Document text
Principal Investigator: Takako Araki
Organization: UNIVERSITY OF MINNESOTA
Fiscal Year: 2022
Award: $392,800
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
PROJECT SUMMARY
COVID-19–related extra-pulmonary damage is common and may even be observed in patients with mild COVID-
19 symptoms. There is an urgent and immediate need to establish optimal post-infection health care strategies
for these patients, yet mechanisms underlying their appearance remain unexamined. For example, post-COVID-
19 chronic fatigue syndrome has been reported in 54% of COVID-19 survivors, including those without severe
symptoms during the acute infection; however, its cause has not been addressed. Post-COVID-19 chronic
fatigue syndrome’s symptoms mimic those experienced by patients with well-described pituitary hormone
deficiencies, supporting the concept that pituitary dysfunction in patients with COVID-19 may be implicated in
post–COVID-19 health complications. Several lines of evidence support the premise that SARS-CoV-2 infection
damages the pituitary, leading to disrupted pituitary function. First, we detected expression of the SARS-CoV-2
receptor ACE2 in the normal human pituitary by immunofluorescence, suggesting that SARS-CoV-2 may directly
damage pituitary endocrine cells. Second, it has been reported that the SARS pandemic in Southeast Asia in
2002, by SARS-CoV-1, caused post-infection pituitary function decline, although direct damage to the pituitary
was not investigated. Third, clinical observations suggest that patients with COVID-19 show aberrant immune
activity and may develop cytokine storm, with particularly acute elevations of IL-6 and TNFα. Cytokine storm,
which can occur as a consequence of with cancer immunotherapy treatment, for example, is frequently
associated with pituitary inflammation and dysfunction, although the detailed pathogenetic mechanisms are not
known. This suggests that aberrant activation of the immune system may also indirectly damage the pituitary in
patients with COVID-19. Elucidating the mechanisms underlying direct and indirect pituitary damage related to
SARS-CoV-2 infection is critical to establishing guidelines for timely diagnosis and management of pituitary
dysfunction in COVID-19 survivors. In Aim 1, we will determine whether SARS-CoV-2 directly invades the
pituitary and causes pituitary structural damage. We will study autopsy-derived pituitary tissues obtained from
COVID-19 deceased patients and normal control pituitary tissues. Moreover, using a novel spatial genomics
technology, we will determine changes in gene expression associated with COVID-19 in each of the five pituitary
endocrine lineages and stroma cells. In Aim 2, we will determine the association and the timeline of pituitary
dysfunction and symptoms in patients who were infected by SARS-CoV-2. By combining detailed and innovative
cellular and molecular analyses, and clinical studies, we will identify the mechanisms responsible for pituitary
dysfunction in COVID-19 patients and determine the course of pituitary dysfunction in COVID-19. These
innovative studies will, in turn, enable the development of an evidence-based clinical guide for evaluation and
management of hormone deficiencies in the vast COVID-19 population across the globe.
Terms: <(TNF)-α><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><21+ years old><ACE2><Active Follow-up><Acute><Address><Adenohypophyseal Hyposecretion><Admission><Admission activity><Adult><Adult Human><Affect><Anterior Pituitary Hyposecretion Syndrome><Appearance><Autopsy><B cell differentiation factor><B cell stimulating factor 2><B-Cell Differentiation Factor><B-Cell Differentiation Factor-2><B-Cell Stimulatory Factor-2><BCDF><BSF-2><BSF2><Blood><Blood Reticuloendothelial System><Body Tissues><Brain><Brain Nervous System><COVID complications><COVID infected patient><COVID patient><COVID positive patient><COVID related complications><COVID survivors><COVID-19><COVID-19 associated death><COVID-19 associated fatality><COVID-19 associated mortality><COVID-19 complications><COVID-19 death><COVID-19 fatality><COVID-19 induced death><COVID-19 induced fatality><COVID-19 induced mortality><COVID-19 infected patient><COVID-19 infection><COVID-19 infection survivors><COVID-19 mortality><COVID-19 patient><COVID-19 positive patient><COVID-19 related complications><COVID-19 related death><COVID-19 related fatality><COVID-19 related mortality><COVID-19 survivors><COVID-19 virus><COVID19><COVID19 associated death><COVID19 associated fatality><COVID19 associated mortality><COVID19 death><COVID19 fatality><COVID19 induced death><COVID19 induced fatality><COVID19 induced mortality><COVID19 infection><COVID19 mortality><COVID19 patient><COVID19 positive patient><COVID19 related death><COVID19 related fatality><COVID19 related mortality><COVID19 virus><CV-19><CV19><Cachectin><Cell Body><Cell