COVID PATHOPHYSIOLOGY

As the COVID-19 pandemic has swept across the world, a striking difference has been seen between the sexes. But why are men so much more susceptible to severe outcomes from COVID-19 than women?

Suspicions naturally turn to the sex hormones, and there have been suggestions that estrogen may be protective against COVID-19 in females and/or that androgens worsen COVID-19 outcomes in males.

New data supporting the androgen theory come from a study in Italy.

These researchers found that patients with prostate cancer being treated with androgen deprivation therapy (ADT) were less likely to become infected with COVID-19 and die from the disease than other groups, including other patients with cancer.

The findings suggest that androgens somehow make the virus more virulent and that this exacerbates the severity of disease in men, they say. They also speculate that ADT may be protective against COVID-19.

The study was published online May 7 in Annals of Oncology.

The team analyzed data from 68 hospitals in the Veneto region, one of the areas in Italy most severely affected by the COVID-19 pandemic.

They found data on 9280 patients with laboratory-confirmed SARS-CoV-2 infection — of whom 4532 were males.

Women in the region were actually slightly more likely to be infected with COVID-19 than men, 56% vs 44%, the researchers point out.

However, men were more prone to develop more severe forms of the disease: 60% of men vs 40% of women required hospitalization, rising to 78% of men vs 22% of women who required intensive care. Also, more men died than women (62% vs 38%).

The team then turned their focus onto patients with cancer.

Of the entire male population of Veneto, those with cancer had an almost twofold higher risk of becoming infected with COVID-19 than men without cancer (P < .0001).

However, when the team looked specifically at men with prostate cancer, they found "strikingly, only four out of 5273 patients receiving ADT developed SARS-CoV-2 infection and none of these patients died."

This compared to 37,161 men with prostate cancer who were not receiving ADT, among whom 114 men developed COVID-19 and 18 died.

Among another 79,661 patients in the Veneto region with cancer other than prostate cancer, 312 developed COVID-19 and 57 died.

"This is the first paper to suggest a link between ADT and COVID-19," commented lead author Andrea Alimonti, MD, PhD, Università della Svizzera Italiana in Lugano, Switzerland.

"Patients with prostate cancer receiving ADT had a significant fourfold reduced risk of COVID-19 infections compared to patients who did not receive ADT. An even greater difference (fivefold reduction in risk) was found when we compared prostate cancer patients receiving ADT to patients with any other type of cancer," he said.

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The finding raises "the hypothesis that androgen levels can facilitate coronavirus infections and increase the severity of symptoms, as has been seen in male patients," he said.

"These data are very interesting and raise a fascinating hypothesis," said Richard Martin, PhD, professor of clinical epidemiology at the University of Bristol, UK, commenting about the study. "But they do need independent validation in other large population-wide datasets...with appropriate statistical analysis including adjustment for important risk factors for SARS-CoV-2."

He noted that the Italian study results were not adjusted for potential confounders, for example, age, body mass index, and cardiometabolic comorbidities, that are strong risk factors for SARS-CoV-2. In addition, men taking ADT may have been more likely to self-isolate and so be at reduced risk of getting the infection, he suggested.

How Do Androgens Interact With the Virus?

Alimonti and colleagues offer a mechanistic explanation of how androgens interact with the virus.  

Coronavirus gains entry into the human cell by binding its viral spike (S) proteins to ACE2 and on S protein priming by TMPRSS2. TMPRSS2 is a member of a family of proteins called type II transmembrane serine proteases, which are involved in a number of processes including cancer and viral infections, they explain.

"Intriguingly, TMPRSS2 is an androgen-regulated gene that is upregulated in prostate cancer where it supports tumor progression," they point out.

There is also evidence that the same androgen receptor regulates TMPRSS2 expression in nonprostatic tissues, including the lung.

"[This] may explain the increased susceptibility of men to develop SARS-CoV-2 severe infections when compared to women," the authors speculate.

Because ADT is known to decrease TMPRSS2 levels, they suggest that androgen receptor antagonists "could be used to block or decrease the severity of SARS-CoV-2 infection in male patients."

They go even further and suggest that men without prostate cancer at high risk for COVID-19 could take ADT to prevent infection.

