Deprecated: Optional parameter $output declared before required parameter $atts is implicitly treated as a required parameter in /var/www/clients/client0/web46/web/wp-content/plugins/td-composer/legacy/common/wp_booster/td_wp_booster_functions.php on line 1740
Deprecated: Optional parameter $depth declared before required parameter $output is implicitly treated as a required parameter in /var/www/clients/client0/web46/web/wp-content/plugins/td-cloud-library/includes/tdb_menu.php on line 251
Deprecated: Optional parameter $caller_id declared before required parameter $channel_that_passed is implicitly treated as a required parameter in /var/www/clients/client0/web46/web/wp-content/themes/Newspaper/includes/wp-booster/tagdiv-remote-http.php on line 124
It’s a strange time for the alcohol industry. With lockdown orders in place across the country, an uptick of to-go orders and grocery store purchases is notable. At the same time, with bars, venues and restaurants closed, on-site drinking has seen a significant decrease, resulting in millions of gallons of beer gone stale.
The good news for fans of hard liquor is that these types of drinks have the longest shelf life. After being opened, bottles of whiskey, vodka, tequila and rum won’t necessarily go bad, but they’ll start to lose their flavor after about 6-8 months (or even up to year). (iStock)
With people seemingly stocking up on drinks and businesses stuck with kegs they can’t sell, some people may be asking, How long does booze stay good for?
Not surprisingly, it depends on the type of alcohol.
The good news for fans of hard liquor is that these types of drinks have the longest shelf life. After being opened, bottles of whiskey, vodka, tequila and rum won’t necessarily go bad, but they’ll start to lose their flavor after about six to eight months (or even up to year), Healthline explains.
Beer, on the other hand, is a different story. According to Bustle, beer will go bad about three months after the sell-by or best-by date. Also, if it isn’t stored properly, beer can develop a sour or earthy aroma (otherwise known as skunk).
Of course, once it’s opened, beer will go flat very quickly. The same is true for any carbonated beverages, including champagne (which can last for a decade unopened).
Wine can be more difficult, but in general, wine can last for up to 10 years if stored properly. Once it’s opened, it can go bad within a day or two unless it’s recorked and refrigerated, at which point it can last for two weeks.
Lastly, while hard liquor won’t go bad, liqueurs and cordials can spoil after a year. This is due to their high sugar content, according to Bin Wise. A good rule of thumb for drinks like this is to remember that the higher the sugar content, the faster it will spoil.
Get all the latest news on coronavirus and more delivered daily to your inbox. Sign up here.
The news media that gave us Bill Clinton, “The Man from Hope,” are now trying to sell us on New York Democrat Gov. Andrew Cuomo, The Candidate From CNN – where his brother Chris anchors.
The Brothers Cuomo created yet another journalism outrage Wednesday night. Younger brother Chris, who anchors for CNN, once again interviewed his older, more successful brother. It wasn’t news.
In fact, it was so horrific that it made news. As reported by NewsBusters Chris whipped out giant swabs and asked his brother, “is it true that when you are having the test administered, you inhaled and the doctor’s finger went all the way up your nose and got stuck and it had to be released with a tool?”
Chris has gone from newsman to Baghdad Bob for the wannabe Cuomo presidency. And that’s especially important since the governor is widely viewed as a potential replacement should Democrat presidential candidate Joe Biden falter before the election. The press is so obvious on this point that MSNBC Host Joy Reid called Andrew “a kind of acting president.”
The CNN half of the duo doesn’t ask tough questions, he clowns with his brother like they were on the set of “Saturday Night Live.”
That might not be so bad if Andrew were in a job more befitting his skill set – performer or perhaps journalist. Instead, Andrew is governor of the state hardest hit by the coronavirus. And it was as governor that Andrew ordered patients infected with the virus into nursing homes where thousands died.
Now, as Politico reported on May 7, Cuomo is “under fire for response to Covid-19 at nursing homes.” He changed course but only after more than 5,300 people had died in nursing homes.
None of that gets discussed when the Cuomos get together on TV. Or at least not when they are yucking it up on air.
Chris even joked that the giant swab was needed to “fit up that double-barrel shotgun that you have mounted on the front of your pretty face.”
The resulting segments are both an embarrassment to what remains of professional journalism and a stain on the body politic.
Even the press has noticed before this. Columbia Journalism Review’s Jon Allsop raised the obvious question, “Should Chris be allowed to interview a family member in a journalistic setting?”
Over at Mediaite, one analyst called the interviews a “conflict of interest” way back in March, which is about seven years in quarantine time. He added that, “For the sake of journalistic integrity, their interviews need to stop.”
More from Opinion
They haven’t. CNN has what it considers to be a winning formula. The audience likes it and the result promotes a Democrat politician who then owes the network big time for creating a phony narrative where he has done a good job.
The Society of Professional Journalists Code of Ethics (Yes, there is one.) is pretty clear on this whole fiasco. “Journalists should: Avoid conflicts of interest, real or perceived. Disclose unavoidable conflicts.”
CNN clearly considers Cuomo a journalist although you almost have to wonder why at this point. Here’s his network bio: “Chris Cuomo anchors CNN’s Cuomo Prime Time, a 9 pm nightly news program where Cuomo tests power with newsmakers and politicians from both sides of the aisle, and reports on the latest breaking news from Washington and around the world.”
Only the first part of that appears to be true — the name and time slot mostly. He’s clearly not testing his brother’s power, he’s testing CNN’s power to put his brother in the White House.
