COVID-19

== Pathophysiology ==
[[File:Fpubh-08-00383-g003.jpg|thumb|COVID‑19 [[pathogenesis]]]]

The SARS-CoV-2 virus can infect a wide range of cells and systems of the body. COVID‑19 is most known for affecting the upper respiratory tract (sinuses, nose, and throat) and the lower respiratory tract (windpipe and lungs).<ref name="pmid33132005">{{#invoke:cite journal || vauthors = Harrison AG, Lin T, Wang P | title = Mechanisms of SARS-CoV-2 Transmission and Pathogenesis | journal = Trends in Immunology | volume = 41 | issue = 12 | pages = 1100–1115 | date = December 2020 | pmid = 33132005 | pmc = 7556779 | doi = 10.1016/j.it.2020.10.004 }}</ref> The lungs are the organs most affected by COVID‑19 because the virus accesses host cells via the [[Receptor (biochemistry)|receptor]] for the enzyme [[angiotensin-converting enzyme 2]] (ACE2), which is most abundant on the surface of [[Type II cell|type II alveolar cells]] of the lungs.<ref>{{#invoke:cite journal || vauthors = Verdecchia P, Cavallini C, Spanevello A, Angeli F | title = The pivotal link between ACE2 deficiency and SARS-CoV-2 infection | journal = European Journal of Internal Medicine | volume = 76 | pages = 14–20 | date = June 2020 | pmid = 32336612 | pmc = 7167588 | doi = 10.1016/j.ejim.2020.04.037 }}</ref> The virus uses a special surface glycoprotein called a "[[coronavirus spike protein|spike]]" to connect to the ACE2 receptor and enter the host cell.<ref name="Nature Microbiology">{{#invoke:cite journal || vauthors = Letko M, Marzi A, Munster V | title = Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses | journal = Nature Microbiology | volume = 5 | issue = 4 | pages = 562–569 | date = April 2020 | pmid = 32094589 | pmc = 7095430 | doi = 10.1038/s41564-020-0688-y | doi-access = free | title-link = doi }}</ref>

=== Respiratory tract ===
Following viral entry, COVID‑19 infects the ciliated epithelium of the nasopharynx and upper airways.<ref>{{#invoke:cite journal || vauthors = Marik PE, Iglesias J, Varon J, Kory P | title = A scoping review of the pathophysiology of COVID-19 | journal = International Journal of Immunopathology and Pharmacology | volume = 35 | pages = 20587384211048026 | date = January 2021 | pmid = 34569339 | pmc = 8477699 | doi = 10.1177/20587384211048026 }}</ref>

Autopsies of people who died of COVID‑19 have found [[diffuse alveolar damage]], and lymphocyte-containing inflammatory infiltrates within the lung.<ref name="Cureus">{{#invoke:cite journal || vauthors = Eketunde AO, Mellacheruvu SP, Oreoluwa P | title = A Review of Postmortem Findings in Patients With COVID-19 | journal = Cureus | volume = 12 | issue = 7 | pages = e9438 | date = July 2020 | pmid = 32864262 | pmc = 7451084 | doi = 10.7759/cureus.9438 | publisher = Cureus, Inc. | s2cid = 221352704 | doi-access = free | title-link = doi }}</ref>