For men who do become infected with COVID-19, ADT might also help reduce symptom severity, they add.

Given that the effects of androgen receptor antagonists are reversible, "they could be used transiently (eg, 1 month) in patients affected by SARS-CoV-2, thereby reducing the risk of side effects due to long-term administration," the authors suggest.

Another Theory: Is Estrogen Protective?  

Another theory to explain the male/female difference for severe COVID-19 is that the female hormone estrogen may be protective. 

"People have to stop putting estrogen in that 'female hormone box' because it's a molecule that we all use as humans, it's just not women," Sharon Nachman, MD, told Medscape Medical News.

"Looking at estrogen as having potentially important immune effects is part of thinking outside the box," she said.

Nachman is associate dean for research at the Renaissance School of Medicine, Stony Brook University in New York, and is working together with Antonios Gasparis, MD, professor of surgery at the same center.

They are exploring the use of a transdermal estrogen patch in patients with COVID-19 in a randomized trial with a placebo-controlled arm. They are recruiting patients who present to their emergency department with signs and symptoms of COVID-19, and enroll them into the trial if they are interested. 

"We are testing everyone as well, but we are starting patients on the medication at the time of entry as opposed to waiting until we have a test result back," Nachman explained.

The primary objective of the study is to evaluate whether the transdermal patch, applied to the skin for 7 days, might reduce the need for intubation in men and women infected with COVID-19 versus standard of care.

The product is the same single-use transdermal estradiol patch (Climara, 25 cm2, Bayer) prescribed for postmenopausal women and will be used at the same dose, which is known to be safe.

After the patch is removed, patients will be carefully tracked for symptoms over the next 45 days to see if the patch reduced symptom severity, and if so, in which patients.

Nachman would have preferred to enroll patients before they had overt symptoms, but this simply isn't possible in a medical center where symptomatic patients present, she told Medscape Medical News.

However, she does know that even at their own medical center, the odds are stacked against male COVID-19 patients — and something is needed to mitigate its severity in this patient group.

As they were developing the protocol for the current study, the team decided to see who was in their ICU during a single study day.

The answer: mostly males. Intubation and death rates in men in their ICU for that single day was approximately 80% compared with only 20% among women.

"We have a new horrific pathogen that is pandemic and we're all probably going to get it, it's just a question of when and how sick we'll be from it," Nachman said.

Alimonti and coauthors have reported no relevant financial relationships as well as Goulder and Nachman.

Ann Oncol. Published online May 7, 2020. Full text

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The younger an ICU patient with severe COVID-19 is, the more obese that patient tends to be, according to a new analysis published in The Lancet.

"By itself, obesity seems to be a sufficient risk factor to start seeing younger people landing in the ICU," said the study's lead author, David Kass, MD, a professor of cardiology and medicine at Johns Hopkins University School of Medicine in Baltimore, Maryland.

"In that sense, there's a simple message: If you're very, very overweight, don't think that if you're 35 you're that much safer [from severe COVID-19] than your mother or grandparents or others in their 60s or 70s," Kass told Medscape Medical News.

The findings, which Kass describes as a "2-week snapshot" of 265 patients (58% male) in late March and early April at a handful of university hospitals in the United States reinforces other recent research indicating that obesity is one of the biggest risk factors for severe COVID-19 disease, particularly among younger patients. In addition, a large British study showed that, after adjusting for comorbidities, obesity was a significant factor associated with in-hospital death in COVID-19.

But this new analysis stands out as the only dataset to date that specifically “asks the question relative to age” of whether severe COVID-19 disease correlates to ICU treatment, he said.

The mean age of his study population of ICU patients was 55, Kass said, "and that was young, not what we were expecting."

"Even with the first 20 patients, we were already seeing younger people and they definitely were heavier, with plenty of patients with a BMI over 35 kg/m2," he added. "The relationship was pretty tight, pretty quick."

"Just don't make the assumption that any of us are too young to be vulnerable if, in fact, this is an aspect of our bodies," he said.

Steven Heymsfield, MD, past president and a spokesperson for The Obesity Society, agrees with Kass' conclusions.

"One thing we've had on our minds is that the prototype of a person with this disease is older...but now if we get [a patient] who's symptomatic and 40 and obese, we shouldn't assume they have some other disease," Heymsfield told Medscape Medical News.