FILE – In this Feb. 26, 2020 file photo, Democratic presidential candidate Sen. Amy Klobuchar, D-Minn., speaks during a campaign event in Charleston, S.C. As presumptive Democratic presidential nominee Joe Biden begins the process of choosing a running mate amid … more >
Sen. Amy Klobuchar, Minnesota Democrat, has reportedly been asked to undergo the lengthy personal-vetting process expected of vice-presidential candidates.
According to CBS News, presumed presidential nominee Joseph R. Biden will ask Ms. Klobuchar to go through “a rigorous multi-week review of her public and private life and work by a hand-picked group of Biden confidantes.”
The team would comb through Ms. Klobuchar’s tax papers, votes, speeches, personal relationships and other matters for potential red flags or scandals.
The coronavirus primarily spreads from person to person and not easily from a contaminated surface. That is the takeaway from the Centers for Disease Control and Prevention, which this month updated its “How COVID-19 Spreads” website.
The revised guidance now states, in headline-size type, “The virus spreads easily between people.” It also notes that the coronavirus, which causes the disease covid-19, “is spreading very easily and sustainably between people.”
The CDC made another key change to its website, clarifying what sources are not major risks. Under the new heading “The virus does not spread easily in other ways,” the agency explains that touching contaminated objects or surfaces does not appear to be a significant mode of transmission. The same is true for exposure to infected animals.
CDC spokeswoman Kristen Nordlund said Thursday that the revisions were the product of an internal review and “usability testing.”
“Our transmission language has not changed,” Nordlund said. “Covid-19 spreads mainly through close contact from person to person.”
The virus travels through the droplets a person produces when talking or coughing, the CDC website says. An individual does not need to feel sick or show symptoms to spread the submicroscopic virus. Close contact means within about six feet, the distance at which a sneeze flings heavy droplets.
Example after example have shown the microbe’s affinity for density. The virus has spread easily in nursing homes, prisons, cruise ships and meatpacking plants — places where many people are living or working in proximity. A recent CDC report described how a choir practice in Washington state in March became a super-spreader event when one sick person infected as many as 52 others.
“Direct contact with people has the highest likelihood of getting infected — being close to an infected person, rather than accepting a newspaper or a FedEx guy dropping off a box,” said virologist Vincent Munster, a researcher in the virus ecology section at Rocky Mountain Laboratories, a National Institute of Allergy and Infectious Diseases facility in Hamilton, Mont.
Munster and his colleagues showed in laboratory experiments that the virus remained potentially viable on cardboard for up to 24 hours and on plastic and metal surfaces for up to three days. But the virus typically degrades within hours when outside a host.
The change to the CDC website, without formal announcement or explanation, concerns Angela L. Rasmussen, a virologist at the Columbia University Mailman School of Public Health.
“A persistent problem in this pandemic has been lack of clear messaging from governmental leadership, and this is another unfortunate example of that trend,” Rasmussen said. “It could even have a detrimental effect on hand hygiene and encourage complacency about physical distancing or other measures.”
Right-wing social media exploited the website tweaks this week. Fox News commentator Sean Hannity promoted a “breaking” report about the change.
But the previous version of the website, archived May 1, includes the same statement about surfaces as the current version: “It may be possible that a person can get COVID-19 by touching a surface or object that has the virus on it and then touching their own mouth, nose, or possibly their eyes. This is not thought to be the main way the virus spreads, but we are still learning more about this virus.”
Rasmussen said the new CDC language will not alter her habits. “I wash my hands after handling packages and wipe down shared surfaces with household disinfectant,” she said. “In my opinion, that’s all that is necessary to reduce risk.”
And if people find comfort in “quarantining” their mail or wiping down plastic packaging with disinfectant, “there’s no harm in doing that,” Rasmussen said. “Just don’t wipe down food with disinfectant.”
Mike Schultz, the San Francisco nurse who shared before and after pictures of himself showing the impact that Covid-19 had on his body, describes his struggle to recover from coronavirus. #Covid#CNN#News
They have high hopes for a coronavirus breakthrough.
A team of Canadian scientists believes it has found strong strains of cannabis that could help prevent and then treat coronavirus infections, according to interviews and a study.
Researchers from the University of Lethbridge said that a study in April showed at least 13 cannabis plants high in CBD that appeared to affect the ACE2 pathways that the bug uses to access the body.
“We were totally stunned at first, and then we were really happy,” one of the researchers, Olga Kovalchuk, told CTV News.
The results, printed in online journal Preprints, indicated hemp extracts high in CBD may help block proteins that provide a “gateway” for COVID-19 to enter host cells.
Shutterstock
Kovalchuk’s husband, Igor, suggested cannabis could reduce the virus’ entry points by up to 70 percent. “Therefore, you have more chance to fight it,” he told CTV.
“Our work could have a huge influence — there aren’t many drugs that have the potential of reducing infection by 70 to 80 percent,” he told the Calgary Herald.
Stressing that more research was needed, the study gave hope that if proven to modulate the enzyme it “may prove a plausible strategy for decreasing disease susceptibility” as well as “become a useful and safe addition to the treatment of COVID-19 as an adjunct therapy.”
Cannabis could even be used to “develop easy-to-use preventative treatments in the form of mouthwash and throat gargle products,” the study suggested, with a “potential to decrease viral entry” through the mouth.
“The key thing is not that any cannabis you would pick up at the store will do the trick,” Olga told CTV, with the study suggesting just a handful of more than 800 varieties of sativa seemed to help.
All were high in anti-inflammatory CBD — but low in THC, the part that produces the cannabis high.
The study, which is yet to be peer-reviewed, was carried out in partnership with Pathway Rx, a cannabis therapy research company, and Swysh Inc, a cannabinoid-based research company.