=== Nervous system ===
One common symptom, loss of smell, results from [[Impact of COVID-19 on neurological, psychological and other mental health outcomes|infection of the support cells of the olfactory epithelium]], with subsequent damage to the [[Olfactory receptor neuron|olfactory neurons]].<ref name="Meunier-2020">{{#invoke:cite journal ||vauthors = Meunier N, Briand L, Jacquin-Piques A, Brondel L, Pénicaud L |title = COVID 19-Induced Smell and Taste Impairments: Putative Impact on Physiology |journal = Frontiers in Physiology |volume = 11 |pages = 625110 |date = June 2020 |pmid = 33574768 |pmc = 7870487 |doi = 10.3389/fphys.2020.625110 |doi-access = free |title-link = doi }}</ref> The involvement of both the central and peripheral nervous system in COVID‑19 has been reported in many medical publications.<ref name="Guerrero2020">{{#invoke:cite journal ||vauthors = Guerrero JI, Barragán LA, Martínez JD, Montoya JP, Peña A, Sobrino FE, Tovar-Spinoza Z, Ghotme KA |title = Central and peripheral nervous system involvement by COVID-19: a systematic review of the pathophysiology, clinical manifestations, neuropathology, neuroimaging, electrophysiology, and cerebrospinal fluid findings |journal = BMC Infectious Diseases |date = June 2021 |volume = 21 |issue = 1 |page = 515 |doi = 10.1186/s12879-021-06185-6| pmid = 34078305 |pmc = 8170436 |doi-access=free |title-link=doi }}</ref> It is clear that many people with [[Impact of COVID-19 on neurological, psychological and other mental health outcomes|COVID-19 exhibit neurological or mental health issues]]. The virus is not detected in the [[central nervous system]] (CNS) of the majority of COVID-19 patients with [[Impact of the COVID-19 pandemic on neurological, psychological and other mental health outcomes|neurological issues]]. However, SARS-CoV-2 has been detected at low levels in the brains of those who have died from COVID‑19, but these results need to be confirmed.<ref name="Pezzini2020">{{#invoke:cite journal ||vauthors = Pezzini A, Padovani A |title = Lifting the mask on neurological manifestations of COVID-19 |journal = Nature Reviews. Neurology |volume = 16 |issue = 11 |pages = 636–644 |date = November 2020 |pmid = 32839585 |pmc = 7444680 |doi = 10.1038/s41582-020-0398-3 }}</ref> While virus has been detected in [[cerebrospinal fluid]] of autopsies, the exact mechanism by which it invades the CNS remains unclear and may first involve invasion of peripheral nerves given the low levels of ACE2 in the brain.<ref>{{#invoke:cite journal ||vauthors = Li YC, Bai WZ, Hashikawa T |title = The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients |journal = Journal of Medical Virology |volume = 92 |issue = 6 |pages = 552–555 |date = June 2020 |pmid = 32104915 |pmc = 7228394 |doi = 10.1002/jmv.25728 |title-link = doi |doi-access = free }}</ref><ref>{{#invoke:cite journal ||vauthors = Baig AM, Khaleeq A, Ali U, Syeda H |title = Evidence of the COVID-19 Virus Targeting the CNS: Tissue Distribution, Host-Virus Interaction, and Proposed Neurotropic Mechanisms |journal = ACS Chemical Neuroscience |volume = 11 |issue = 7 |pages = 995–998 |date = April 2020 |pmid = 32167747 |pmc = 7094171 |doi= 10.1021/acschemneuro.0c00122 }}</ref><ref>{{#invoke:cite journal ||vauthors = Yavarpour-Bali H, Ghasemi-Kasman M |title = Update on neurological manifestations of COVID-19 |journal = Life Sciences |volume = 257 |pages = 118063 |date = September 2020 |pmid = 32652139 |pmc = 7346808 |doi = 10.1016/j.lfs.2020.118063 }}</ref> The virus may also enter the bloodstream from the lungs and cross the blood–brain barrier to gain access to the CNS, possibly within an infected white blood cell.<ref name="Pezzini2020" />
[[File:Ijms-21-05932-g003.webp|thumb|[[Host tropism|Tropism]] and [[Multiple organ dysfunction syndrome|multiple organ injuries]] in SARS-CoV-2 infection]] Research conducted when Alpha was the dominant variant has suggested COVID-19 may cause brain damage.<ref>{{#invoke:Cite journal ||last1=Douaud |first1=Gwenaëlle |last2=Lee |first2=Soojin |last3=Alfaro-Almagro |first3=Fidel |last4=Arthofer |first4=Christoph |last5=Wang |first5=Chaoyue |last6=McCarthy |first6=Paul |last7=Lange |first7=Frederik |last8=Andersson |first8=Jesper L. R. |last9=Griffanti |first9=Ludovica |last10=Duff |first10=Eugene |last11=Jbabdi |first11=Saad |last12=Taschler |first12=Bernd |last13=Keating |first13=Peter |last14=Winkler |first14=Anderson M. |last15=Collins |first15=Rory |last16=Matthews |first16= Paul M. |last17=Naomi |first17=Allen |last18=Miller |first18=Karla L. |last19=Nichols |first19=Thomas E. |last20=Smith |first20=Stephen M. |date=March 2022 |title=SARS-CoV-2 is associated with changes in brain structure in UK Biobank |journal=[[Nature (journal)|Nature]] |volume=604 |issue=7907 |pages=697–707 |doi=10.1038/s41586-022-04569-5 |issn=1476-4687 |lccn=12037118 |oclc=01586310 |pmc=9046077 |pmid=35255491 |bibcode=2022Natur.604..697D |doi-access=free}}</ref> Later research showed that all variants studied (including Omicron) killed brain cells, but the exact cells killed varied by variant.<ref>{{#invoke:Cite journal ||last1=Proust |first1=Alizé
|last2= Queval|first2= Christophe J. |last3= Harvey|first3= Ruth |last4= Adams|first4= Lorin |last5= Bennett|first5= Michael |last6= Wilkinson |first6= Robert J.|date= 2023 |title= Diferential efects of SARS-CoV-2 variants on central nervous system cells and blood–brain barrier functions|journal= Journal of Neuroinflammation |volume=20 |issue=184 |page=184
|doi=10.1186/s12974-023-02861-3
|pmid=37537664
|pmc=10398935
|doi-access=free
}}</ref> It is unknown if such damage is temporary or permanent.<ref>{{#invoke:Cite news ||last1=Geddes |first1=Linda |last2=Sample |first2=Ian |date=7 March 2022 |title=Covid can shrink brain and damage its tissue, finds research |work=[[The Guardian]] |url=https://www.theguardian.com/world/2022/mar/07/covid-can-shrink-brain-and-damage-its-tissue-finds-research |url-status=live |access-date=4 September 2023 |archive-url=https://web.archive.org/web/20220307161107/https://www.theguardian.com/world/2022/mar/07/covid-can-shrink-brain-and-damage-its-tissue-finds-research |archive-date=7 March 2022}}</ref><ref>{{#invoke:Cite news ||last=Morelle |first=Rebecca |date=7 March 2022 |title=Scans reveal how Covid may change the brain |work=[[BBC News]] |publisher=[[BBC]] |url=https://www.bbc.com/news/health-60591487 |url-status= |access-date=4 September 2023}}</ref> Observed individuals infected with COVID-19 (most with mild cases) experienced an additional 0.2% to 2% of brain tissue lost in regions of the brain connected to the sense of smell compared with uninfected individuals, and the overall effect on the brain was equivalent on average to at least one extra year of normal ageing; infected individuals also scored lower on several cognitive tests. All effects were more pronounced among older ages.<ref>{{#invoke:Cite web||url=https://www.nbcnews.com/health/health-news/long-covid-even-mild-covid-linked-damage-brain-months-infection-rcna18959|title=Even mild Covid is linked to brain damage months after illness, scans show |date=7 March 2022 |publisher=NBC News}}</ref>

