New Coronavirus News from 23 Mar 2023

Why China’s COVID Comeback Is Still In The Early Innings, With Upside Ahead [Forbes, 23 Mar 2023]

By Drew Bernstein

When you unshackle 1.4 billion consumers who have been penned up at home for three years, it’s reasonable to expect some fireworks.

For the residents of Mainland China, life under “zero COVID” policies was a dreary round of rolling travel restrictions and lockdowns – as if the United States was permanently stuck on a skipping record of the Spring of 2020. While most of the population was able to find a way to get back to work eventually, the everyday routines of travel, dining out, and visiting friends and family were severely curtailed. Wallets stayed snapped shut.

Since China executed its “COVID pivot” in late December 2022, economists have been scrutinizing the data to see if the country will be able to achieve its goal of 5% growth in 2023. If achieved, China will serve as an engine to help developed economies avoid tipping into recession. This is particularly relevant in the new era of higher interest rates, shrinking money supply, and rolling banking jitters.

Initial government data for the first two months provided some early hints. China’s retail sales jumped by 3.5% in January and February of 2023 after a decline of 1.8% last December.

Spending on catering leaped by 9.2% after dropping by 14.1% in December. Clearly, Chinese consumers are beginning to find their footing. China has also indicated the need to expand domestic demand and prioritize expansion of consumption.

PROMOTED
The Chinese government appears to be turning on the taps of fiscal stimulus, with infrastructure investment surging by 9% during the first two months this year. However, property buyers mostly stayed on the sidelines, with investment dropping by 5.7%. This raises the question of how long the government coffers can float the economy, given that the finances of so many local entities are already stressed from the burdens of financing years of COVID containment amid declining revenues from property sales.

Further, China’s fabled export machine appears to be still stuck in the mud. Exports slid by 6.8% by January and February, and imports were down by 10.2% in the same period, missing analysts' estimates by a country mile. The hopes of Australian raw materials producers and German machinery manufacturers' that China will enable them to dodge a downturn may be a mirage.

A Generation at Risk
The statistic that should catch the authorities' attention is youth unemployment, which remained stubbornly high at 18.1% for those aged 16 to 24 in February. These young people are the most educated and invested generation in China’s history, with nearly 58% of Chinese enrolling in tertiary education in 2021, up from just 12.5% in 2000 and 3.4% in 1990. These are the children whose parents have sacrificed everything to lift them to the next rung on the ladder of educational attainment and financial security. Now many are “lying flat” or sidelined by a lack of jobs.

If China is to leap into a technologically advanced, wealthy society, it must allow this generation to recognize its full productive and economic potential. Because if this cohort of talent is squandered, China indeed risks “getting old before it gets rich.”

China has an opportunity to build a more sustainable, balanced economic model that policymakers have recognized as desirable for over a decade.

1. Reopening – While China has lifted most of the formal travel obstacles, tremendous logistical friction remains. Airliners must be removed from mothballs, and routes to popular overseas destinations restored. After three years, China just announced that it would begin issuing tourist visas to U.S. citizens on March 15th. Hong Kong fully reopened to Mainland China in February 2023. Before this, even American CEOs have had to wait a month or more to visit their operations in the PRC, inhibiting their understanding of conditions on the ground and willingness to invest in growth. Chinese citizens wishing to visit Hong Kong or travel overseas must compete for a limited supply of visas. More important than the flow of tourists, China has now lifted the travel restrictions on Chinese students studying overseas, which peaked at more than 700,000 students in 2019 but has subsequently dropped by half.

The U.S. government has also played a role in discouraging the flow through sometimes baseless harassment of students and scholars in STEM fields. If China truly wishes to grow into a global leadership position in the coming decades, it will need a generation that can understand and negotiate various cultural, political, and business environments. Today, the post-COVID youth generation – the so-called “Generation N” - is reported to be both pessimistic and isolated and more nationalistic than their predecessors. Optimism is essential to embracing careers, starting families, and launching new businesses – all ingredients China desperately needs.

2. Rebalancing – For the past decade, Chinese policymakers have explicitly acknowledged that the asset-intensive growth model driven by speculative real estate development and infrastructure investment is inherently unstable. Capital investment rose from 24% of GDP in 1990 to 45% in 2013 and has remained in the low- to mid-40% range ever since. There has been increased recognition that much of this investment has gone toward piling up non-productive investment that increases the debt stock without producing economic returns. President Xi Jinping announced as much when he wrote that China needs “to shift focus to improving the quality and returns of economic growth, to promoting sustained and healthy development rather than inflated GDP growth.” Yet whenever the government has moved to restrain the non-productive, highly leveraged real estate sector, it has backed off for fear of instability. As economist Michael Pettis has pointed out, China’s household consumption accounts for less than 40% of GDP. Combined with 10 to 15% of government consumption, China has the lowest consumption share of any economy in the world. Coming out of the COVID era, the Chinese government can now act boldly to rebalance the economy toward private consumption, services, and internal demand. This will require putting in place more robust systems of social and health insurance to reduce China’s outsized savings rate, continuing to support robust capital markets that funnel savings towards productive enterprises, and creating incentives for family formation that make it feasible to raise more than one child in an ultra-competitive educational system.