The researchers are seeking funding to continue its efforts to support scientific initiatives to address COVID-19.
“While our most effective extracts require further large-scale validation, our study is crucial for the future analysis of the effects of medical cannabis on COVID-19,” the research said.
“Given the current dire and rapidly evolving epidemiological situation, every possible therapeutic opportunity and avenue must be considered.”
The coronavirus pandemic continues its deadly march through rural counties and small towns across the country, led by flareups in Southern and Midwestern states that are becoming new epicenters of the outbreak.
Almost 80 percent of Americans now live in counties where the virus is spreading widely, according to an analysis by the Brookings Institution demographer William Frey.
In the last week, 176 counties have started to see substantial spread of the virus. The vast majority of those, 159, are smaller exurban or rural counties. The increased transmission in those areas shows the virus’s spread outward from its initial hubs in major cities like New York, Detroit, San Francisco, Seattle and New Orleans and into neighboring regions.
But the virus is also beginning to attack some cities that avoided an initial wave, a troubling reminder that it could still infect millions of Americans who have so far been safe.
Highly populated areas like Tampa and St. Petersburg, Fla., are now reporting dozens of new cases. Collin County, Texas, in the Dallas metroplex, and Wake County, N.C., are also showing signs of broader spread.
So are smaller, more rural communities like Yell County, Ark., and exurban areas outside of major cities like Minneapolis, Milwaukee and Columbus, Ohio.
“The U.S. is very large and diverse in terms of population density and movement. This is partially why we are seeing different experiences across the country,” said Amira Roess, an epidemiologist at George Mason University’s College of Health and Human Services. “In general, we are continuing to see outbreaks in less urban areas in the U.S.”
In the last week, more than half the counties reporting widespread infection for the first time are suburban, and almost 30 percent are rural or small-town counties. Only 15 percent of those are urban cores like Tampa and St. Petersburg, Fla.
Most of the counties now reporting high prevalence, 59 percent, are in Southern states. Midwestern counties make up 22 percent of those newly worrying counties, and Western counties make up 17 percent. Only a few Northeastern counties — two in New York and one in Maine — have been added to the highly prevalent list, in part because the region was hit so hard in the virus’s first wave.
More than three times as many counties where the virus is spreading widely favored Trump over Clinton, according to Frey’s analysis.
“There is a clear trend in the works among counties now experiencing a high COVID-19 prevalence for the first time,” Frey wrote. “Compared to the counties where the pandemic first hit, these look much more like the rest of America, and in particular, reflect the kinds of areas that carried President Trump to victory in 2016.”
The electoral calculus matters in part because those residents of more rural and conservative areas are the most likely to listen to and trust advice coming from Trump himself.
Trump has downplayed the threat of the virus from its earliest days, and in recent weeks, he has called on governors to begin unlocking their economies, hopeful that a rebounding economy would aid his reelection chances this year.
If the president tells Americans to continue practicing social distancing, even as economies reopen, he could possibly influence the people who are just now becoming more likely to be exposed to the virus.
The virus arriving in Trump country “suggests that rhetoric from some of the president’s supporters against maintaining public health measures may become more muted,” Frey wrote.
Netflix has started to terminate accounts that people haven’t used…
At least seven states may have botched their coronavirus testing tallies — potentially providing a distorted picture of how COVID-19 has spread, according to new reports.
Virginia, Texas, Georgia and Vermont have been combining the results of two types of COVID-19 tests — swabs for the disease itself and antibody blood tests — in their total tallies, a serious concern as the nation begins to reopen, CNN reported Thursday.
In a separate report this week, The Atlantic reported that Florida, Maine and Pennsylvania had also been conflating the two because of testing guidelines from the Centers for Disease Control and Prevention.
Nose swab or saliva samples help determine if a patient currently has coronavirus, while antibody blood tests look for biological signals that a person has been exposed to the bug in the past.
Combining the two could paint an inaccurate picture of where and when the virus has spread in each state — and overstate the extent of their testing, experts said.
“You only know how many cases you have if you do a lot of testing,” CNN senior medical correspondent Elizabeth Cohen said. “If you put the two tests together, you fool yourself into thinking you’ve done more testing than you have.”
Antibody tests are generally used on the broader population, rather than just those displaying symptoms, so they typically have a lower positive rate than nasal swabs — meaning a mix of the two “will drive down your positive rate in a very dramatic way,” Ashish Jha, a professor of global health at Harvard and director of the Harvard Global Health Institute, told The Atlantic.
Health officials in Texas, Virginia and Vermont said in recent days that they clued into the problem and are working to fix it. Florida hopes to separate the two tests in the next few weeks, according to The Atlantic. Georgia officials said its combined test numbers are in keeping with the CDC testing guidelines.
A new University of Minnesota report found that coronavirus testing nationwide was generally disorganized and not well coordinated among the states, CNN said in another report.
“It’s a mess out there,” Mike Osterholm, head of the school’s Center for Infectious Disease Research and Policy, told the outlet. “Testing is very, very important, but we’re not doing the right testing.”
“The data is really kind of screwed up,” he added. “It’s because the public health system is overwhelmed.”
As of Thursday, there have been more than 1.5 million COVID-19 cases in the US, with 93,000 people killed by the virus, according to Johns Hopkins University.
Progressive respiratory failure is the primary cause of death in the coronavirus disease 2019 (Covid-19) pandemic. Despite widespread interest in the pathophysiology of the disease, relatively little is known about the associated morphologic and molecular changes in the peripheral lung of patients who die from Covid-19.