=== Gastrointestinal tract ===
The virus also affects gastrointestinal organs as ACE2 is abundantly expressed in the [[gland]]ular cells of [[Stomach|gastric]], [[Duodenum|duodenal]] and [[Rectum|rectal]] [[epithelium]]<ref name="Gu-2020">{{#invoke:cite journal || vauthors = Gu J, Han B, Wang J | title = COVID-19: Gastrointestinal Manifestations and Potential Fecal-Oral Transmission | journal = Gastroenterology | volume = 158 | issue = 6 | pages = 1518–1519 | date = May 2020 | pmid = 32142785 | pmc = 7130192 | doi = 10.1053/j.gastro.2020.02.054 }}</ref> as well as [[Endothelium|endothelial]] cells and [[enterocyte]]s of the [[small intestine]].<ref name="pmid32343593">{{#invoke:cite journal || vauthors = Mönkemüller K, Fry L, Rickes S | title = COVID-19, coronavirus, SARS-CoV-2 and the small bowel | journal = Revista Espanola de Enfermedades Digestivas | volume = 112 | issue = 5 | pages = 383–388 | date = May 2020 | pmid = 32343593 | doi = 10.17235/reed.2020.7137/2020 | s2cid = 216645754 }}</ref>

=== Cardiovascular system ===
The virus can cause [[Myocardial infarction|acute myocardial injury]] and chronic damage to the [[Circulatory system|cardiovascular system]].<ref>{{#invoke:cite journal || vauthors = Almamlouk R, Kashour T, Obeidat S, Bois MC, Maleszewski JJ, Omrani OA, Tleyjeh R, Berbari E, Chakhachiro Z, Zein-Sabatto B, Gerberi D, Tleyjeh IM, Paniz Mondolfi AE, Finn AV, Duarte-Neto AN, Rapkiewicz AV, Frustaci A, Keresztesi AA, Hanley B, Märkl B, Lardi C, Bryce C, Lindner D, Aguiar D, Westermann D, Stroberg E, Duval EJ, Youd E, Bulfamante GP, Salmon I, Auer J, Maleszewski JJ, Hirschbühl K, Absil L, Barton LM, Ferraz da Silva LF, Moore L, Dolhnikoff M, Lammens M, Bois MC, Osborn M, Remmelink M, Nascimento Saldiva PH, Jorens PG, Craver R, Aparecida de Almeida Monteiro R, Scendoni R, Mukhopadhyay S, Suzuki T, Mauad T, Fracasso T, Grimes Z  | title = COVID-19-Associated cardiac pathology at the postmortem evaluation: a collaborative systematic review | journal = Clinical Microbiology and Infection | volume = 28 | issue = 8 | pages = 1066–1075 | date = August 2022 | pmid = 35339672 | pmc = 8941843 | doi = 10.1016/j.cmi.2022.03.021 }}</ref><ref name="Zheng-2020">{{#invoke:cite journal || vauthors = Zheng YY, Ma YT, Zhang JY, Xie X | title = COVID-19 and the cardiovascular system | journal = Nature Reviews. Cardiology | volume = 17 | issue = 5 | pages = 259–260 | date = May 2020 | pmid = 32139904 | pmc = 7095524 | doi = 10.1038/s41569-020-0360-5 }}</ref> An acute cardiac injury was found in 12% of infected people admitted to the hospital in Wuhan, China,<ref name="Huang24Jan2020" /> and is more frequent in severe disease.<ref>{{#invoke:Cite web|| title=Coronavirus disease 2019 (COVID-19): Myocardial infarction and other coronary artery disease issues | website=UpToDate | url=https://www.uptodate.com/contents/coronavirus-disease-2019-covid-19-myocardial-infarction-and-other-coronary-artery-disease-issues | access-date=28 September 2020}}</ref> Rates of cardiovascular symptoms are high, owing to the systemic inflammatory response and immune system disorders during disease progression, but acute myocardial injuries may also be related to ACE2 receptors in the heart.<ref name="Zheng-2020" /> ACE2 receptors are highly expressed in the heart and are involved in heart function.<ref name="Zheng-2020" /><ref>{{#invoke:cite journal || vauthors = Turner AJ, Hiscox JA, Hooper NM | title = ACE2: from vasopeptidase to SARS virus receptor | journal = Trends in Pharmacological Sciences | volume = 25 | issue = 6 | pages = 291–4 | date = June 2004 | pmid = 15165741 | pmc = 7119032 | doi = 10.1016/j.tips.2004.04.001 | doi-access = free | title-link = doi }}</ref>