3. Rallying the Private Sector – The undeniable economic miracle that took place in China had two central pillars. First, a state sector that prioritized economic growth and provided world-class infrastructure and a trained, plentiful workforce has proved irresistible to multinationals seeking to become more competitive in a globalizing world. Second, China made a very conscious decision to unleash the entrepreneurial energies of its people by destigmatizing the accumulation of wealth and promoting domestic champions through various implicit and explicit means. According to Harvard’s Kennedy School, China’s private sector contributes to 60% of China’s GDP but 70% of innovation, 80% of urban employment, and 90% of new jobs. Put another way, a bright future for China’s young college graduates is intrinsically tied to a vibrant private sector economy. Unfortunately, the combination of economic dampening during COVID and the drive to reign in the economic influence of China’s private technology sector has diminished the private sector’s expansion and business confidence. For the first time since the beginning of the reform era, the private sector’s share of employment and market value dropped significantly in 2020 and 2021. In recent weeks, Xi Jinping has been quoted in state media about the vital role of the private sector in economic development, saying on March 7th that “We should improve the development environment for private enterprises, remove the institutional obstacles that prevent them from fairly participating in market competition, and safeguard the property rights of private enterprises and the rights and the interests of private entrepreneurs according to law. We should… support the development of the private sector and the growth of private enterprises and boost market expectations and confidence.” If the government follows these warm words with consistent and predictable actions, the animal spirits of a revived private sector will provide a powerful “third leg” to the post-COVID snapback.

The markets appear confused about what to make of China’s COVID comeback prospects.

After an explosive 55% rally between November and late January to 22,688 points, Hong Kong’s Hang Seng Index has retraced about half of its gains. The word on the street is that no buyer wanted to get steamrolled by the COVID reopening train, but they were not “conviction owners” of the rally.

Investors will likely have the chance to dip their toes back into Chinese equities in the second half of 2023. Based on market activity, we expect many China tech names to seek to launch overseas IPOs, particularly via the SPAC vehicle. Of note, beginning on March 31st, China’s securities regulator, the CSRC, will, for the first time, implement a system for reviewing and approving overseas listings. Although this presents an additional hurdle to clear, it means that these issuers will have the government's imprimatur as appropriate for foreign ownership – removing one major risk factor for those who want to play the China comeback.

The Chinese government has also shown a tremendous talent for keeping equity investors on their toes, if not to say tearing out their hair. But if we begin to see the consistent implementation of the three “Policy Rs” outlined above, it would be foolish to bet against the vast, untapped commercial energies and appetite for a better life of China’s 1.4 billion people.

New Coronavirus News from 25 Mar 2023

The rest of the story — how to read the medical literature [Williamsport Sun-Gazette, 25 Mar 2023]

A recent Let’s end COVID! article (February 25th) talked about the process of medical research and how the results are communicated to the world at large via public and social media. Journalists who translate the mysterious pronouncements of medical researchers and other scientists provide a valuable public service by helping us non-scientists keep up with current developments. This is especially important in a public health crisis such as the current COVID-19 pandemic, where it is a matter of life and death.

Scientific research is supposed to be objective, impartial. Of course, scientists are human, and even the most careful scientist can unknowingly let bias affect their work and how they interpret and communicate their results. When scientific information is communicated by non-scientists to other non-scientists, it’s a little like the “telephone game” where one person whispers a word or phrase to the person beside them, that person whispers to the next one in line and so on, until the last person announces what they heard, which often is not what the first person said. Journalists reporting medical news may have their own biases that unintentionally color their communication.

Sometimes the people communicating research results deliberately misinterpret scientific findings that disagree with their own partisan agendas. We have seen this several times during the current pandemic including, for example, when some people continued to recommend using ivermectin to prevent or treat COVID-19 although no studies have shown that it works.

When reading a news article about COVID-19 (or any medical issue) I look for the source of the information. If the author hasn’t included a link to the study being discussed, or at least enough information (author and journal title) to find the study easily, I get suspicious. Does the author not want me to look at the original information for some reason? As the Russian proverb popularized by Ronald Reagan advises, I like to “trust but verify.” If I’m going to apply this new information to my own healthcare, I want to see–and decide–for myself.