Methods
We examined 7 lungs obtained during autopsy from patients who died from Covid-19 and compared them with 7 lungs obtained during autopsy from patients who died from acute respiratory distress syndrome (ARDS) secondary to influenza A(H1N1) infection and 10 age-matched, uninfected control lungs. The lungs were studied with the use of seven-color immunohistochemical analysis, micro–computed tomographic imaging, scanning electron microscopy, corrosion casting, and direct multiplexed measurement of gene expression.
Results
In patients who died from Covid-19–associated or influenza-associated respiratory failure, the histologic pattern in the peripheral lung was diffuse alveolar damage with perivascular T-cell infiltration. The lungs from patients with Covid-19 also showed distinctive vascular features, consisting of severe endothelial injury associated with the presence of intracellular virus and disrupted cell membranes. Histologic analysis of pulmonary vessels in patients with Covid-19 showed widespread thrombosis with microangiopathy. Alveolar capillary microthrombi were 9 times as prevalent in patients with Covid-19 as in patients with influenza (P<0.001). In lungs from patients with Covid-19, the amount of new vessel growth — predominantly through a mechanism of intussusceptive angiogenesis — was 2.7 times as high as that in the lungs from patients with influenza (P<0.001).
Conclusions
In our small series, vascular angiogenesis distinguished the pulmonary pathobiology of Covid-19 from that of equally severe influenza virus infection. The universality and clinical implications of our observations require further research to define. (Funded by the National Institutes of Health and others.)
Introduction
Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in humans is associated with a broad spectrum of clinical respiratory syndromes, ranging from mild upper airway symptoms to progressive life-threatening viral pneumonia.1,2 Clinically, patients with severe coronavirus disease 2019 (Covid-19) have labored breathing and progressive hypoxemia and often receive mechanical ventilatory support. Radiographically, peripheral lung ground-glass opacities on computed tomographic (CT) imaging of the chest fulfill the Berlin criteria for acute respiratory distress syndrome (ARDS).3,4 Histologically, the hallmark of the early phase of ARDS is diffuse alveolar damage with edema, hemorrhage, and intraalveolar fibrin deposition, as described by Katzenstein et al.5 Diffuse alveolar damage is a nonspecific finding, since it may have noninfectious or infectious causes, including Middle East respiratory syndrome coronavirus (MERS-CoV),6 SARS-CoV,7 SARS-CoV-2,8-10 and influenza viruses.11
Among the distinctive features of Covid-19 are the vascular changes associated with the disease. With respect to diffuse alveolar damage in SARS-CoV7 and SARS-CoV-2 infection,8,12 the formation of fibrin thrombi has been observed anecdotally but not studied systematically. Clinically, many patients have elevated d-dimer levels, as well as cutaneous changes in their extremities suggesting thrombotic microangiopathy.13 Diffuse intravascular coagulation and large-vessel thrombosis have been linked to multisystem organ failure.14-16 Peripheral pulmonary vascular changes are less well characterized; however, vasculopathy in the gas-exchange networks, depending on its effect on the matching of ventilation and perfusion that results, could potentially contribute to hypoxemia and the effects of posture (e.g., prone positioning) on oxygenation.17
Despite previous experience with SARS-CoV18 and early experience with SARS-CoV-2, the morphologic and molecular changes associated with these infections in the peripheral lung are not well documented. Here, we examine the morphologic and molecular features of lungs obtained during autopsy from patients who died from Covid-19, as compared with those of lungs from patients who died from influenza and age-matched, uninfected control lungs.
Methods
Patient Selection and Workflow
We analyzed pulmonary autopsy specimens from seven patients who died from respiratory failure caused by SARS-CoV-2 infection and compared them with lungs from seven patients who died from pneumonia caused by influenza A virus subtype H1N1 (A[H1N1]) — a strain associated with the 1918 and 2009 influenza pandemics. The lungs from patients with influenza were archived tissue from the 2009 pandemic and were chosen for the best possible match with respect to age, sex, and disease severity from among the autopsies performed at the Hannover Medical School. Ten lungs that had been donated but not used for transplantation served as uninfected control specimens. The Covid-19 group consisted of lungs from two female and five male patients with mean (±SD) ages of 68±9.2 years and 80±11.5 years, respectively (clinical data are provided in Table S1A in the Supplementary Appendix, available with the full text of this article at NEJM.org). The influenza group consisted of lungs from two female and five male patients with mean ages of 62.5±4.9 years and 55.4±10.9 years, respectively. Five of the uninfected lungs were from female donors (mean age, 68.2±6.9 years), and five were from male donors (mean age, 79.2±3.3 years) (clinical data are provided in Table S1B). The study was approved by and conducted according to requirements of the ethics committees at the Hannover Medical School and the University of Leuven. There was no commercial support for this study.
All lungs were comprehensively analyzed with the use of microCT, histopathological, and multiplexed immunohistochemical analysis, transmission and scanning electron microscopy, corrosion casting, and direct multiplexed gene-expression analysis, as described in detail in the Methods section of the Supplementary Appendix.
Statistical Analysis
All comparisons of numeric variables (including those in the gene-expression analysis) were conducted with Student’s t-test familywise error rates due to multiplicity set at 0.05 with the use of the Benjamini–Hochberg method of controlling false discovery rates. Original P values are reported only for the tests that met the criteria for false discovery rates. All confidence intervals have been calculated on the basis of the t-distribution, as well. Additional details are provided in the Methods section of the Supplementary Appendix.