A high incidence of [[thrombosis]] and [[venous thromboembolism]] occurs in people transferred to [[intensive care unit]]s with COVID‑19 infections, and may be related to poor prognosis.<ref>{{#invoke:cite journal || vauthors = Abou-Ismail MY, Diamond A, Kapoor S, Arafah Y, Nayak L | title = The hypercoagulable state in COVID-19: Incidence, pathophysiology, and management | journal = Thrombosis Research | volume = 194 | pages = 101–115 | date = October 2020 | pmid = 32788101 | pmc = 7305763 | doi = 10.1016/j.thromres.2020.06.029 | publisher = Elsevier BV }}</ref> Blood vessel dysfunction and clot formation (as suggested by high [[D-dimer]] levels caused by blood clots) may have a significant role in mortality, incidents of clots leading to [[pulmonary embolism]]s, and [[stroke|ischaemic events]] (strokes) within the brain found as complications leading to death in people infected with COVID‑19.<ref name=Science/> Infection may initiate a chain of [[vasoconstriction|vasoconstrictive responses]] within the body, including pulmonary vasoconstriction {{ndash}} a possible mechanism in which oxygenation decreases during pneumonia.<ref name="Science">{{#invoke:cite journal || vauthors = Wadman M |doi=10.1126/science.abc3208 |title=How does coronavirus kill? Clinicians trace a ferocious rampage through the body, from brain to toes |journal=Science |date=April 2020 |doi-access = free | title-link = doi }}</ref> Furthermore, damage of [[arterioles]] and [[capillaries]] was found in brain tissue samples of people who died from COVID‑19.<ref>{{#invoke:cite news ||title=NIH study uncovers blood vessel damage and inflammation in COVID-19 patients' brains but no infection |url=https://www.nih.gov/news-events/news-releases/nih-study-uncovers-blood-vessel-damage-inflammation-covid-19-patients-brains-no-infection |access-date=17 January 2021 |work=National Institutes of Health (NIH) |date=30 December 2020 }}</ref><ref>{{#invoke:cite journal || vauthors = Lee MH, Perl DP, Nair G, Li W, Maric D, Murray H, Dodd SJ, Koretsky AP, Watts JA, Cheung V, Masliah E, Horkayne-Szakaly I, Jones R, Stram MN, Moncur J, Hefti M, Folkerth RD, Nath A  | title = Microvascular Injury in the Brains of Patients with Covid-19 | journal = The New England Journal of Medicine | volume = 384 | issue = 5 | pages = 481–483 | date = February 2021 | pmid = 33378608 | pmc = 7787217 | doi = 10.1056/nejmc2033369 }}</ref>

COVID{{nbhyph}}19 may also cause substantial structural changes to [[blood cell]]s, sometimes persisting for months after hospital discharge.<ref>{{#invoke:cite journal || vauthors = Kubánková M, Hohberger B, Hoffmanns J, Fürst J, Herrmann M, Guck J, Kräter M  | title = Physical phenotype of blood cells is altered in COVID-19 | journal = Biophysical Journal | volume = 120 | issue = 14 | pages = 2838–2847 | date = July 2021 | pmid = 34087216 | pmc = 8169220 | doi = 10.1016/j.bpj.2021.05.025 | bibcode = 2021BpJ...120.2838K }}</ref> [[Lymphopenia|A low level of blood lymphocytes]] may result from the virus acting through ACE2-related entry into lymphocytes.<ref>{{#invoke:cite journal|| vauthors = Gupta A, Madhavan MV, Sehgal K, Nair N, Mahajan S, Sehrawat TS, Bikdeli B, Ahluwalia N, Ausiello JC, Wan EY, Freedberg DE, Kirtane AJ, Parikh SA, Maurer MS, Nordvig AS, Accili D, Bathon JM, Mohan S, Bauer KA, Leon MB, Krumholz HM, Uriel N, Mehra MR, Elkind MS, Stone GW, Schwartz A, Ho DD, Bilezikian JP, Landry DW |title=Extrapulmonary manifestations of COVID-19 |journal=Nature Medicine |date=July 2020 |volume=26 |issue=7 |pages=1017–1032 |doi=10.1038/s41591-020-0968-3|pmid=32651579 |s2cid=220462000 | doi-access=free | title-link=doi }}</ref>

===Kidneys===
Another common cause of death is complications related to the [[kidney]]s.<ref name="Science" /> Early reports show that up to 30% of hospitalised patients both in China and in New York have experienced some injury to their kidneys, including some persons with no previous kidney problems.<ref>{{#invoke:Cite web|| title=Coronavirus: Kidney Damage Caused by COVID-19 | website=Johns Hopkins Medicine | date=14 May 2020 | url=https://www.hopkinsmedicine.org/health/conditions-and-diseases/coronavirus/coronavirus-kidney-damage-caused-by-covid19 | access-date=25 January 2022}}</ref>