Researchers strive for clarity, conciseness, and precision when reporting their results because they are communicating to other busy scientists who are coping with the same daily flood of information, and who need to determine quickly whether the article is relevant or provides new knowledge.

Fortunately, this helps the rest of us, too. Professional journals publish several kinds of articles, including editorials, case reports, and even letters to the editor, but when you are following up medical news you will be looking at primary research articles. These reports of studies and results follow a consistent outline:

• Abstract (Summary)
• Introduction (Context)
• Methods and Materials (The Experiment)
• Results (The Data)
• Discussion (Explanation)
• Conclusions (Interpretation)

The abstract reviews the article’s key points–the question being studied, why it’s important, how the research was conducted, and the study results and conclusions. Non-scientists should read the abstract first to get a sense of what information the article contains, but don’t stop there. Read the introduction next for context and background information, including previous studies on which the new research builds. It helps you understand where the new research “fits.” The introduction will clearly state the purpose of the research and the question (the hypothesis) it answers.

Some experts recommend reading the introduction first and the abstract last. That way you can draw your own conclusions and see whether they match the authors’.

It’s OK to skip the methods section, which explains in detail how the research was done so that other scientists can evaluate the study’s quality, repeat the research to confirm the results, or develop new studies based on its methods and findings. You may also–unless you are familiar with statistical concepts and vocabulary–skip the results section, which presents and analyzes the data the investigation produced.

Finally, read the discussion and conclusions (sometimes separate sections) to see how the authors interpret their findings. They should also tell you of any limitations in the study that might affect the results, the strength of their evidence, the implications for practice change and future research, and what additional studies may be needed.

Various online guides for nonscientist readers exist. “Anatomy of a Scientific Journal Article” by Erica Mitchell (https://blog.eoscu.com/blog/anatomy-of-a-scientific-journal-article) and “How to read and understand a scientific article” by Jennifer Raff
(https://cdn.ymaws.com/www.oandp.org/resource/resmgr/docs/skc/journalclub/How_to_Read_and_Understand.pdf) are good ones.
Michael Heyd, a retired medical librarian from Fairfield Township who spent more than 40 years searching the literature for professional hospital staff, is a member of Let’s end COVID!, a group of concerned people in Northcentral PA working to overcome the COVID-19 pandemic through education, outreach and mitigation. Currently the Lycoming County COVID-19 Community Level used to define interaction in general public spaces is low. At this level the CDC recommends optional masking any time for extra protection.

FDA warning shuts down ivermectin site [North Platte Telegraph, 25 Mar 2023]

By GEORGE HAWS

website promoting ivermectin to treat COVID-19 has been shut down. The action was in response to a warning letter issued by the U.S. Food and Drug Administration on March 16.
Legal products containing ivermectin have long used for control of parasites, especially in livestock, and are available only by prescription.

However, according to the FDA warning, ivermectin4covid.com was promoting a product called Iverheal 12mg, manufactured by Healing Pharma, to control not only parasites, but also COVID-19, a viral infection.

The FDA’s letter noted that Iverheal 12mg is not an approved product and that ivermectin is not approved for COVID-19. The letter listed a number of alleged violations related to lack of FDA approval, mislabeling, violations of rules related to interstate commerce, etc.

The letter also lists addition concerns related to unapproved or misbranded drugs, and contains the following statement:

“There are inherent risks to consumers who purchase unapproved new drugs and misbranded drugs. Unapproved new drugs do not carry the same assurances of safety and effectiveness as those drugs subject to FDA oversight,” the warning said. “Drugs that have circumvented regulatory safeguards may be contaminated, counterfeit, contain varying amounts of active ingredients, or contain different ingredients altogether. We request that you cease the sale of any unapproved and misbranded products, whether for the mitigation, prevention, treatment, diagnosis, or cure of COVID‐19, or any other disease for which the drugs you are selling are not approved by FDA for distribution in the U.S.”

The warning letter was also posted to the FDA website.

New Coronavirus News from 21 Mar 2023

FDA Warning Letter Issued to Website Purveying Ivermectin Pills for Covid-19 [MedCity News, 21 Mar 2023]

By FRANK VINLUAN

The FDA has issued a warning letter to a website that has been selling the antiparasitic drug ivermectin as a treatment for Covid-19. The correspondence directs the company to stop selling its products and correct any misleading language in its marketing material.

A website that markets ivermectin as a Covid-19 treatment has run afoul of the FDA. The agency issued a warning letter notifying the site that it is selling unapproved and misbranded products over the internet to consumers in the U.S.

The warning letter, dated March 16, was posted by the FDA on Tuesday. According to the agency, the website ivermectin4covid.com stated: “Ivermectin (Iverheal 12) is an antiparasitic, and also an antiviral drug manufactured by Healing Pharma. It is used to kill the parasites in the body. It is also useful in Covid 19 care.”