Lineage><Cells><Chronic Fatigue Disorder><Chronic Fatigue Syndrome><Chronic Fatigue and Immune Dysfunction Syndrome><Chronic Fatigue-Fibromyalgia Syndrome><Chronic Infectious Mononucleosis-Like Syndrome><Cities><Clinical><Clinical Research><Clinical Study><CoV-2><CoV2><Complication><Cross Sectional Analysis><Cross-Sectional Analyses><Cross-Sectional Studies><Cross-Sectional Survey><D-dimer><D-dimer fibrin><D-dimer fragments><Development><Diagnosis><Disease><Disease Frequency Surveys><Disorder><Dysfunction><Encephalon><Endocrine><Endocrine Gland Secretion><Evaluation><Fatigue><Female><Fibrin fragment D><Formalin><Foundations><Functional disorder><Gene Expression><Gene Transcription><Genes><Genetic Transcription><Genomics><Guidelines><HPGF><Health><Health Care Costs><Health Costs><Healthcare><Healthcare Costs><Hepatocyte-Stimulating Factor><Histologic><Histologically><Hormones><Hospital Referrals><Hour><Human><Hybridoma Growth Factor><Hypophysis><Hypophysis Cerebri><Hypopituitarism><Hypotension><IFN-beta 2><IFNB2><IL-6><IL6 Protein><Immune><Immune Cell Activation><Immune reaction><Immune system><Immunes><Immunofluorescence><Immunofluorescence Immunologic><In Situ><Individual><Infection><Inflammation><Interleukin-6><Invaded><Lack of Energy><Length of Stay><Long COVID><Long COVID-19><Long coronavirus disease><Long coronavirus disease 2019><Longitudinal Studies><Los Angeles><Low Blood Pressure><Lung damage><ME/CFS><MGI-2><Macrophage-Derived TNF><Measures><Medical center><Messenger RNA><Modern Man><Molecular Analysis><Monocyte-Derived TNF><Myalgic Encephalomyelitis><Myeloid Differentiation-Inducing Protein><Myocardial depression><Myocardial dysfunction><New York City><Number of Days in Hospital><Outcome><Paraffin Embedding><Participant><Patients><Physiopathology><Pituitary><Pituitary Gland><Pituitary Hormones><Pituitary Nervous System><Pituitary insufficiency><Plasmacytoma Growth Factor><Population><Postviral Fatigue Syndrome><Process><Public Health><QOL><Quality of life><Questionnaires><RNA Expression><Receptor Protein><Reporting><Research><Risk><Royal Free Disease><SARS><SARS Virus><SARS corona virus><SARS corona virus 2><SARS coronavirus><SARS coronavirus disease><SARS-Associated Coronavirus><SARS-CO-V2><SARS-COVID-2><SARS-CoV><SARS-CoV disease><SARS-CoV-1><SARS-CoV-2><SARS-CoV-2 associated death><SARS-CoV-2 associated fatality><SARS-CoV-2 associated mortality><SARS-CoV-2 death><SARS-CoV-2 fatality><SARS-CoV-2 induced death><SARS-CoV-2 induced fatality><SARS-CoV-2 induced mortality><SARS-CoV-2 infected patient><SARS-CoV-2 infection><SARS-CoV-2 mortality><SARS-CoV-2 patient><SARS-CoV-2 positive patient><SARS-CoV-2 related death><SARS-CoV-2 related fatality><SARS-CoV-2 related mortality><SARS-CoV-2 survivors><SARS-CoV2><SARS-CoV2 infection><SARS-Related Coronavirus><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Severe Acute Respiratory Coronavirus><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome CoV disease><Severe Acute Respiratory Syndrome Virus><Severe Acute Respiratory Syndrome corona virus><Severe Acute Respiratory Syndrome coronavirus><Severe Acute Respiratory Syndrome coronavirus disease><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome related corona virus 2><Site><Sleep disturbances><Southeast Asia><Southeastern Asia><Structure><Symptoms><Syndrome><System><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><Technology><Testing><Therapeutic Hormone><Time><TimeLine><Tissue Embedding><Tissues><Transcription><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Vascular Hypotensive Disorder><Visit><Wuhan coronavirus><aberrant sleep><active followup><acute infection><adulthood><allergic/immunologic body system><allergic/immunologic organ system><angiotensin converting enzyme 2><angiotensin converting enzyme II><anti-cancer immunotherapy><anticancer immunotherapy><cancer immunotherapy><cardiac dysfunction><cell stroma><cell type><chronic COVID><chronic COVID-19><chronic novel coronavirus disease 2019><cognitive function><complications due to COVID-19><corona virus disease 2019><coronavirus disease 2019><coronavirus disease 2019 associated death><coronavirus disease 2019 associated fatality><coronavirus disease 2019 associated mortality><coronavirus disease 2019 death><coronavirus disease 2019 fatality><coronavirus disease 2019 induced death><coronavirus disease 2019 induced fatality><coronavirus disease 2019 induced mortality><coronavirus disease 2019 infected patient><coronavirus disease 2019 infection><coronavirus disease 2019 mortality><coronavirus disease 2019 patient><coronavirus disease 2019 positive patient><coronavirus disease 2019 related death><coronavirus disease 2019 related fatality><coronavirus disease 2019 related mortality><coronavirus disease 2019 virus><coronavirus disease infected patient><coronavirus disease patient><coronavirus disease positive patient><coronavirus