=== Immunopathology ===
[[File:Fimmu-11-579250-g003.jpg|thumb|Key components of the [[Adaptive immune system|adaptive immune response]] to SARS-CoV-2]]

Although SARS-CoV-2 has a tropism for ACE2-expressing epithelial cells of the respiratory tract, people with severe COVID‑19 have symptoms of systemic hyperinflammation. Clinical laboratory findings<!-- Spellings in this paragraph have been meticulously compared link-by-link; if you spot an error, please correct the other article first. --> of elevated [[Interleukin 2|IL{{nbh}}2]], [[Interleukin 7|IL{{nbh}}7]], [[Interleukin 6|IL{{nbh}}6]], [[granulocyte-macrophage colony-stimulating factor]] (GM{{nbh}}CSF), [[CXCL10|interferon gamma-induced protein{{spaces}}10]] (IP{{nbh}}10), [[Monocyte chemoattractant protein-1|monocyte chemoattractant protein{{spaces}}1]] (MCP1), [[CCL3|macrophage inflammatory protein 1{{nbh}}alpha]] (MIP{{nbh}}1{{nbh}}alpha), and [[tumour necrosis factor]] (TNF{{nbh}}α) indicative of [[cytokine release syndrome]] (CRS) suggest an underlying immunopathology.<ref name="Huang24Jan2020" />

[[Interferon-alpha|Interferon alpha]] plays a complex, Janus-faced role in the pathogenesis of COVID-19. Although it promotes the elimination of virus-infected cells, it also upregulates the expression of ACE-2, thereby facilitating the SARS-Cov2 virus to enter cells and to replicate.<ref>{{#invoke:cite journal ||last1=Ziegler |first1=CGK |last2=Allon |first2=SJ |last3=Nyquist |first3=SK |last4=Mbano |first4=IM |last5=Miao |first5=VN |last6=Tzouanas |first6=CN |last7=Cao |first7=Y |last8=Yousif |first8=AS |last9=Bals |first9=J |last10=Hauser |first10=BM |last11=Feldman |first11=J |last12=Muus |first12=C |last13=Wadsworth |first13=MH |last14=Kazer |first14=SW |last15=Hughes |first15=TK |last16=Doran |first16=B |last17=Gatter |first17=GJ |last18=Vukovic |first18=M |last19=Taliaferro |first19=F |last20=Mead |first20=BE |last21=Guo |first21=Z |last22=Wang |first22=JP |last23=Gras |first23=D |last24=Plaisant |first24=M |last25=Ansari |first25=M |last26=Angelidis |first26=I |last27=Adler |first27=H |last28=Sucre |first28=JMS |last29=Taylor |first29=CJ |last30=Lin |first30=B |last31=Waghray |first31=A |last32=Mitsialis |first32=V |last33=Dwyer |first33=DF |last34=Buchheit |first34=KM |last35=Boyce |first35=JA |last36=Barrett |first36=NA |last37=Laidlaw |first37=TM |last38=Carroll |first38=SL |last39=Colonna |first39=L |last40=Tkachev |first40=V |last41=Peterson |first41=CW |last42=Yu |first42=A |last43=Zheng |first43=HB |last44=Gideon |first44=HP |last45=Winchell |first45=CG |last46=Lin |first46=PL |last47=Bingle |first47=CD |last48=Snapper |first48=SB |last49=Kropski |first49=JA |last50=Theis |first50=FJ |last51=Schiller |first51=HB |last52=Zaragosi |first52=LE |last53=Barbry |first53=P |last54=Leslie |first54=A |last55=Kiem |first55=HP |last56=Flynn |first56=JL |last57=Fortune |first57=SM |last58=Berger |first58=B |last59=Finberg |first59=RW |last60=Kean |first60=LS |last61=Garber |first61=M |last62=Schmidt |first62=AG |last63=Lingwood |first63=D |last64=Shalek |first64=AK |last65=Ordovas-Montanes |first65=J |title=SARS-CoV-2 Receptor ACE2 Is an Interferon-Stimulated Gene in Human Airway Epithelial Cells and Is Detected in Specific Cell Subsets across Tissues. |journal=Cell |series=HCA Lung Biological Network |date=28 May 2020 |volume=181 |issue=5 |pages=1016–1035.e19 |doi=10.1016/j.cell.2020.04.035 |pmid=32413319|pmc=7252096 }}</ref><ref>{{#invoke:cite journal ||last1=Sajuthi |first1=SP |last2=DeFord |first2=P |last3=Li |first3=Y |last4=Jackson |first4=ND |last5=Montgomery |first5=MT |last6=Everman |first6=JL |last7=Rios |first7=CL |last8=Pruesse |first8=E |last9=Nolin |first9=JD |last10=Plender |first10=EG |last11=Wechsler |first11=ME |last12=Mak |first12=ACY |last13=Eng |first13=C |last14=Salazar |first14=S |last15=Medina |first15=V |last16=Wohlford |first16=EM |last17=Huntsman |first17=S |last18=Nickerson |first18=DA |last19=Germer |first19=S |last20=Zody |first20=MC |last21=Abecasis |first21=G |last22=Kang |first22=HM |last23=Rice |first23=KM |last24=Kumar |first24=R |last25=Oh |first25=S |last26=Rodriguez-Santana |first26=J |last27=Burchard |first27=EG |last28=Seibold |first28=MA |title=Type 2 and interferon inflammation regulate SARS-CoV-2 entry factor expression in the airway epithelium. |journal=Nature Communications |date=12 October 2020 |volume=11 |issue=1 |pages=5139 |doi=10.1038/s41467-020-18781-2 |pmid=33046696|pmc=7550582 |bibcode=2020NatCo..11.5139S }}</ref> A competition of negative feedback loops (via protective effects of interferon alpha) and positive feedback loops (via upregulation of ACE-2) is assumed to determine the fate of patients suffering from COVID-19.<ref>{{#invoke:cite journal ||last1=Tretter |first1=F |last2=Peters |first2=EMJ |last3=Sturmberg |first3=J |last4=Bennett |first4=J |last5=Voit |first5=E |last6=Dietrich |first6=JW |last7=Smith |first7=G |last8=Weckwerth |first8=W |last9=Grossman |first9=Z |last10=Wolkenhauer |first10=O |last11=Marcum |first11=JA |title=Perspectives of (/memorandum for) systems thinking on COVID-19 pandemic and pathology. |journal=Journal of Evaluation in Clinical Practice |date=28 September 2022 |volume=29 |issue=3 |pages=415–429 |doi=10.1111/jep.13772 |pmid=36168893|pmc=9538129 |s2cid=252566067 }}</ref>