Iverheal12 is a generic version of ivermectin manufactured by Healing Pharma, a Mumbai, India-based generic medicines company. The drug is a 12 mg dose that Healing Pharma offers in packages of 10 tablets per box. The language the FDA quoted from ivermectin4covid’s site is a word-for-word restatement of language in Healing Pharma’s description of the product.
The FDA letter states that that while approved versions of ivermectin are available in the U.S., the Iverheal 12 mg product from Healing Pharma is not one of them. The agency also said approved versions of ivermectin are for treating parasitic infections, and they are available only by prescription.

“In addition, ivermectin has not been approved by FDA for use in the prevention, diagnosis, treatment, mitigation, or cure of COVID-19,” the warning letter stated.

The letter tells the company to review its website, labels, and promotional materials to ensure that they do not misleadingly represent products as safe and effective for uses that are not approved by the FDA. Furthermore, the company is directed to respond to the FDA within 48 hours with an email describing the steps it has taken to address violations and to prevent their recurrence.

The ivermectin4covid website now shows a single page stating it has been temporarily suspended according to guidance by the FDA. An archived version shows it was also selling hydroxychloroquine in packages of 100 tablets per box. According to a check of the website on hostingchecker.com, ivermectin4covid.com is hosted in Singapore by DigitalOcean, a New York-based company that operates data centers across the world.

Ivermectin traces its origins to Japan, where scientists isolated a microorganism from a soil sample in the 1970s, according to a 2011 paper published in Proceedings of the Japan Academy, Series B. This microorganism was found to have properties useful in killing internal and external parasites. A partnership between Kitasato Institute in Japan and pharmaceutical giant Merck led to the development of broad-spectrum antiparasitic agents called avermectins.

Ivermectin is a semisynthetic antiparasitic derived from avermectin and made for oral dosing.

Merck brought the product to market under the name Stromectal. Though patents on this product have long expired and generic versions are widely available, Merck still sells Stromectal. In 2021, during the height of the pandemic, the company reiterated that preclinical and clinical research found no scientific basis for using ivermectin to treat Covid-19.
Well-controlled scientific studies continue to show that ivermectin does not help in the treatment of Covid-19. A randomized, placebo-controlled study that enrolled more than 1,500 U.S. patients when the delta and omicron variants were dominant found that ivermectin did not significantly improve the time to recovery from mild-to-moderate Covid-19. The peer-reviewed results were published last October in the Journal of the American Medical Association.

New Coronavirus News from 21 Mar 2023

FDA Warning Letter Issued to Website Purveying Ivermectin Pills for Covid-19 [MedCity News, 21 Mar 2023]

By FRANK VINLUAN

The FDA has issued a warning letter to a website that has been selling the antiparasitic drug ivermectin as a treatment for Covid-19. The correspondence directs the company to stop selling its products and correct any misleading language in its marketing material.

A website that markets ivermectin as a Covid-19 treatment has run afoul of the FDA. The agency issued a warning letter notifying the site that it is selling unapproved and misbranded products over the internet to consumers in the U.S.

The warning letter, dated March 16, was posted by the FDA on Tuesday. According to the agency, the website ivermectin4covid.com stated: “Ivermectin (Iverheal 12) is an antiparasitic, and also an antiviral drug manufactured by Healing Pharma. It is used to kill the parasites in the body. It is also useful in Covid 19 care.”

Iverheal12 is a generic version of ivermectin manufactured by Healing Pharma, a Mumbai, India-based generic medicines company. The drug is a 12 mg dose that Healing Pharma offers in packages of 10 tablets per box. The language the FDA quoted from ivermectin4covid’s site is a word-for-word restatement of language in Healing Pharma’s description of the product.
The FDA letter states that that while approved versions of ivermectin are available in the U.S., the Iverheal 12 mg product from Healing Pharma is not one of them. The agency also said approved versions of ivermectin are for treating parasitic infections, and they are available only by prescription.

“In addition, ivermectin has not been approved by FDA for use in the prevention, diagnosis, treatment, mitigation, or cure of COVID-19,” the warning letter stated.

The letter tells the company to review its website, labels, and promotional materials to ensure that they do not misleadingly represent products as safe and effective for uses that are not approved by the FDA. Furthermore, the company is directed to respond to the FDA within 48 hours with an email describing the steps it has taken to address violations and to prevent their recurrence.

The ivermectin4covid website now shows a single page stating it has been temporarily suspended according to guidance by the FDA. An archived version shows it was also selling hydroxychloroquine in packages of 100 tablets per box. According to a check of the website on hostingchecker.com, ivermectin4covid.com is hosted in Singapore by DigitalOcean, a New York-based company that operates data centers across the world.