Results
Gross Examination
The mean (±SE) weight of the lungs from patients with proven influenza pneumonia was significantly higher than that from patients with proven Covid-19 (2404±560 g vs. 1681±49 g; P=0.04). The mean weight of the uninfected control lungs (1045±91 g) was significantly lower than those in the influenza group (P=0.003) and the Covid-19 group (P<0.001).
Angiocentric Inflammation
Figure 1. Figure 1. Lymphocytic Inflammation in a Lung from a Patient Who Died from Covid-19.
The gross appearance of a lung from a patient who died from coronavirus disease 2019 (Covid-19) is shown in Panel A (the scale bar corresponds to 1 cm). The histopathological examination, shown in Panel B, revealed interstitial and perivascular predominantly lymphocytic pneumonia with multifocal endothelialitis (hematoxylin–eosin staining; the scale bar corresponds to 200 μm).
All lung specimens from the Covid-19 group had diffuse alveolar damage with necrosis of alveolar lining cells, pneumocyte type 2 hyperplasia, and linear intraalveolar fibrin deposition (Figure 1). In four of seven cases, the changes were focal, with only mild interstitial edema. The remaining three cases had homogeneous fibrin deposits and marked interstitial edema with early intraalveolar organization. The specimens in the influenza group had florid diffuse alveolar damage with massive interstitial edema and extensive fibrin deposition in all cases. In addition, three specimens in the influenza group had focal organizing and resorptive inflammation (Fig. S2). These changes were reflected in the much higher weight of the lungs from patients with influenza.
Immunohistochemical analysis of angiotensin-converting enzyme 2 (ACE2) expression, measured as mean (±SD) relative counts of ACE2-positive cells per field of view, in uninfected control lungs showed scarce expression of ACE2 in alveolar epithelial cells (0.053±0.03) and capillary endothelial cells (0.066±0.03). In lungs from patients with Covid-19 and lungs from patients with influenza, the relative counts of ACE2-positive cells per field of view were 0.25±0.14 and 0.35±0.15, respectively, for alveolar epithelial cells and 0.49±0.28 and 0.55±0.11, respectively, for endothelial cells. Furthermore, ACE2-positive lymphocytes were not seen in perivascular tissue or in the alveoli of the control lungs but were present in the lungs in the Covid-19 group and the influenza group (relative counts of 0.22±0.18 and 0.15±0.09, respectively). (Details of counting are provided in Table S2.)
In the lungs from patients with Covid-19 and patients with influenza, similar mean (±SD) numbers of CD3-positive T cells were found within a 200-μm radius of precapillary and postcapillary vessel walls in 20 fields of examination per patient (26.2±13.1 for Covid-19 and 14.8±10.8 for influenza). With the same field size used for examination, CD4-positive T cells were more numerous in lungs from patients with Covid-19 than in lungs from patients with influenza (13.6±6.0 vs. 5.8±2.5, P=0.04), whereas CD8-positive T cells were less numerous (5.3±4.3 vs. 11.6±4.9, P=0.008). Neutrophils (CD15 positive) were significantly less numerous adjacent to the alveolar epithelial lining in the Covid-19 group than in the influenza group (0.4±0.5 vs. 4.8±5.2, P=0.002).
A multiplexed analysis of inflammation-related gene expression examining 249 genes from the nCounter Inflammation Panel (NanoString Technologies) revealed similarities and differences between the specimens in the Covid-19 group and those in the influenza group. A total of 79 inflammation-related genes were differentially regulated only in specimens from patients with Covid-19, whereas 2 genes were differentially regulated only in specimens from patients with influenza; a shared expression pattern was found for 7 genes (Fig. S1).
Thrombosis and Microangiopathy
Figure 2. Figure 2. Microthrombi in the Interalveolar Septa of a Lung from a Patient Who Died from Covid-19.
The interalveolar septum of this patient (Patient 4 in Table S1A in the Supplementary Appendix) shows slightly expanded alveolar walls with multiple fibrinous microthrombi (arrowheads) in the alveolar capillaries. Extravasated erythrocytes and a loose network of fibrin can be seen in the intraalveolar space (hematoxylin–eosin staining; the scale bar corresponds to 50 μm).
The pulmonary vasculature of the lungs in the Covid-19 group and the influenza group was analyzed with hematoxylin–eosin, trichrome, and immunohistochemical staining (as described in the Methods section of the Supplementary Appendix). Analysis of precapillary vessels showed that in four of the seven lungs from patients with Covid-19 and four of the seven lungs from the patients with influenza, thrombi were consistently present in pulmonary arteries with a diameter of 1 mm to 2 mm, without complete luminal obstruction (Figs. S3 and S5). Fibrin thrombi of the alveolar capillaries could be seen in all the lungs from both groups of patients (Figure 2). Alveolar capillary microthrombi were 9 times as prevalent in patients with Covid-19 as in patients with influenza (mean [±SD] number of distinct thrombi per square centimeter of vascular lumen area, 159±73 and 16±16, respectively; P=0.002). Intravascular thrombi in postcapillary venules of less than 1 mm diameter were seen in lower numbers in the lungs from patients with Covid-19 than in those from patients with influenza (12±14 vs. 35±16, P=0.02). Two lungs in the Covid-19 group had involvement of all segments of the vasculature, as compared with four of the lungs in the influenza group; in three of the lungs in the Covid-19 group and three of the lungs in the influenza group, combined capillary and venous thrombi were found without arterial thrombi.
The histologic findings were supported by three-dimensional microCT of the pulmonary specimens: the lungs from patients with Covid-19 and from patients with influenza showed nearly total occlusions of precapillary and postcapillary vessels.
Angiogenesis
Figure 3. Figure 3. Microvascular Alterations in Lungs from Patients Who Died from Covid-19.