Additionally, people with COVID‑19 and [[acute respiratory distress syndrome]] (ARDS) have classical [[Serum (blood)|serum]] [[Biomarker (medicine)|biomarkers]] of CRS, including elevated [[C-reactive protein]] (CRP), [[lactate dehydrogenase]] (LDH), [[D-dimer]], and [[ferritin]].<ref>{{#invoke:cite journal || vauthors = Zhang C, Wu Z, Li JW, Zhao H, Wang GQ | title = Cytokine release syndrome in severe COVID-19: interleukin-6 receptor antagonist tocilizumab may be the key to reduce mortality | journal = International Journal of Antimicrobial Agents | volume = 55 | issue = 5 | pages = 105954 | date = May 2020 | pmid = 32234467 | pmc = 7118634 | doi = 10.1016/j.ijantimicag.2020.105954 }}</ref>

Systemic inflammation results in [[vasodilation]], allowing inflammatory lymphocytic and monocytic infiltration of the lung and the heart. In particular, pathogenic GM-CSF-secreting [[T&nbsp;cell]]s were shown to correlate with the recruitment of inflammatory IL-6-secreting [[monocyte]]s and severe lung pathology in people with COVID‑19.<ref>{{#invoke:cite journal || vauthors = Gómez-Rial J, Rivero-Calle I, Salas A, Martinón-Torres F | title = Role of Monocytes/Macrophages in Covid-19 Pathogenesis: Implications for Therapy | journal = Infection and Drug Resistance | volume = 13 | pages = 2485–2493 | year = 2020 | pmid = 32801787 | pmc = 7383015 | doi = 10.2147/IDR.S258639 | doi-access = free | title-link = doi }}</ref> Lymphocytic infiltrates have also been reported at autopsy.<ref name="Cureus" />

=== Viral and host factors ===

==== Virus proteins ====
[[File:Fpubh-08-00383-g004.jpg|thumb|The association between SARS-CoV-2 and the [[Renin–angiotensin system|Renin-Angiotensin-Aldosterone System]] (RAAS)]]

Multiple viral and host factors affect the pathogenesis of the virus. The S-protein, otherwise known as the spike protein, is the viral component that attaches to the host receptor via the [[Angiotensin-converting enzyme 2|ACE2]] receptors. It includes two subunits: S1 and S2. S1 determines the virus-host range and cellular tropism via the receptor-binding domain. S2 mediates the membrane fusion of the virus to its potential cell host via the H1 and HR2, which are [[heptad repeat]] regions. Studies have shown that S1 domain induced [[IgG]] and [[IgA]] antibody levels at a much higher capacity. It is the focus spike proteins expression that are involved in many effective COVID‑19 vaccines.<ref name="pmid33340022">{{#invoke:cite journal || vauthors = Dai L, Gao GF | title = Viral targets for vaccines against COVID-19 | journal = Nature Reviews. Immunology | volume = 21 | issue = 2 | pages = 73–82 | date = February 2021 | pmid = 33340022 | pmc = 7747004 | doi = 10.1038/s41577-020-00480-0 |issn=1474-1733 }}</ref>

The M protein is the viral protein responsible for the transmembrane transport of nutrients. It is the cause of the bud release and the formation of the viral envelope.<ref name="Boopathi-2020">{{#invoke:cite journal || vauthors = Boopathi S, Poma AB, Kolandaivel P | title = Novel 2019 coronavirus structure, mechanism of action, antiviral drug promises and rule out against its treatment | journal = Journal of Biomolecular Structure & Dynamics | pages = 3409–3418 | date = April 2020 | volume = 39 | issue = 9 | pmid = 32306836 | pmc = 7196923 | doi = 10.1080/07391102.2020.1758788 }}</ref> The N and E protein are accessory proteins that interfere with the host's immune response.<ref name="Boopathi-2020" />