Ivermectin traces its origins to Japan, where scientists isolated a microorganism from a soil sample in the 1970s, according to a 2011 paper published in Proceedings of the Japan Academy, Series B. This microorganism was found to have properties useful in killing internal and external parasites. A partnership between Kitasato Institute in Japan and pharmaceutical giant Merck led to the development of broad-spectrum antiparasitic agents called avermectins.

Ivermectin is a semisynthetic antiparasitic derived from avermectin and made for oral dosing.

Merck brought the product to market under the name Stromectal. Though patents on this product have long expired and generic versions are widely available, Merck still sells Stromectal. In 2021, during the height of the pandemic, the company reiterated that preclinical and clinical research found no scientific basis for using ivermectin to treat Covid-19.

Well-controlled scientific studies continue to show that ivermectin does not help in the treatment of Covid-19. A randomized, placebo-controlled study that enrolled more than 1,500 U.S. patients when the delta and omicron variants were dominant found that ivermectin did not significantly improve the time to recovery from mild-to-moderate Covid-19. The peer-reviewed results were published last October in the Journal of the American Medical Association.

New Coronavirus News from 27 Feb 2023

High-dose ivermectin does not reduce COVID-19 symptom duration among mild-to-moderate outpatients [News-Medical.Net, 27 Feb 2023]

By Pooja Toshniwal Paharia

In a recent study published in JAMA, researchers evaluate the efficacy of ivermectin in a maximum dosage of 600 μg/kg/day over six days in treating early mild-to-moderate coronavirus disease 2019 (COVID-19).

Background
The continual emergence of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with greater transmissibility and immune evasiveness has threatened the efficacy of COVID-19 vaccines and therapeutic agents such as antiviral drugs and monoclonal antibodies. As a result, research is needed to identify new drugs with anti-SARS-CoV-2 activity.

It remains unknown whether a daily dose of ivermectin 600 μg/kg can reduce the duration of symptoms or prevent hospital admissions in individuals with mild-to-moderate SARS-CoV-2 infections in outpatient settings.

About the study
In the present accelerating COVID-19 therapeutic interventions and vaccines 6 (ACTIV-6) randomized controlled trial, researchers investigate whether 600 μg/kg/day of ivermectin for six days reduces the duration of symptoms among individuals with symptomatic mild-to-moderate SARS-CoV-2 infection in outpatient settings.

In the ongoing, national, double-blinded, randomized, decentralized, and placebo-controlled clinical trial investigating repurposed drugs for treating individuals with mild or moderate SARS-CoV-2 infections 1,206 confirmed-SARS-CoV-2-positive individuals 30 years or older who experienced at least two acute symptoms for less than one week were recruited across 93 sites throughout the U.S.

Individuals were recruited between February 16, 2022, and July 22, 2022, and followed up through November 10, 2022. COVID-19 diagnosis was confirmed by polymerase chain reaction (PCR) assay or SARS-CoV-2 antigen testing, including at-home tests.

In the analysis, 602 participants received ivermectin at a maximum dosage of 600 μg/kg/day, whereas 604 individuals received a placebo daily for six days. The prime study outcome was the duration of sustained COVID-19 recovery or at least three successive and asymptomatic days.

Secondary study outcomes included hospital admissions, deaths, or emergency department visits by COVID-19 outpatients through week four. The team excluded individuals who were hospitalized, consumed ivermectin within the two previous weeks, or had known contraindications or allergies to ivermectin.

The other study drug under investigation during the period was fluvoxamine. Proportional hazards regression modelling was performed and the hazard ratios (HR) were calculated.

Ivermectin was supplied in bottles comprising 7.0 mg tablets to participants’ homes.

Dosing schedules were based on participants’ weight. Participants were asked to complete daily assessments and report adverse events through week two.

Self-documented data were obtained on individual demographics including age, sex, body mass index (BMI), race, ethnicity, history of medical diseases, concomitant medications, COVID-19 symptoms, the status of vaccination, and responses to questionnaires distributed for assessing the quality of life.

Study findings
Among the study participants, 59% were female with a median age of 48 years and 84% were fully vaccinated against COVID-19. In both groups, the median duration for sustained recovery from COVID-19 was 11 days.

The median dose of ivermectin was 498 μg/kg/day. In the large vaccinated outpatient population, the posterior probability for benefit using ivermectin was 0.7 for the primary outcome of time to COVID-19 recovery. The posterior probability of reduction of COVID-19 symptom duration by one or more days using ivermectin was less than 0.10% with an HR value of 1.0.

Among ivermectin-treated individuals, 6% were admitted to hospitals, died, or visited the emergency department as compared to 36 placebo-treated individuals with an HR 1.0. Among ivermectin-treated individuals, four were hospitalized and one died. The number of corresponding individuals was two and zero among placebo-treated individuals.

