Causes of death and comorbidities in hospitalized patients with COVID-19

Elezkurtaj, Sefer; Greuel, Selina; Ihlow, Jana; Michaelis, Edward; Bischoff, Philip; Kunze, Catarina Alisa; Sinn, Bruno Valentin; Gerhold, Manuela; Hauptmann, Kathrin; Ingold-Heppner, Barbara; Miller, Florian; Herbst, Hermann; Corman, Victor M.; Martin, H; Radbruch, Helena; Heppner, Frank L.; Horst, David

doi:10.1038/s41598-021-82862-5

Cited by 302 publications

(243 citation statements)

References 20 publications

(13 reference statements)

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“…Lung tissue from deceased patients with clinical and autoptic signs of non-COVID pneumonia (n = 3) and without signs of pneumonia (n = 3) was used as controls. COVID-19 patients were randomly selected out of our autopsy cohort (n = 6 out of 25) 87 . Inclusion criteria were presence of cryopreserved material and viral RNA load in the lungs.…”

Section: Methodsmentioning

confidence: 99%

SARS-CoV-2-mediated dysregulation of metabolism and autophagy uncovers host-targeting antivirals

et al. 2021

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Viruses manipulate cellular metabolism and macromolecule recycling processes like autophagy. Dysregulated metabolism might lead to excessive inflammatory and autoimmune responses as observed in severe and long COVID-19 patients. Here we show that SARS-CoV-2 modulates cellular metabolism and reduces autophagy. Accordingly, compound-driven induction of autophagy limits SARS-CoV-2 propagation. In detail, SARS-CoV-2-infected cells show accumulation of key metabolites, activation of autophagy inhibitors (AKT1, SKP2) and reduction of proteins responsible for autophagy initiation (AMPK, TSC2, ULK1), membrane nucleation, and phagophore formation (BECN1, VPS34, ATG14), as well as autophagosome-lysosome fusion (BECN1, ATG14 oligomers). Consequently, phagophore-incorporated autophagy markers LC3B-II and P62 accumulate, which we confirm in a hamster model and lung samples of COVID-19 patients. Single-nucleus and single-cell sequencing of patient-derived lung and mucosal samples show differential transcriptional regulation of autophagy and immune genes depending on cell type, disease duration, and SARS-CoV-2 replication levels. Targeting of autophagic pathways by exogenous administration of the polyamines spermidine and spermine, the selective AKT1 inhibitor MK-2206, and the BECN1-stabilizing anthelmintic drug niclosamide inhibit SARS-CoV-2 propagation in vitro with IC50 values of 136.7, 7.67, 0.11, and 0.13 μM, respectively. Autophagy-inducing compounds reduce SARS-CoV-2 propagation in primary human lung cells and intestinal organoids emphasizing their potential as treatment options against COVID-19.

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Section: Methodsmentioning

confidence: 99%

SARS-CoV-2-mediated dysregulation of metabolism and autophagy uncovers host-targeting antivirals

et al. 2021

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“…It has been reported that a hypercoagulable state may occur due to COVID-19, correlating strongly with mortality (Tang et al, 2020;Hanff et al, 2020). In another study published by our research group, showing autopsy results of all age groups, the occurrence of pulmonary thromboembolisms was diagnosed in approximately every fourth patient mm in E, and 50 mm in F. (Elezkurtaj et al, 2021). Higher rates of thromboembolic events have been reported by Schurink et al (2020), with thromboembolic occurrences in 48% of decedents, and Wichmann et al (2020), with venous thromboembolism in 58% and pulmonary thromboembolism as cause of death in 33.3% of decedents.…”

Section: Discussionmentioning

confidence: 58%

“…To date, several autopsy studies of COVID-19 decedents have been published with observations on comorbidities and causes of death in unselected COVID-19 cohorts of all age groups. In these cohorts, the median age of investigated patients was approximately 70 years, and the proportion of younger adults was no more than 20% (Bryce et al, 2020;Chen et al, 2020;Elezkurtaj et al, 2021;Keresztesi et al, 2020;Onder et al, 2020;Wichmann et al, 2020). However, the analysis of younger decedents as a separate subgroup may be of particular interest, since younger patients tend to have fewer preexisting medical conditions.…”