==== Host factors ====
Human [[angiotensin converting enzyme 2]] (hACE2) is the host factor that SARS-CoV-2 virus targets causing COVID‑19. Theoretically, the usage of [[Angiotensin II receptor blocker|angiotensin receptor blockers]] (ARB) and [[ACE inhibitor]]s upregulating ACE2 expression might increase [[morbidity]] with COVID‑19, though animal data suggest some potential protective effect of ARB; however no clinical studies have proven susceptibility or outcomes. Until further data is available, guidelines and recommendations for hypertensive patients remain.<ref>{{#invoke:cite journal || vauthors = Kai H, Kai M | title = Interactions of coronaviruses with ACE2, angiotensin II, and RAS inhibitors-lessons from available evidence and insights into COVID-19 | journal = Hypertension Research | volume = 43 | issue = 7 | pages = 648–654 | date = July 2020 | pmid = 32341442 | pmc = 7184165 | doi = 10.1038/s41440-020-0455-8 }}</ref>

The effect of the virus on ACE2 cell surfaces leads to leukocytic infiltration, increased blood vessel permeability, alveolar wall permeability, as well as decreased secretion of lung surfactants. These effects cause the majority of the respiratory symptoms. However, the aggravation of local inflammation causes a cytokine storm eventually leading to a [[systemic inflammatory response syndrome]].<ref>{{#invoke:cite journal || vauthors = Chen HX, Chen ZH, Shen HH | title = [Structure of SARS-CoV-2 and treatment of COVID-19] | journal = Sheng Li Xue Bao | volume = 72 | issue = 5 | pages = 617–630 | date = October 2020 | pmid = 33106832 }}</ref>

Among healthy adults not exposed to SARS-CoV-2, about 35% have [[CD4+ T cell|CD4<sup>+</sup> T cells]] that recognise the SARS-CoV-2 [[Peplomer|S protein]] (particularly the S2 subunit) and about 50% react to other proteins of the virus, suggesting [[cross-reactivity]] from previous [[common cold]]s caused by other coronaviruses.<ref>{{#invoke:cite journal ||vauthors=Jeyanathan M, Afkhami S, Smaill F, Miller MS, Lichty BD, Xing Z |date=4 September 2020 |title=Immunological considerations for COVID-19 vaccine strategies |journal=Nature Reviews Immunology |volume=20 |issue=10 |pages=615–632 |doi=10.1038/s41577-020-00434-6 |pmid=32887954 |pmc=7472682 |issn=1474-1741}}</ref>

It is unknown whether different persons use similar antibody genes in response to COVID‑19.<ref>{{#invoke:cite journal || vauthors = Zhang Q, Ju B, Ge J, Chan JF, Cheng L, Wang R, Huang W, Fang M, Chen P, Zhou B, Song S, Shan S, Yan B, Zhang S, Ge X, Yu J, Zhao J, Wang H, Liu L, Lv Q, Fu L, Shi X, Yuen KY, Liu L, Wang Y, Chen Z, Zhang L, Wang X, Zhang Z  | title = Potent and protective IGHV3-53/3-66 public antibodies and their shared escape mutant on the spike of SARS-CoV-2 | journal = Nature Communications | volume = 12 | issue = 1 | pages = 4210 | date = July 2021 | pmid = 34244522 | pmc = 8270942 | doi = 10.1038/s41467-021-24514-w | bibcode = 2021NatCo..12.4210Z | s2cid = 235786394 }}</ref>

=== Host cytokine response ===
[[File:Ijms-21-05932-g004.webp|thumb|Mild versus severe [[Immune system|immune response]] during [[Viral disease|virus infection]]]]

The severity of the inflammation can be attributed to the severity of what is known as the [[cytokine storm]].<ref name="pmid32474885">{{#invoke:cite journal || vauthors = Soy M, Keser G, Atagündüz P, Tabak F, Atagündüz I, Kayhan S | title = Cytokine storm in COVID-19: pathogenesis and overview of anti-inflammatory agents used in treatment | journal = Clinical Rheumatology | volume = 39 | issue = 7 | pages = 2085–2094 | date = July 2020 | pmid = 32474885 | pmc = 7260446 | doi = 10.1007/s10067-020-05190-5 }}</ref> Levels of [[Interleukin 1 beta|interleukin{{spaces}}1B]], [[Interferon gamma|interferon-gamma]], interferon-inducible protein 10, and monocyte chemoattractant protein{{spaces}}1 were all associated with COVID‑19 disease severity. Treatment has been proposed to combat the cytokine storm as it remains to be one of the leading causes of [[morbidity]] and mortality in COVID‑19 disease.<ref>{{#invoke:cite journal || vauthors = Quirch M, Lee J, Rehman S | title = Hazards of the Cytokine Storm and Cytokine-Targeted Therapy in Patients With COVID-19: Review | journal = Journal of Medical Internet Research | volume = 22 | issue = 8 | pages = e20193 | date = August 2020 | pmid = 32707537 | pmc = 7428145 | doi = 10.2196/20193 |doi-access=free}}</ref>