The team did not commonly observe adverse events in any group. Adverse events documented more than two times following ivermectin treatment included cognitive impairments, blurring of vision, increased sensitivity to light, dizziness, asthma, and photophobia. The death of an ivermectin-treated individual was documented as occurring by accident and was not associated with COVID-19 or ivermectin use.

The difference in the duration spent feeling sick due to COVID-19 was estimated as three hours and 20 minutes faster with ivermectin as compared to the placebo. The COVID-19 clinical progression scale scores at weeks one, two, and four could not meet predetermined threshold values for therapeutic benefit from ivermectin.

Conclusions
Overall, the study findings showed that ivermectin at a maximum dose of 600/μg/kg/day treatment for six days did not reduce the duration of sustained COVID-19 recovery among mild-to-moderate outpatients with SARS-CoV-2 Omicron variant infections. Taken together, these data do not support the use of in treating individuals with mild-to-moderate SARS-CoV-2 infections.

Journal reference:
• Naggie, S., Boulware, D. R., Lindsell, C. J., et al. (2023). Effect of Higher-Dose Ivermectin for 6 Days vs Placebo on Time to Sustained Recovery in Outpatients With COVID-19 A Randomized Clinical Trial. JAMA. doi:10.1001/jama.2023.1650.

New Coronavirus News from 6 Oct 2021

Ivermectin: How false science created a Covid 'miracle' drug [BBC News, 6 Oct 2021]

By Rachel Schraer & Jack Goodman

Ivermectin has been called a Covid "miracle" drug, championed by vaccine opponents, and recommended by health authorities in some countries. But the BBC can reveal there are serious errors in a number of key studies that the drug's promoters rely on.

For some years ivermectin has been a vital anti-parasitic medicine used to treat humans and animals.

But during the pandemic there has been a clamour from some proponents for using the drug for something else - to fight Covid and prevent deaths.

The health authorities in the US, UK and EU have found there is insufficient evidence for using the drug against Covid, but thousands of supporters, many of them anti-vaccine activists, have continued to vigorously campaign for its use.

Members of social media groups swap tips on getting hold of the drug, even advocating the versions used for animals.

The hype around ivermectin - based on the strength of belief in the research - has driven large numbers of people around the world to use it.

Campaigners for the drug point to a number of scientific studies and often claim this evidence is being ignored or covered up. But a review by a group of independent scientists has cast serious doubt on that body of research.

The BBC can reveal that more than a third of 26 major trials of the drug for use on Covid have serious errors or signs of potential fraud. None of the rest show convincing evidence of ivermectin's effectiveness.

Dr Kyle Sheldrick, one of the group investigating the studies, said they had not found "a single clinical trial" claiming to show that ivermectin prevented Covid deaths that did not contain "either obvious signs of fabrication or errors so critical they invalidate the study".

Major problems included:
• The same patient data being used multiple times for supposedly different people
• Evidence that selection of patients for test groups was not random
• Numbers unlikely to occur naturally
• Percentages calculated incorrectly
• Local health bodies unaware of the studies

The scientists in the group - Gideon Meyerowitz-Katz, Dr James Heathers, Dr Nick Brown and Dr Sheldrick - each have a track record of exposing dodgy science. They've been working together remotely on an informal and voluntary basis during the pandemic.

They formed a group looking deeper into ivermectin studies after biomedical student Jack Lawrence spotted problems with an influential study from Egypt. Among other issues, it contained patients who turned out to have died before the trial started. It has now been retracted by the journal that published it.

The group of independent scientists examined virtually every randomised controlled trial (RCT) on ivermectin and Covid - in theory the highest quality evidence - including all the key studies regularly cited by the drug's promoters.

RCTs involve people being randomly chosen to receive either the drug which is being tested or a placebo - a dummy drug with no active properties.

The team also looked at six particularly influential observational trials. This type of trial looks at what happens to people who are taking the drug anyway, so can be biased by the types of people who choose to take the treatment.

Out of a total of 26 studies examined, there was evidence in five that the data may have been faked - for example they contained virtually impossible numbers or rows of identical patients copied and pasted.

In a further five there were major red flags - for example, numbers didn't add up, percentages were calculated incorrectly or local health bodies weren't aware they had taken place.

On top of these flawed trials, there were 14 authors of studies who failed to send data back. The independent scientists have flagged this as a possible indicator of fraud.

The sample of research papers examined by the independent group also contains some high-quality studies from around the world. But the major problems were all in the studies making big claims for ivermectin - in fact, the bigger the claim in terms of lives saved or infections prevented, the greater the concerns suggesting it might be faked or invalid, the researchers discovered.

While it's extremely difficult to rule out human error in these trials, Dr Sheldrick, a medical doctor and researcher at the University of New South Wales in Sydney, believes it is highly likely at least some of them may have been knowingly manipulated.

