing|last5=Jackson|first5=Laurie|last6=Nishibori|first6=Eiji|last7=Ribeiro|first7=Ana|last8=Simmons|first8=William|last9=Jagadeesh|first9=Jaya|last10=Sugimoto|first10=Hiroshi|last11=Alam|first11=Md Zahidul|date=2019|title=Hemozoin produced by mammals confers heme tolerance|journal=eLife|volume=8|pages=e49503|doi=10.7554/eLife.49503|issn=2050-084X|pmc=6773446|pmid=31571584 |doi-access=free }}</ref> Because of this, haemozoin is also known as malarial pigment.<ref>{{Cite journal|last1=Olivier|first1=Martin|last2=Van Den Ham|first2=Kristin|last3=Shio|first3=Marina Tiemi|last4=Kassa|first4=Fikregabrail Aberra|last5=Fougeray|first5=Sophie|date=2014|title=Malarial pigment hemozoin and the innate inflammatory response|journal=Frontiers in Immunology|volume=5|pages=25|doi=10.3389/fimmu.2014.00025|issn=1664-3224|pmc=3913902|pmid=24550911|doi-access=free}}</ref><ref>{{Cite journal|last1=Shio|first1=Marina T.|last2=Kassa|first2=Fikregabrail A.|last3=Bellemare|first3=Marie-Josée|last4=Olivier|first4=Martin|date=2010|title=Innate inflammatory response to the malarial pigment hemozoin|url=https://pubmed.ncbi.nlm.nih.gov/20637890|journal=Microbes and Infection|volume=12|issue=12–13|pages=889–899|doi=10.1016/j.micinf.2010.07.001|issn=1769-714X|pmid=20637890}}</ref> Unlike other forms of malaria, which show regular periodicity of fever, falciparum, though exhibiting a 48-hour cycle, usually presents as irregular bouts of fever''.'' This difference is due to the ability of ''P. falciparum'' merozoites to invade a large number of RBCs sequentially without coordinated intervals, which is not seen in other malarial parasites.<ref name=":1"/> ''P. falciparum'' is therefore responsible for almost all severe human illnesses and deaths due to malaria, in a condition called pernicious or complicated or severe malaria. Complicated malaria occurs more commonly in children under age 5,<ref name="trampuz03" /> and sometimes in pregnant women (a condition specifically called [[pregnancy-associated malaria]]).<ref name="moya14">{{cite journal|last1=Moya-Alvarez|first1=Violeta|last2=Abellana|first2=Rosa|last3=Cot|first3=Michel|date=2014|title=Pregnancy-associated malaria and malaria in infants: an old problem with present consequences|journal=Malaria Journal|volume=13|issue=1|pages=271|doi=10.1186/1475-2875-13-271|pmc=4113781|pmid=25015559 |doi-access=free }}</ref> Women become susceptible to severe malaria during their first pregnancy. Susceptibility to severe malaria is reduced in subsequent pregnancies due to increased antibody levels against variant surface [[antigens]] that appear on infected erythrocytes.<ref>{{cite journal|last1=Kourtis|first1=Athena P.|last2=Read|first2=Jennifer S.|last3=Jamieson|first3=Denise J.|date=2014|title=Pregnancy and Infection|journal=New England Journal of Medicine|volume=370|issue=23|pages=2211–2218|doi=10.1056/NEJMra1213566|pmc=4459512|pmid=24897084}}</ref> But increased immunity in the mother increases susceptibility to malaria in newborn babies.<ref name="moya14" /> ''P. falciparum'' works via sequestration, a process by which group of infected RBCs are clustered, which is not exhibited by any other species of malarial parasites.<ref>{{Cite journal|last1=Tembo|first1=Dumizulu L.|last2=Nyoni|first2=Benjamin|last3=Murikoli|first3=Rekah V.|last4=Mukaka|first4=Mavuto|last5=Milner|first5=Danny A.|last6=Berriman|first6=Matthew|last7=Rogerson|first7=Stephen J.|last8=Taylor|first8=Terrie E.|last9=Molyneux|first9=Malcolm E.|last10=Mandala|first10=Wilson L.|last11=Craig|first11=Alister G.|date=2014|title=Differential PfEMP1 expression is associated with cerebral malaria pathology|journal=PLOS Pathogens|volume=10|issue=12|pages=e1004537|doi=10.1371/journal.ppat.1004537|pmc=4256257|pmid=25473835 |doi-access=free }}</ref> The mature schizonts change the surface properties of infected erythrocytes, causing them to stick to blood vessel walls (cytoadherence). This leads to obstruction of the microcirculation and results in dysfunction of multiple organs, such as the brain in [[cerebral malaria]].