Panels A and B show scanning electron micrographs of microvascular corrosion casts from the thin-walled alveolar plexus of a healthy lung (Panel A) and the substantial architectural distortion seen in lungs injured by Covid-19 (Panel B). The loss of a clearly visible vessel hierarchy in the alveolar plexus is the result of new blood-vessel formation by intussusceptive angiogenesis. Panel C shows the intussusceptive pillar localizations (arrowheads) at higher magnification. Panel D is a transmission electron micrograph showing ultrastructural features of endothelial cell destruction and SARS-CoV-2 visible within the cell membrane (arrowheads) (the scale bar corresponds to 5 μm). RC denotes red cell.
We examined the microvascular architecture of the lungs from patients with Covid-19, lungs from patients with influenza, and uninfected control lungs with the use of scanning electron microscopy and microvascular corrosion casting. The lungs in the Covid-19 group had a distorted vascularity with structurally deformed capillaries (Figure 3). Elongated capillaries in the lungs from patients with Covid-19 showed sudden changes in caliber and the presence of intussusceptive pillars within the capillaries (Figure 3C). Transmission electron microscopy of the Covid-19 endothelium showed ultrastructural damage to the endothelium, as well as the presence of intracellular SARS-CoV-2 (Figure 3D). The virus could also be identified in the extracellular space.
Figure 4. Figure 4. Numeric Density of Features of Intussusceptive and Sprouting Angiogenesis in Lungs from Patients Who Died from Covid-19 or Influenza A(H1N1).
Angiogenic features of sprouting and intussusceptive angiogenesis (intussusceptive pillars and sprouts, respectively) were counted per field of view in microvascular corrosion casts of lungs from patients with Covid-19 (red), lungs from patients with influenza A(H1N1) (blue), and control lungs (white). In Panels A and B, the numeric densities of angiogenic features are summarized as box plots for intussusceptive and sprouting angiogenesis. The boxes reflect the interquartile range, and the whiskers indicate the range (up to 1.5 times the interquartile range). Outliers are denoted by singular points. A statistical comparison between lungs from patients Covid-19 and those from patients with influenza and uninfected control lungs showed a significantly higher frequency of angiogenesis in the patients with Covid-19 lungs, especially intussusceptive angiogenesis (P values were calculated with Student’s t-test, controlled for the familywise error rate with a Benjamini–Hochberg false discovery rate threshold of 0.05). Panels C and D show a chronological comparison of intussusceptive and sprouting angiogenesis in lungs from patients with Covid-19 and lungs from patients with influenza A(H1N1) plotted as a function of the duration of hospitalization. The numbers shown are Pearson correlation coefficients and P values (all displayed P values of 0.05 or lower also pass the false discovery rate threshold of 0.05). The median angiogenic feature count for each patient is displayed as one dot. The shaded areas encompassing the dotted linear regression lines are smoothed 95% confidence intervals. As a reference for increased blood-vessel formation in lung diseases, intussusceptive and sprouting angiogenesis as found in end-stage nonspecific interstitial pneumonia (NSIP), a chronic interstitial lung disease, at the time of lung transplantation (a mean of 1650 days from first consultation to lung transplantation) are shown (purple box plots). Findings in healthy control lungs are also indicated (white box plots). The white and purple box plots are displayed in relation to the y axis but not the x axis (as indicated by vertical dashed lines).
In the lungs from patients with Covid-19, the density of intussusceptive angiogenic features (mean [±SE], 60.7±11.8 features per field) was significantly higher than that in lungs from patients with influenza (22.5±6.9) or in uninfected control lungs (2.1±0.6) (P<0.001 for both comparisons) (Figure 4A). The density of features of conventional sprouting angiogenesis was also higher in the Covid-19 group than in the influenza group (Figure 4B). When the pulmonary angiogenic feature count was plotted as a function of the length of hospital stay, the degree of intussusceptive angiogenesis was found to increase significantly with increasing duration of hospitalization (P<0.001) (Figure 4C). In contrast, the lungs from patients with influenza had less intussusceptive angiogenesis and no increase over time (Figure 4C). A similar pattern was seen for sprouting angiogenesis (Figure 4D).
Figure 5. Figure 5. Relative Expression Analysis of Angiogenesis-Associated Genes in Lungs from Patients Who Died from Covid-19 or Influenza A(H1N1).
RNA was isolated from sections sampled directly adjacent to those used for complementary histologic and immunohistochemical analyses. RNA was isolated with the Maxwell RNA extraction system (Promega) and, after quality control through Qubit analysis (ThermoFisher), was used for further analysis. During the NanoString procedure, individual copies of all RNA molecules were labeled with gene-specific bar codes and counted individually with the nCounter Analysis System (NanoString Technologies). The expression of angiogenesis-associated genes was measured with the NanoString nCounter PanCancer Progression panel (323 target genes annotated as relevant for angiogenesis). The resulting gene-expression data were normalized to negative control lanes (arithmetic mean background subtraction), positive control lanes (geometric mean normalization factor), and all reference genes present on the panel (geometric mean normalization factor) with the use of nSolver Analysis Software, version 4.0. Shown in the Venn diagram are only genes that are statistically differentially expressed as compared with expression in controls in both disease groups (Student’s t-test, controlled for the familywise error rate with a Benjamini–Hochberg false discovery rate threshold of 0.05). Up-regulation and down-regulation of genes is indicated by colored arrowheads suffixed to the gene symbols (purple denotes up-regulation, red denotes down-regulation).