A recent study in Lebanon was found to have blocks of details of 11 patients that had been copied and pasted repeatedly - suggesting many of the trial's apparent patients didn't really exist.

The study's authors told the BBC that the "original set of data was rigged, sabotaged or mistakenly entered in the final file" and that they have submitted a retraction to the scientific journal which published it.

Another study from Iran seemed to show that ivermectin prevented people dying from Covid.
But the scientists who investigated it found issues. The records of how much iron was in patients' blood contained numbers in a sequence that was unlikely to come up naturally.

And the patients given the placebo turned out to have had much lower levels of oxygen in their blood before the trial started than those given ivermectin. So they were already sicker and statistically more likely to die.

But this pattern was repeated across a wide range of different measurements. The people with "bad" measurements ended up in the placebo group, the ones with "good" measurements in the ivermectin group.

The likelihood of this happening randomly across all these different measurements was vanishingly small, Dr Sheldrick said.

Dr Morteza Niaee, who led the Iran study, defended the results and the methodology and disagreed with problems pointed out to him, adding that it was "very normal to see such randomisation" when lots of different factors were considered and not all of them had any bearing on participants' Covid risk.

But the Lebanon and Iran trials were excluded from a paper for Cochrane - the international experts in reviewing scientific evidence - because they were "such poorly reported studies".

The review concluded there was no evidence of benefit for ivermectin when it comes to Covid.
The largest and highest quality ivermectin study published so far is the Together trial at the McMaster University in Canada. It found no benefit for the drug when it comes to Covid.

Calls over suspected ivermectin poisonings in the US have increased a lot but from a very small base (435 to 1,143 this year) and most of these cases were not serious. Patients have had vomiting, diarrhoea, hallucinations, confusion, drowsiness and tremors.

But indirect harm can come from giving people a false sense of security, especially if they choose ivermectin instead of seeking hospital treatment for Covid, or getting vaccinated in the first place.

Dr Patricia Garcia, a public health expert in Peru, said at one stage she estimated that 14 out of every 15 patients she saw in hospital had been taking ivermectin and by the time they came in they were "really, really sick".

Large pro-ivermectin Facebook groups have turned into forums for people to find advice on where to buy it, including preparations meant for animals.

Some groups regularly contain posts about conspiracy theories of ivermectin cover-ups, as well as pushing anti-vaccine sentiment or encouraging patients to leave hospital if they aren't getting the drug.

The groups often provide a gateway to more fringe communities on the encrypted app Telegram.

These channels have co-ordinated harassment of doctors who fail to prescribe ivermectin and abuse has been aimed at scientists. Dr Andrew Hill, from the University of Liverpool, wrote an influential positive review of ivermectin, originally saying the world should "get prepared, get supplies, get ready to approve [the drug]".

Now he says the studies don't stand up to scrutiny - but after he changed his view, based on new evidence emerging, he received vicious abuse.

A small number of qualified doctors have had an exaggerated influence on the ivermectin debate. Noted proponent Dr Pierre Kory's views have not changed despite the major questions over the trials. He criticised "superficial interpretations of emerging trials data".

Dr Tess Lawrie - a medical doctor who specialises in pregnancy and childbirth - founded the British Ivermectin Recommendation Development (Bird) Group.

She has called for a pause to the Covid-19 vaccination programme and has made unsubstantiated claims implying the Covid vaccine had led to a large number of deaths based on a common misreading of safety data.

When asked during an online panel what evidence might persuade her ivermectin didn't work she replied: "Ivermectin works. There's nothing that will persuade me." She told the BBC: "The only issues with the evidence base are the relentless efforts to undermine it."

Around the world it was originally not opposition to vaccines but a lack of them that led people to ivermectin.

The drug has at various points been approved, recommended or prescribed for Covid in India, South Africa, Peru and much of the rest of Latin America, as well as in Slovakia.

Health authorities in Peru and India have stopped recommending ivermectin in treatment guidelines.

In February, Merck - one of the companies that makes the drug - said there was "no scientific basis for a potential therapeutic effect against Covid-19".

In South Africa, the drug has become a battleground - doctors point out the lack of evidence but many patients desperately want access as the vaccine rollout has been patchy and problematic. One GP in the country described a relative, a registered nurse, who didn't book a coronavirus vaccine she was eligible for and then caught the virus.

"When she started getting worse, instead of getting proper assessment and treatment, she treated herself with ivermectin," she said.

"Instead of consulting a doctor, she continued with the ivermectin and got home oxygen. By the time I heard how low her oxygen saturation levels were (66%), I begged her daughter to take her to casualty.