<ref>{{cite journal |last1=Dondorp |first1=Arjen M. |last2=Pongponratn |first2=Emsri |last3=White |first3=Nicholas J. |title=Reduced microcirculatory flow in severe falciparum malaria: pathophysiology and electron-microscopic pathology |journal=Acta Tropica |date=February 2004 |volume=89 |issue=3 |pages=309–317 |doi=10.1016/j.actatropica.2003.10.004 |pmid=14744557}}</ref> Cerebral malaria is the most dangerous condition of any malarial infection and the most severe form of [[neurological disorders]]. According to the WHO definition, the clinical symptom is indicated by coma and diagnosis by a high level of merozoites in the peripheral blood samples.<ref>{{Cite journal|last=Anonymous|date=2000|title=Severe falciparum malaria. World Health Organization, Communicable Diseases Cluster|url=https://pubmed.ncbi.nlm.nih.gov/11103309/|journal=Transactions of the Royal Society of Tropical Medicine and Hygiene|volume=94|issue=Suppl 1 |pages=S1–90|issn=0035-9203|pmid=11103309}}</ref><ref>{{Cite journal|last1=Omar|first1=Mohamed|last2=Marchionni|first2=Luigi|last3=Häcker|first3=Georg|last4=Badr|first4=Mohamed Tarek|date=2021|title=Host Blood Gene Signatures Can Detect the Progression to Severe and Cerebral Malaria|journal=Frontiers in Cellular and Infection Microbiology|volume=11|pages=743616|doi=10.3389/fcimb.2021.743616|issn=2235-2988|pmc=8569259|pmid=34746025|doi-access=free}}</ref> It is the deadliest form of malaria, and to it are attributed to 0.2 million to over a million annual deaths throughout the ages. Most deaths are of children of below 5 years of age.<ref>{{Cite journal|last1=Murphy|first1=S. C.|last2=Breman|first2=J. G.|date=2001|title=Gaps in the childhood malaria burden in Africa: cerebral malaria, neurological sequelae, anemia, respiratory distress, hypoglycemia, and complications of pregnancy|url=https://www.ncbi.nlm.nih.gov/books/NBK2621/|journal=The American Journal of Tropical Medicine and Hygiene|volume=64|issue=1-2 Suppl|pages=57–67|doi=10.4269/ajtmh.2001.64.57|pmid=11425178|s2cid=847217 |doi-access=free}}</ref><ref>{{Cite journal|last=Breman|first=J. G.|date=2001|title=The ears of the hippopotamus: manifestations, determinants, and estimates of the malaria burden|journal=The American Journal of Tropical Medicine and Hygiene|volume=64|issue=1-2 Suppl|pages=1–11|doi=10.4269/ajtmh.2001.64.1|issn=0002-9637|pmid=11425172|doi-access=free}}</ref> It occurs when the merozoites invade the brain and cause brain damage of varying degrees. Death is caused by oxygen deprivation (hypoxia) due to inflammatory cytokine production and vascular leakage induced by the merozoites.<ref>{{Cite journal|last1=Luzolo|first1=Ange Landela|last2=Ngoyi|first2=Dieudonné Mumba|date=2019|title=Cerebral malaria|url=https://pubmed.ncbi.nlm.nih.gov/30658131|journal=Brain Research Bulletin|volume=145|pages=53–58|doi=10.1016/j.brainresbull.2019.01.010|issn=1873-2747|pmid=30658131|s2cid=58560596}}</ref> Among the surviving individuals, persistent medical conditions such as neurological impairment, [[intellectual disability]], and [[Emotional and behavioral disorders|behavioural problems]] exist. Among them, [[epilepsy]] is the most common condition, and cerebral malaria is the leading cause of acquired epilepsy among African children.<ref>{{Cite journal|last1=Idro|first1=Richard|last2=Marsh|first2=Kevin|last3=John|first3=Chandy C|last4=Newton|first4=Charles RJ|date=2010|title=Cerebral Malaria; Mechanisms Of Brain Injury And Strategies For Improved Neuro-Cognitive Outcome|journal=Pediatric Research|volume=68|issue=4|pages=267–274|doi=10.1203/PDR.0b013e3181eee738|issn=0031-3998|pmc=3056312|pmid=20606600}}</ref> The reappearance of falciparum symptom, a phenomenon called recrudescence, is often seen in survivors.<ref>{{Cite journal|last=Shanks|first=G. Dennis|date=2015|title=Historical review: does stress provoke ''Plasmodium falciparum'' recrudescence?