SARS-CoV-2 may enter the brain through the nose

A small German autopsy study of COVID-19 victims in Nature Neuroscience today demonstrates the presence of SARS-CoV-2—the virus that causes COVID-19—in nasal structures and the brain, suggesting that the virus crosses into the central nervous system (CNS) via nasal surfaces that contain nerve endings for smell.

COVID-19 CNS effects—loss of smell and taste, headache, fatigue, nausea, vomiting, acute cerebrovascular disease, and impaired consciousness—are widely reported and suggest viral penetration of the CNS, but the mechanism of entry remains unclear.

The researchers assessed nasal olfactory surfaces, associated nerve structures, and several CNS regions for evidence of viral RNA and proteins using in-situ hybridization and immunohistochemical staining in 33 patients who died of COVID-19 between March and August. COVID-19–associated neurologic symptoms in the study patients had included impaired consciousness, bleeding in the brain, headache, behavioral changes, and strokes. 

Of the 33 autopsy patients, 60.6% (20 of 33) showed evidence of SARS-CoV-2 RNA in olfactory mucosa—the lining of the nasal cavity containing sensory nerve endings for smell. The presence of viral particles in the olfactory tract and the proximity of nerve tissues suggests that SARS-CoV-2 may invade the CNS through olfactory nerves that control the sense of smell, the authors wrote.  

In a news release emailed to journalists, the authors highlighted the detection of SARS-CoV-2 spike protein in cells expressing markers of neurons. "Olfactory sensory neurons may be infected, as well as in the brain areas that receive smell and taste signals," they noted.  

"The findings are not surprising," Gitte Moos Knudsen, MD, DMSc, of Copenhagen University, said in a Science Media Centre statement today. "Central nervous system entry through the nasal epithelium is a recognized mode of viral uptake and would not be unique to SARS-CoV-2," she added.

Dysfunction of the cardiovascular, pulmonary, and renal systems is considered a major cause of severe or lethal COVID-19 cases. Notably, 18.1% (6 of 33) of autopsies revealed the presence of the virus in the medulla oblongata, or brain stem—a structure that controls breathing and cardiac function—suggesting that SARS-CoV-2 invasion of brain structures may play a role in COVID-19 complications.  

"It is possible that SARS-CoV-2 infection, at least in some instances, might aggravate respiratory or cardiac insufficiency—or even cause failure—in a CNS-mediated manner," the authors wrote.
Nov 30 Nat Neurosci study  
Nov 30 Science Media Centre statement

Estradiol hormone therapy may protect against COVID-19 death

A study late last week in BMC Medicine found that pre-menopausal women with higher natural levels of the sex hormone estradiol are 15% more likely to be infected with SARS-CoV-2 than men but less likely to become seriously ill or die, pointing to a potential protective role of sex hormones in COVID-19 outcomes. The study also found that estradiol hormone therapy for peri- and post-menopausal women significantly improves survival rates for infected women.

Estradiol is known to influence the expression of the human angiotensin-converting enzyme 2 (ACE2) protein, which facilitates SARS-CoV-2 cellular entry. It also appears to play a role in blocking cytokine production pathways, which may be implicated in the "cytokine storm"—an immune system overreaction seen in some patients with severe COVID-19.

Researchers collected retrospective data from 68,466 COVID-19 patient electronic health records in the 17-country TriNetX Real-World database, classifying patients into 5-year age-groups, and two female subgroups—women ages 15 to 49 and those 50 years and older. The 37,086 SARS-CoV-2–infected women were further classified into groups receiving supplementary estradiol in the form of either oral contraceptives or estradiol hormone therapy for peri- and post-menopausal conditions ("users") and women not taking supplemental hormones ("non-users").

The COVID-19 fatality risk for peri- and post-menopausal users was 50% less than in non-users (odds ratio [OR], 0.33; 95% confidence interval [CI], 0.18 to 0.62; hazard ratio [HR], 0.29; 95% CI; 0.11 to 0.76). Only 2.3% of older women users died from COVID-19, versus 6.6% of non-users.

Younger, pre-menopausal women have 15% higher frequencies of COVID-19 than age-matched men, but men have 50% higher fatality rates than women, suggesting a possible association with higher estrogen levels, the study authors wrote.

Smaller effects were observed for younger women taking estradiol hormones than in non-users, with similar fatality risk for both groups. "This may be the case because endogenous estradiol levels are typically already higher in younger women than for post-menopausal women, thus drowning out any differences between user/not-user groups," the authors noted.

The authors urge further study of the protective role of estradiol in light of its strong effect on COVID-19 fatality in older women.

"A brief, 7-day course of estradiol, delivered via a transdermal patch, could be a safe approach to reduce symptom severity in adult men and in older women, when administered prior to intubation," the authors concluded.
Nov 25 BMC Med study

CDC: Symptoms not enough to tell COVID-19 from similar infections

A Centers for Disease Control and Prevention (CDC) study published in Open Forum Infectious Diseases late last week found wide overlap between symptoms of COVID-19 and those of other respiratory illnesses, demonstrating that clinical symptoms alone are insufficient to distinguish between them.  

The researchers compared symptoms of non-hospitalized patients of all ages—with and without laboratory-confirmed SARS-CoV-2 infection—who sought medical care for an acute respiratory illness at US Flu Vaccine Effectiveness (VE) network study sites in Michigan, Pennsylvania, Texas, Washington, and Wisconsin from Mar 26 to Aug 15.

Of a total of 4,961 patients, 916 tested positive for SARS-CoV-2 via reverse-transcription polymerase chain reaction, and 4,045 had respiratory symptoms but tested negative for the virus. Phone interviews and online questionnaires gathered information on demographics, health behaviors such as smoking status, and underlying medical conditions.

Cough was the most commonly reported symptom in both SARS-CoV-2–positive and –negative patients (86% and 83%, respectively; P < 0.01). Shortness of breath/difficulty breathing was reported less often by those with COVID-19 than without (40% vs 47%; P < 0.01), and 99% of patients reported fever and/or cough.

"Persons with COVID-19 reported a median of 7 (IQR, 5–8) of the assessed symptoms versus 6 (IQR, 4–7) for persons without COVID-19 (P < 0.01)," the authors said. "Among 4102 participants asked, 59% of persons with COVID-19 versus 19% of persons without COVID-19 reported diminished taste or smell (P < 0.01). Generalized symptoms (muscle aches or headache) and gastrointestinal symptoms (vomiting, diarrhea, or abdominal pain) were more common among persons with COVID-19 (91% and 57%, respectively) than among those without COVID-19 (83% and 50%, respectively; P < 0.01 for both)."

"Because of the wide overlap in COVID-19 symptoms with those of other respiratory illnesses, laboratory confirmation of SARS-CoV-2 infection will be critical, not only for limiting disease spread, contact tracing, and monitoring clinical course, but also for assessing the effectiveness of interventions during periods of co-circulation of SARS-CoV-2 and other respiratory viruses, including influenza," the authors noted.
Nov 26 Open Forum Infect Dis study