A multiplexed analysis of angiogenesis-related gene expression examining 323 genes from the nCounter PanCancer Progression Panel (NanoString Technologies) revealed differences between the specimens from patients with Covid-19 and those from patients with influenza. A total of 69 angiogenesis-related genes were differentially regulated only in the Covid-19 group, as compared with 26 genes differentially regulated only in the influenza group; 45 genes had shared changes in expression (Figure 5).
Discussion
In this study, we examined the morphologic and molecular features of seven lungs obtained during autopsy from patients who died from SARS-CoV-2 infection. The lungs from these patients were compared with those obtained during autopsy from patients who had died from ARDS secondary to influenza A(H1N1) infection and from uninfected controls. The lungs from the patients with Covid-19 and the patients with influenza shared a common morphologic pattern of diffuse alveolar damage and infiltrating perivascular lymphocytes. There were three distinctive angiocentric features of Covid-19. The first feature was severe endothelial injury associated with intracellular SARS-CoV-2 virus and disrupted endothelial cell membranes. Second, the lungs from patients with Covid-19 had widespread vascular thrombosis with microangiopathy and occlusion of alveolar capillaries.12,19 Third, the lungs from patients with Covid-19 had significant new vessel growth through a mechanism of intussusceptive angiogenesis. Although our sample was small, the vascular features we identified are consistent with the presence of distinctive pulmonary vascular pathobiologic features in some cases of Covid-19.
Our finding of enhanced intussusceptive angiogenesis in the lungs from patients with Covid-19 as compared with the lungs from patients with influenza was unexpected. New vessel growth can occur by conventional sprouting or intussusceptive (nonsprouting) angiogenesis. The characteristic feature of intussusceptive angiogenesis is the presence of a pillar or post spanning the lumen of the vessel.20 Typically referred to as an intussusceptive pillar, this endothelial-lined intravascular structure is not seen by light microscopy but is readily identifiable by corrosion casting and scanning electron microscopy.21 Although tissue hypoxia was probably a common feature in the lungs from both these groups of patients, we speculate that the greater degree of endothelialitis and thrombosis in the lungs from patients with Covid-19 may contribute to the relative frequency of sprouting and intussusceptive angiogenesis observed in these patients. The relationship of these findings to the clinical course of Covid-19 requires further research to elucidate.
A major limitation of our study is that the sample was small; we studied only 7 patients among the more than 320,000 people who have died from Covid-19, and the autopsy data also represent static information. On the basis of the available data, we cannot reconstruct the timing of death in the context of an evolving disease process. Moreover, there could be other factors that account for the differences we observed between patients with Covid-19 and those with influenza. For example, none of the patients in our study who died from Covid-19 had been treated with standard mechanical ventilation, whereas five of the seven patients who died from influenza had received pressure-controlled ventilation. Similarly, it is possible that differences in detectable intussusceptive angiogenesis could be due to the different time courses of Covid-19 and influenza. These and other unknown factors must be considered when evaluating our data.22 Nonetheless, our analysis suggests that this possibility is unlikely, particularly since the degree of intussusceptive angiogenesis in the patients with Covid-19 increased significantly with increasing length of hospitalization, whereas in the patients with influenza it remained stable at a significantly lower level. Moreover, we have shown intussusceptive angiogenesis to be the predominant angiogenic mechanism even in late stages of chronic lung injury.21
ACE2 is an integral membrane protein that appears to be the host-cell receptor for SARS-CoV-2.23,24 Our data showed significantly greater numbers of ACE2-positive cells in the lungs from patients with Covid-19 and from patients with influenza than in those from uninfected controls. We found greater numbers of ACE2-positive endothelial cells and significant changes in endothelial morphology, a finding consistent with a central role of endothelial cells in the vascular phase of Covid-19. Endothelial cells in the specimens from patients with Covid-19 showed disruption of intercellular junctions, cell swelling, and a loss of contact with the basal membrane. The presence of SARS-CoV-2 virus within the endothelial cells, a finding consistent with other studies,25 suggests that direct viral effects as well as perivascular inflammation may contribute to the endothelial injury.
We report the presence of pulmonary intussusceptive angiogenesis and other pulmonary vascular features in the lungs of seven patients who died from Covid-19. Additional work is needed to relate our findings to the clinical course in these patients. To aid others in their research, our full data set is available on the Vivli platform (https://vivli.org/) and can be requested with the use of the following digital object identifier: https://doi.org/10.25934/00005576.
Funding and Disclosures
Supported by grants (HL94567 and HL134229, to Drs. Ackermann and Mentzer) from the National Institutes of Health, a grant from the Botnar Research Centre for Child Health (to Dr. Tzankov), a European Research Council Consolidator Grant (XHale) (771883, to Dr. Jonigk), and a grant (KFO311, to Dr. Jonigk) from Deutsche Forschungsgemeinschaft (Project Z2).
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
This article was published on May 21, 2020, at NEJM.org.
We thank Kerstin Bahr, Jan Hinrich Braesen, Peter Braubach, Emily Brouwer, Annette Mueller Brechlin, Regina Engelhardt, Jasmin Haslbauer, Anne Hoefer, Nicole Kroenke, Thomas Menter, Mahtab Taleb Naghsh, Christina Petzold, Vincent Schmidt, and Pauline Tittmann for technical support; Peter Boor of the German Covid-19 registry; and Lynnette Sholl, Hans Kreipe, Hans Michael Kvasnicka, and Jean Connors for helpful comments. Dr. Jonigk thanks Anita Swiatlak for her continued support.