|url=https://pubmed.ncbi.nlm.nih.gov/25918217|journal=Transactions of the Royal Society of Tropical Medicine and Hygiene|volume=109|issue=6|pages=360–365|doi=10.1093/trstmh/trv032|issn=1878-3503|pmid=25918217}}</ref> Recrudescence can occur even after successful antimalarial medication.<ref>{{Cite journal|last1=Teuscher|first1=Franka|last2=Gatton|first2=Michelle L.|last3=Chen|first3=Nanhua|last4=Peters|first4=Jennifer|last5=Kyle|first5=Dennis E.|last6=Cheng|first6=Qin|date=2010|title=Artemisinin-induced dormancy in plasmodium falciparum: duration, recovery rates, and implications in treatment failure|journal=The Journal of Infectious Diseases|volume=202|issue=9|pages=1362–1368|doi=10.1086/656476|issn=1537-6613|pmc=2949454|pmid=20863228}}</ref><ref>{{Cite journal|last=WorldWide Antimalarial Resistance Network (WWARN) Lumefantrine PK/PD Study Group|date=2015|title=Artemether-lumefantrine treatment of uncomplicated Plasmodium falciparum malaria: a systematic review and meta-analysis of day 7 lumefantrine concentrations and therapeutic response using individual patient data|journal=BMC Medicine|volume=13|pages=227|doi=10.1186/s12916-015-0456-7|issn=1741-7015|pmc=4574542|pmid=26381375 |doi-access=free }}</ref> It may take a few months or even several years. In some individuals, it takes as long as three years.<ref>{{Cite journal|last1=Al Hammadi|first1=Ahmed|last2=Mitchell|first2=Michael|last3=Abraham|first3=George M.|last4=Wang|first4=Jennifer P.|date=2017|title=Recrudescence of Plasmodium falciparum in a Primigravida After Nearly 3 Years of Latency|journal=The American Journal of Tropical Medicine and Hygiene|volume=96|issue=3|pages=642–644|doi=10.4269/ajtmh.16-0803|issn=1476-1645|pmc=5361538|pmid=28044045}}</ref> In isolated cases, the duration can reach or exceed 10 years.<ref>{{Cite journal|last1=Salas-Coronas|first1=Joaquín|last2=Soriano-Pérez|first2=Manuel Jesús|last3=Lozano-Serrano|first3=Ana B.|last4=Pérez-Moyano|first4=Rosario|last5=Porrino-Herrera|first5=Carmen|last6=Cabezas-Fernández|first6=María Teresa|date=2017|title=Symptomatic Falciparum Malaria After Living in a Nonendemic Area for 10 Years: Recrudescence or Indigenous Transmission?|journal=The American Journal of Tropical Medicine and Hygiene|volume=96|issue=6|pages=1427–1429|doi=10.4269/ajtmh.17-0031|issn=1476-1645|pmc=5462582|pmid=28719260}}</ref><ref>{{Cite journal|last1=Ismail|first1=Arif|last2=Auclair|first2=Francois|last3=McCarthy|first3=Anne E.|date=2020|title=Recrudescence of chronic Plasmodium falciparum malaria 13 years after exposure|url=https://pubmed.ncbi.nlm.nih.gov/31712180/|journal=Travel Medicine and Infectious Disease|volume=33|pages=101518|doi=10.1016/j.tmaid.2019.101518|issn=1873-0442|pmid=31712180|s2cid=207949553}}</ref> It is also a common incident among pregnant women.<ref>{{Cite journal|last1=Mayor|first1=Alfredo|last2=Serra-Casas|first2=Elisa|last3=Bardají|first3=Azucena|last4=Sanz|first4=Sergi|last5=Puyol|first5=Laura|last6=Cisteró|first6=Pau|last7=Sigauque|first7=Betuel|last8=Mandomando|first8=Inacio|last9=Aponte|first9=John J.|last10=Alonso|first10=Pedro L.|last11=Menéndez|first11=Clara|date=2009|title=Sub-microscopic infections and long-term recrudescence of Plasmodium falciparum in Mozambican pregnant women|journal=Malaria Journal|volume=8|pages=9|doi=10.1186/1475-2875-8-9|issn=1475-2875|pmc=2633011|pmid=19134201 |doi-access=free }}</ref><ref>{{Cite journal|last1=Laochan|first1=Natthapon|last2=Zaloumis|first2=Sophie G.|last3=Imwong|first3=Mallika|last4=Lek-Uthai|first4=Usa|last5=Brockman|first5=Alan|last6=Sriprawat|first6=Kanlaya|last7=Wiladphaingern|first7=Jacher|last8=White|first8=Nicholas J.|last9=Nosten|first9=François|last10=McGready|first10=Rose|date=2015|title=Intervals to Plasmodium falciparum recurrence after anti-malarial treatment in pregnancy: a longitudinal prospective cohort|journal=Malaria Journal|volume=14|pages=221|doi=10.1186/s12936-015-0745-9|issn=1475-2875|pmc=4449611|pmid=26017553 |doi-access=free }}</ref>
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