A cytokine storm is due to an acute hyperinflammatory response that is responsible for clinical illness in an array of diseases but in COVID‑19, it is related to worse prognosis and increased fatality. The storm causes acute respiratory distress syndrome, blood clotting events such as strokes, myocardial infarction, [[encephalitis]], [[acute kidney injury]], and [[vasculitis]]. The production of [[Interleukin 1|IL-1]], [[Interleukin 2|IL-2]], [[Interleukin 6|IL-6]], [[Tumor necrosis factor|TNF-alpha]], and [[Interferon gamma|interferon-gamma]], all crucial components of normal immune responses, inadvertently become the causes of a cytokine storm. The cells of the [[central nervous system]], the [[microglia]], [[neuron]]s, and [[astrocyte]]s, are also involved in the release of [[pro-inflammatory cytokine]]s affecting the nervous system, and effects of cytokine storms toward the [[Central nervous system|CNS]] are not uncommon.<ref>{{#invoke:cite journal || vauthors = Bhaskar S, Sinha A, Banach M, Mittoo S, Weissert R, Kass JS, Rajagopal S, Pai AR, Kutty S  | title = Cytokine Storm in COVID-19-Immunopathological Mechanisms, Clinical Considerations, and Therapeutic Approaches: The REPROGRAM Consortium Position Paper | journal = Frontiers in Immunology | volume = 11 | pages = 1648 | year = 2020 | pmid = 32754159 | pmc = 7365905 | doi = 10.3389/fimmu.2020.01648 | doi-access = free | title-link = doi }}</ref>

=== Pregnancy response ===

There are many unknowns for pregnant women during the COVID-19 pandemic. Given that they are prone to have complications and severe disease infection with other types of coronaviruses, they have been identified as a vulnerable group and advised to take supplementary preventive measures.<ref name="Wastnedge_2021">{{#invoke:cite journal||vauthors=Wastnedge EA, Reynolds RM, van Boeckel SR, Stock SJ, Denison FC, Maybin JA, Critchley HO  |date=January 2021|title=Pregnancy and COVID-19|journal=Physiological Reviews|volume=101|issue=1|pages=303–318|doi=10.1152/physrev.00024.2020|pmc=7686875|pmid=32969772}}</ref>

Physiological responses to pregnancy can include:
* Immunological: The immunological response to COVID-19, like other viruses, depends on a working immune system. It adapts during pregnancy to allow the development of the foetus whose genetic load is only partially shared with their mother, leading to a different immunological reaction to infections during the course of pregnancy.<ref name="Wastnedge_2021" />
* Respiratory: Many factors can make pregnant women more vulnerable to hard respiratory infections. One of them is the total reduction of the lungs' capacity and inability to clear secretions.<ref name="Wastnedge_2021" />
* Coagulation: During pregnancy, there are higher levels of circulating coagulation factors, and the pathogenesis of SARS-CoV-2 infection can be implicated. The thromboembolic events with associated mortality are a risk for pregnant women.<ref name="Wastnedge_2021" />

However, from the evidence base, it is difficult to conclude whether pregnant women are at increased risk of grave consequences of this virus.<ref name="Wastnedge_2021" />

In addition to the above, other clinical studies have proved that SARS-CoV-2 can affect the period of pregnancy in different ways. On the one hand, there is little evidence of its impact up to 12 weeks gestation. On the other hand, COVID-19 infection may cause increased rates of unfavourable outcomes in the course of the pregnancy. Some examples of these could be foetal growth restriction, preterm birth, and perinatal mortality, which refers to the foetal death past 22 or 28 completed weeks of pregnancy as well as the death among live-born children up to seven completed days of life.<ref name="Wastnedge_2021" /> For preterm birth, a 2023 review indicates that there appears to be a correlation with COVID-19.<ref>{{#invoke:cite journal ||last1=Digby |first1=Alyson M. |last2=Dahan |first2=Michael H. |title=Obstetrical and gynecologic implications of COVID-19: what have we learned over the first two years of the pandemic |journal=Archives of Gynecology and Obstetrics |date=12 January 2023 |volume=308 |issue=3 |pages=813–819 |doi=10.1007/s00404-022-06847-z|pmid=36633677 |pmc=9838509 }}</ref>

Unvaccinated women in later stages of pregnancy with COVID-19 are more likely than other patients to need very intensive care. Babies born to mothers with COVID-19 are more likely to have breathing problems. Pregnant women are strongly encouraged to get [[COVID-19 vaccine|vaccinated]].<ref>{{#invoke:Cite web|| vauthors = Campbell D | title=One in six most critically ill NHS Covid patients are unvaccinated pregnant women | website=The Guardian | date=10 October 2021 | url=https://www.theguardian.com/lifeandstyle/2021/oct/11/one-in-six-most-critically-ill-patients-are-unvaccinated-pregnant-women-with-covid | access-date=25 January 2022 }}</ref>