"We should think of them as a susceptible population."

Kass and colleagues agree. "Public messaging to younger adults, reducing the threshold for virus testing in obese individuals, and maintaining greater vigilance for this at-risk population should reduce the prevalence of severe COVID-19 disease [among those with obesity]," they state.

"I think it's a mental adjustment from a healthcare standpoint, which might hopefully help target the folks who are at higher risk before they get into trouble," Kass told Medscape Medical News.

Trio of Mechanisms Explain Obesity's Extra COVID-19 Risks

Kass and coauthors write that, in analyzing their data, they anticipated similar results to the largest study of 1591 ICU patients from Italy in which only 203 were younger than 51 years. Common comorbidities among those patients included hypertension, cardiovascular disease, and type 2 diabetes, with similar data reported from China.

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When the COVID-19 epidemic accelerated in the United States, older age was also identified as a risk factor. Obesity had not yet been added to this list, Kass noted. But following informal discussions with colleagues in other ICUs around the country, he decided to investigate further as to whether it was an underappreciated risk factor.

Kass and colleagues did a quick evaluation of the link between BMI and age of patients with COVID-19 admitted to ICUs at Johns Hopkins, University of Cincinnati, New York University, University of Washington, Florida Health, and University of Pennsylvania.

The "significant inverse correlation between age and BMI" showed younger ICU patients were more likely to be obese, with no difference by gender.

Median BMI among study participants was 29.3 kg/m2, with only a quarter having a BMI lower than 26 kg/m2 and another 25% having a BMI higher than 34.7 kg/m2.

Kass acknowledged that it wasn't possible with this simple dataset to account for any other potential confounders, but he told Medscape Medical News that "While diabetes, cardiovascular disease, and hypertension, for example, can occur with obesity, this is generally less so in younger populations as it takes time for the other comorbidities to develop."

He said several mechanisms could explain why obesity predisposes patients with COVID-19 to severe disease.

For one, obesity places extra pressure on the diaphragm while lying on the back, restricting breathing.

"Morbid obesity itself is sort of proinflammatory," he continued.

"Here we've got a viral infection where the early reports suggest that cytokine storms and immune mishandling of the virus are why it's so much more severe than other forms of coronavirus we've seen before. So if you have someone with an already underlying proinflammatory state, this could be a reason there's higher risk."

Additionally, the angiotensin-converting enzyme-2 (ACE-2) receptor to which the SARS-CoV-2 virus that causes COVID-19 attaches is expressed in higher amounts in adipose tissue than the lungs, Kass noted.

"This could turn into kind of a viral replication depot," he explained. "You may well be brewing more virus as a component of obesity."

Sensitivity Needed in Public Messaging About Risks, But Test Sooner 

With an obesity rate of about 40% in the United States, the results are particularly relevant for Americans, Kass and Heymsfield say, noting that the country's "obesity belt" runs through the South.

Heymsfield, who wasn't part of the new analysis, notes that public messaging around severe COVID-19 risks to younger adults with obesity is "tricky," especially because the virus is "still pretty common in nonobese people."

Kass agrees, noting, "it's difficult to turn to 40% of the population and say, 'You guys have to watch it.'"

But the mounting research findings necessitate linking obesity with severe COVID-19 disease and perhaps testing patients in this category for the virus sooner before symptoms become severe.

And of note, since shortness of breath is common among people with obesity regardless of illness, similar COVID-19 symptoms might catch these individuals unaware, pointed out Heymsfield, who is also a professor in the Metabolism and Body Composition Lab at Pennington Biomedical Research Center at Louisiana State University, Baton Rouge.

"They may find themselves literally unable to breathe, and the concern would be that they wait much too long to come in" for treatment, he said. Typically, people can deteriorate between day 7 and 10 of the COVID-19 infection.  

Individuals with obesity "need to be educated to recognize the serious complications of COVID-19 often appear suddenly, although the virus has sometimes been working its way through the body for a long time," he concluded.

Kass and Heymsfield have declared no relevant financial relationships. 

Lancet. Published online April 30, 2020. Full text

Two new studies have been published that further focus attention on how the renin–angiotensin system — and specifically the ACE2 receptor — may be involved in COVID-19 infection.