disease-19><coronavirus disease-19 mortality><coronavirus disease-19 patient><coronavirus disease-19 virus><coronavirus infectious disease-19><coronavirus patient><cytokine><cytokine release syndrome><cytokine storm><death due to COVID-19><death due to COVID19><death due to SARS-CoV-2><death due to coronavirus disease 2019><death due to severe acute respiratory syndrome coronavirus 2><death in COVID><death in COVID-19><death in SARS-CoV-2><death in coronavirus disease><death in coronavirus disease 2019><death in severe acute respiratory syndrome coronavirus 2><decline in function><decline in functional status><developmental><digital><disrupted sleep><disturbed sleep><evidence base><experience><fatality due to COVID-19><fatality due to COVID19><fatality due to SARS-CoV-2><fatality due to coronavirus disease 2019><fatality due to severe acute respiratory syndrome coronavirus 2><fibrin fragment D-dimer><fibrin fragment D1 dimer><fibrin fragment DD><follow up><follow-up><followed up><followup><functional decline><functional status decline><growth hormone deficiency><hCoV19><health care><health care management><health management><healthcare management><heart dysfunction><high resolution imaging><hormone deficiency><hospital days><hospital length of stay><hospital stay><imaging system><immune activation><immune-based cancer therapies><immunoreaction><immunotherapy for cancer><immunotherapy of cancer><impaired sleep><infected with COVID-19><infected with COVID19><infected with SARS-CoV-2><infected with SARS-CoV2><infected with coronavirus disease 2019><infected with severe acute respiratory syndrome coronavirus 2><inflammation marker><inflammatory marker><innovate><innovation><innovative><interferon beta 2><irregular sleep><lactotroph><long haul COVID><long haul COVID-19><long haul coronavirus disease><long haul coronavirus disease 2019><long-hauler COVID><long-hauler COVID-19><long-hauler coronavirus disease 2019><long-hauler syndrome><long-term COVID><long-term COVID-19><long-term coronavirus disease><long-term coronavirus disease 2019><long-term study><longitudinal outcome studies><longterm COVID><longterm COVID-19><longterm coronavirus disease><longterm coronavirus disease 2019><longterm study><lung injury><mRNA><mRNA Expression><male><mortality due to COVID-19><mortality due to COVID19><mortality due to SARS-CoV-2><mortality due to coronavirus disease 2019><mortality due to severe acute respiratory syndrome coronavirus 2><nCoV2><necropsy><novel><pandemic><pandemic disease><pathophysiology><patient infected with COVID><patient infected with COVID-19><patient infected with SARS-CoV-2><patient infected with coronavirus disease><patient infected with coronavirus disease 2019><patient infected with severe acute respiratory syndrome coronavirus 2><patient subgroups><patient subpopulations><patient subsets><patient subtypes><patient with COVID><patient with COVID-19><patient with COVID19><patient with SARS-CoV-2><patient with coronavirus disease><patient with coronavirus disease 2019><patient with severe acute respiratory distress syndrome coronavirus 2><pituitary development><pituitary gland development><post COVID syndrome><post COVID-19 syndrome><post acute COVID syndrome><post acute COVID-19><post acute COVID-19 syndrome><post acute SARS-CoV-2><post acute coronavirus disease 2019><post acute coronavirus disease 2019 syndrome><post acute coronavirus disease syndrome><post acute severe acute respiratory syndrome coronavirus 2><post coronavirus disease 2019 syndrome><post coronavirus disease syndrome><post-COVID><post-COVID-19><post-acute phases of COVID-19><post-coronavirus disease 2019><postmortem><prevent><preventing><protocol development><pulmonary damage><pulmonary injury><pulmonary tissue damage><pulmonary tissue injury><receptor><severe acute respiratory syndrome coronavirus 2 associated death><severe acute respiratory syndrome coronavirus 2 associated fatality><severe acute respiratory syndrome coronavirus 2 associated mortality><severe acute respiratory syndrome coronavirus 2 death><severe acute respiratory syndrome coronavirus 2 fatality><severe acute respiratory syndrome coronavirus 2 induced death><severe acute respiratory syndrome coronavirus 2 induced fatality><severe acute respiratory syndrome coronavirus 2 induced mortality><severe acute respiratory syndrome coronavirus 2 infected patient><severe acute respiratory syndrome coronavirus 2 mortality><severe acute respiratory syndrome coronavirus 2 patient><severe acute respiratory syndrome coronavirus 2 positive patient><severe acute respiratory syndrome coronavirus 2 related death><severe acute respiratory syndrome coronavirus 2 related fatality><severe acute respiratory syndrome coronavirus 2 related mortality><severe acute respiratory syndrome-CoV><sleep disruption><sleep dysregulation><societal costs><standard of care><success><survive COVID-19><survive SARS-CoV-2>