Author Affiliations
From the Institute of Pathology and Department of Molecular Pathology, Helios University Clinic Wuppertal, University of Witten–Herdecke, Wuppertal (M.A.), the Institute of Functional and Clinical Anatomy, University Medical Center of the Johannes Gutenberg University Mainz, Mainz (M.A.), the Institute of Pathology (M.K., F.L., C.W., H.S., D.J.), the Department of Cardiothoracic, Transplantation, and Vascular Surgery (A.H.), and the Clinic of Pneumology (T.W.), Hannover Medical School, and the German Center for Lung Research, Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH) (M.K., A.H., T.W., F.L., C.W., H.S., D.J.), Hannover — all in Germany; the Laboratory of Respiratory Diseases, BREATH, Department of Chronic Diseases, Metabolism, and Aging, KU Leuven, Leuven, Belgium (S.E.V., A.V.); the Institute of Pathology and Medical Genetics, University Hospital Basel, Basel, Switzerland (A.T.); and the Angiogenesis Foundation, Cambridge (W.W.L., V.W.L.), and the Laboratory of Adaptive and Regenerative Biology and the Division of Thoracic Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston (S.J.M.) — all in Massachusetts.
Address reprint requests to Dr. Mentzer at the Division of Thoracic Surgery, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis St., Boston, MA 02115, or at [email protected].
Supplementary Material
References (25)
1. Zhu N, Zhang D, Wang W, et al. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med 2020;382:727–733.
2. Chen N, Zhou M, Dong X, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 2020;395:507–513.
3. Raptis CA, Hammer MM, Short RG, et al. Chest CT and coronavirus disease (COVID-19): a critical review of the literature to date. AJR Am J Roentgenol 2020April16 (Epub ahead of print).
4. Thompson BT, Chambers RC, Liu KD. Acute respiratory distress syndrome. N Engl J Med 2017;377:562–572.
5. Katzenstein AL, Bloor CM, Leibow AA. Diffuse alveolar damage — the role of oxygen, shock, and related factors: a review. Am J Pathol 1976;85:209–228.
6. Alsaad KO, Hajeer AH, Al Balwi M, et al. Histopathology of Middle East respiratory syndrome coronovirus (MERS-CoV) infection — clinicopathological and ultrastructural study. Histopathology 2018;72:516–524.
7. Nicholls JM, Poon LLM, Lee KC, et al. Lung pathology of fatal severe acute respiratory syndrome. Lancet 2003;361:1773–1778.
8. Barton LM, Duval EJ, Stroberg E, Ghosh S, Mukhopadhyay S. COVID-19 autopsies, Oklahoma, USA. Am J Clin Pathol 2020;153:725–733.
9. Tian S, Hu W, Niu L, Liu H, Xu H, Xiao SY. Pulmonary pathology of early-phase 2019 novel coronavirus (COVID-19) pneumonia in two patients with lung cancer. J Thorac Oncol 2020;15:700–704.
10. Menter T, Haslbauer JD, Nienhold R, et al. Post-mortem examination of COVID19 patients reveals diffuse alveolar damage with severe capillary congestion and variegated findings of lungs and other organs suggesting vascular dysfunction. Histopathology 2020May4 (Epub ahead of print).
11. Voltersvik P, Aqrawi LA, Dudman S, et al. Pulmonary changes in Norwegian fatal cases of pandemic influenza H1N1 (2009) infection: a morphologic and molecular genetic study. Influenza Other Respir Viruses 2016;10:525–531.
12. Magro C, Mulvey JJ, Berlin D, et al. Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: a report of five cases. Transl Res 2020April15 (Epub ahead of print).
13. Liu PP, Blet A, Smyth D, Li H. The science underlying COVID-19: implications for the cardiovascular system. Circulation 2020April15 (Epub ahead of print).
14. Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost 2020;18:1094–1099.
15. Zhu J, Ji P, Pang J, et al. Clinical characteristics of 3,062 COVID-19 patients: a meta-analysis. J Med Virol 2020April15 (Epub ahead of print).
16. Porfidia A, Pola R. Venous thromboembolism in COVID-19 patients. J Thromb Haemost 2020April15 (Epub ahead of print).
17. Scholten EL, Beitler JR, Prisk GK, Malhotra A. Treatment of ARDS with prone positioning. Chest 2017;151:215–224.
18. Gu J, Gong E, Zhang B, et al. Multiple organ infection and the pathogenesis of SARS. J Exp Med 2005;202:415–424.
20. Mentzer SJ, Konerding MA. Intussusceptive angiogenesis: expansion and remodeling of microvascular networks. Angiogenesis 2014;17:499–509.
21. Ackermann M, Stark H, Neubert L, et al. Morphomolecular motifs of pulmonary neoangiogenesis in interstitial lung diseases. Eur Respir J 2020;55(3):1900933–1900933.
22. Buja LM, Wolf D, Zhao B, et al. Emerging spectrum of cardiopulmonary pathology of the coronavirus disease 2019 (COVID-19): report of three autopsies from Houston, Texas and review of autopsy findings from other United States cities. May 7, 2020 (https://www.sciencedirect.com/science/article/pii/S1054880720300375). preprint.
23. Hoffmann M, Kleine-Weber H, Krueger N, Mueller MA, Drosten C, Poehlmann S. The novel coronavirus 2019 (2019-nCoV) uses the SARS-coronavirus receptor ACE2 and the cellular protease TMPRSS2 for entry into target cells. January 31, 2020 (https://www.biorxiv.org/content/10.1101/2020.01.31.929042v1). preprint.
24. Yan R, Zhang Y, Li Y, Xia L, Guo Y, Zhou Q. Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. Science 2020;367:1444–1448.
25. Varga Z, Flammer AJ, Steiger P, et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet 2020;395:1417–1418.