Leading experts suggest that effects of the virus on the renin–angiotensin system may be the key to understanding why men and individuals with underlying cardiovascular diseases appear to have worse outcomes from COVID-19. 

One study, published in the European Heart Journal, found higher plasma levels of the ACE2 receptor/enzyme in men vs women in two large samples of patients with heart failure.

Noting that the SARS-CoV-2 virus that causes COVID-19 interacts with the ACE2 receptor, the authors suggest that their findings may explain why men have worse outcomes with the virus.

The study also shows that neither ACE inhibitors nor angiotensin-receptor blockers (ARBs) were associated with higher plasma ACE2 concentrations.

A second study, published as a letter to the New England Journal of Medicine, studied the relationship between ACE-inhibitor and ARB use and influenza A infection in a large United Kingdom patient database.

The authors note that influenza A has been shown to use the ACE2 receptor to mediate lung damage, similar to that seen in severe acute respiratory syndrome(SARS) with COVID-19.  

"Understanding the shared mechanism between SARS and influenza may help to address the question as to how ACE inhibitors and ARBs may modulate the manifestations of certain viral respiratory infections," they write.

Results showed that during a median 8.7 years of follow-up, individuals who had received a prescription for an ACE inhibitor had a lower risk of influenza than those who had not (adjusted hazard ratio, 0.66).

A second analysis found that the longer the duration of ACE-inhibitor use, the lower the risk of influenza infection. Similar results were found for ARBs.

"These associations regarding observed susceptibility to influenza may reflect mechanisms that are shared with coronaviruses, including SARS-CoV-2," the researchers conclude.

Is COVID-19 Activating the Renin–Angiotensin System?

In an editorial accompanying the European Heart Journal publication, Gavin Oudit, MD, University of Alberta, Edmonton, Canada, and Mark Pfeffer, MD, Brigham and Women's Hospital, Boston, Massachusetts, suggest that further work should measure plasma angiotensin peptides and plasma ACE2 levels and activity in COVID-19 patients to provide a direct evaluation of the state of the renin–angiotensin system, which could guide therapeutic interventions.

In comments to Medscape Medical News, Oudit, who has researched extensively on ACE2, put forward a hypothesis that the COVID-19 virus could be bringing about its harmful effects by causing an over-activation of the renin–angiotensin system.

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He explained that higher plasma levels of ACE2 may actually reflect lower tissue levels. "Tissue ACE2 is beneficial. It is nature's own inhibitor of the renin–angiotensin system, breaking down harmful angiotensin II to the protective angiotensin 1-7," he said. 

"The enzyme ADAM-17 is the key to regulating tissue and plasma ACE2 levels. This enzyme, which is thought to be more active in men than women, cleaves tissue ACE2 to form plasma ACE2, and it is believed that the virus responsible for COVID-19 activates ADAM-17," he noted.  

Activation of ADAM-17 is detrimental on two levels, Oudit says. "It directly causes a super inflammatory response, and it also reduces cardioprotective ACE2 in tissue." 

Oudit believes ACE2 has been wrongly cast as the villain regarding COVID-19 infection. "Yes, the virus does bind to ACE2 to enter cells, but only a small amount of ACE2 is needed for this. Higher levels are needed to protect from cardiovascular disease."

"By activating ADAM-17 the virus causes shedding of ACE2 from tissue into plasma, and the reduction of ACE2 in tissue leads to over-activation of the renin–angiotensin system in tissues, which causes cardiovascular disease to get worse," Oudit explained.

He believes there has been a lot of misinformation surrounding COVID-19, which has included speculation about ACE inhibitors and ARBs. "The science that we know suggests that these drugs are more likely to be beneficial than harmful. Observational clinical studies reported so far support this view.

"As we believe the renin–angiotensin system is being over-activated by the virus, this could also explain why patients with underlying cardiovascular diseases are having worse outcomes and would suggest that taking an ACE inhibitor or ARB would actually be protective." 

On the influenza study, Oudit said: "The influenza virus may well also activate the renin–angiotensin system. That study suggests that ACE inhibitors and ARBs may be protective here as well."

Eur Heart J. Published online May 10, 2020.  Full text, Editorial

N Eng J Med. Published online May 8, 2020. Letter

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