Section: Discussionmentioning

confidence: 99%

COVID-19: Autopsy findings in six patients between 26 and 46 years of age

Greuel¹,

Ihlow²,

Dragomir³

et al. 2021

International Journal of Infectious Diseases

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Objectives Studies on the coronavirus disease 2019 (COVID-19) usually focus on middle aged and older adults. However, younger patients may present with severe COVID-19 and potentially fatal outcomes. For optimized, more specialized therapeutic regimens in this particular patient group, a better understanding of underlying pathomechanisms is of uttermost importance. Methods This study investigates relevant pre-existing medical conditions, clinical histories and autopsy findings, together with SARS-CoV-2-RNA, determined by qPCR, and laboratory data in six COVID-19 decedents at an age of 50 years or younger who were autopsied at the Charité University Hospital. Results From a total of 76 COVID-19 patients who underwent an autopsy at our institution, 6 (7.9%) were 50 years old or younger. Most COVID-19 decedents of younger age presented with pre-existing medical conditions prior to SARS-CoV-2 infection. These included overweight and obesity, arterial hypertension, asthma, obstructive sleep apnea as well as graft-versus-host disease following cancer and bone marrow transplantation. Furthermore, clinical histories and autopsy results revealed a disproportionally high prevalence of thromboembolism and ischemic organ damage in this patient cohort. Histopathology and laboratory results indicated coagulopathies, signs of immune dysregulation and liver damage. Conclusions In conclusion, pre-existing health conditions may increase the risk of severe and fatal COVID-19 in younger patients who may be especially prone to developing thromboembolic complications, immune dysregulation and liver damage.

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“…ARDS is associated with an uncontrolled immune activation, characterized by a massive upregulation of proinflammatory cytokines, chemokines, and hematopoietic growth factors (IFN-g, IL-1b, IL-6, IL-7, IL-8, IL-2, TNF, CXCL10, CCL2, GM-CSF) called cytokine storm (3)(4)(5), culminating in hyperinflammation and multi-organ disease (6), which is the leading cause of mortality (7). Septic shock and multiorgan failure were the most common immediate cause of death, often due to suppurative pulmonary infection as shown by Elezkurtaj et al (8).…”

Section: Introductionmentioning

confidence: 99%

How Children Are Protected From COVID-19? A Historical, Clinical, and Pathophysiological Approach to Address COVID-19 Susceptibility

Massalska

Gober

2021

Front. Immunol.

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The origin and the global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing coronavirus disease 2019 (COVID-19) in early 2020 was accompanied by high rates of mortality in regions belonging to the ancient silk road, such as the south of China, Iran, Turkey and the northern parts of Italy. However, children seem to be spared in the epidemic as very small percentage worldwide being ill. The protection of children and neonates suggests the involvement of a specific component of adaptive immunity present at early development. Native immunoglobulin belonging to the class of IgM is abundantly present in neonates and children and is known for its recognition of self- and altered self-antigens. Native IgM may be able to neutralize virus by the recognition of endogenous “danger signal” encoded in the viral envelope and originally imprinted in the membranes of infected and stressed cells. Noteworthy, thrombosis and vasculitis, two symptoms in severely affected adult and pediatric patients are shared between COVID-19 and patients with Behcet’s disease, an autoimmune disorder exhibiting a region-specific prevalence in countries of the former silk road. Molecular mechanisms and clinical indicators suggest reactive oxygen species as trigger factor for severe progression of COVID-19 and establish a link to the innate immune defense against bacteria. The selective pressure exerted by bacterial pathogens may have shaped the genetics of inhabitants at this ancient trade route in favor of bacterial defense, to the detriment of severe COVID-19 progression in the 21th century.

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Causes of death and comorbidities in hospitalized patients with COVID-19

Cited by 302 publications

References 20 publications

SARS-CoV-2-mediated dysregulation of metabolism and autophagy uncovers host-targeting antivirals

SARS-CoV-2-mediated dysregulation of metabolism and autophagy uncovers host-targeting antivirals

COVID-19: Autopsy findings in six patients between 26 and 46 years of age

How Children Are Protected From COVID-19? A Historical, Clinical, and Pathophysiological Approach to Address COVID-19 Susceptibility

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