"At first they were reluctant, but I convinced them to go. She passed away a few hours later."
Additional reporting by Shruti Menon

New Coronavirus News from 23 Mar 2023

China's only now revealed crucial COVID-19 origins data. Earlier disclosure may have saved us 3 years of political argy-bargy [The Conversation、 23 Mar 2023]

By Dominic Dwyer

Once more, we’re talking about the origins of SARS-CoV-2, the virus that causes COVID-19.
First the US Department of Energy’s review gave more emphasis to the laboratory leak hypothesis than previously, although the confidence for this conclusion was low.

Second, and more importantly, is the release and analysis this week of viral and animal genetic material collected from the Huanan wet market in Wuhan, the place forever associated with the beginning of the pandemic.

It’s a subject close to me. I was the Australian representative on the international World Health Organization (WHO) investigation into the origins of SARS-CoV-2. I went to Wuhan on a fact-finding mission in early 2021. I visited the now-closed market.

Now we have stronger evidence that places raccoon dogs at the market as a possible animal reservoir of SARS-CoV-2, potentially infecting humans.

If we’d had this evidence three years ago, we need to ask ourselves how different recent history would have been. We would have reduced the enormous energy, media frenzy and political argy-bargy about less likely hypotheses of the pandemic’s origins. We might have better focused our research attention.

Read more: COVID origins debate: what to make of new findings linking the virus to raccoon dogs

The twists, turns and puzzles
Samples were taken from various places in the market, in January 2020, within weeks of the early COVID-19 cases in Wuhan. SARS-CoV-2 RNA and human DNA were identified in these environmental samples, although no animal swabs were positive for the virus.

This was presented to the WHO team investigating the origins of the pandemic in January 2021, of which I was part.

The work was published as a preprint (posted online, before being independently verified) in February 2022.

The underlying “metagenomic” data to support the conclusions in the preprint – that SARS-CoV-2 and human (but not animal) sequences were present – needed to be provided to allow further analyses. This is something that is generally required by journals and regarded as appropriate in the spirit of scientific openness and collaboration.

However, it wasn’t until early March 2023 that the international community had access to the data.

That’s when there was a “drop” of these environmental metagenomic sequences into the GISAID database, the international open access repository of viral sequences.

This allowed an independent team of international experts to analyse them. In a startling revelation, they identified large amounts of raccoon dog and other animal DNA in conjunction with SARS-CoV-2. Raccoon dogs can be readily infected with SARS-CoV-2 and can transmit it. The international team published their observations as a preprint earlier this week.

Of note was the physical co-location of these virus and animal sequences in the corner of what is a very large market, the corner associated with early human cases. It is now known (but initially rejected by Chinese authorities) that wild and farmed animals were sold in this area of the market.

After the sequences were analysed by the international team, the Chinese scientists who had performed the market testing were contacted for comment and discussion – especially around the important observation that mixed in among the SARS-CoV-2 sequences were a large proportion of raccoon dog and other animal DNA.

The sequences were then withdrawn from the GISAID database within a few hours of the study authors being approached. This is perhaps unusual for an open database such as GISAID, and clarity could be sought why this occurred.

Why is this work important?
This latest work does not prove raccoon dogs were definitely the source of SARS-CoV-2. Presumably, they are likely to have been an intermediate host between bats and humans. Bats harbour many coronaviruses, including ones related to SARS-CoV-2.

However, the data fits the narrative of the animal/human connections of SARS-CoV-2.

This, along with other examination of animal links to SARS-CoV-2, should be taken in the context of the lack of robust data to support the other SARS-CoV-2 origins hypotheses, such as a laboratory leak, contaminated frozen food, and acquisition outside China. Bit by bit, the evidence supports animal origins of the outbreak, centred on the Huanan market in Wuhan.

The length of time taken for this early work to surface and the difficulty in accessing the raw data are unfortunate, points made recently by the WHO.

Sympathetically, one might say, the wrong analysis of the original data collected in early 2020 was undertaken and the researchers missed the animal links.

Cynically, (and without evidence) one might say that the significance of the data was recognised, but not made readily available. This is a question for the Chinese researchers at the Chinese Center for Disease Control to answer.

What are the implications of this delay?
If this had been identified in early 2020 then further studies to understand the viral origins in animals could have been undertaken.

Three years on, it is very difficult to do such studies, tracking backwards from the now closed market to the animal sources and the people who handled these animals.

Clearer answers would have taken some of the heat out of the debate around the possible viral origins. Of course, all hypotheses should remain on the table, but some of these could have been much better explored with earlier data.

Would it have changed the course of the pandemic? Probably not. The virus had already spread worldwide and adapted very well to human-to-human transmission by the time this work was available. However, it would have driven research in better directions and improved future pandemic planning.

What now?
Lessons for the future are obvious. Open disclosure of sequence data is the best way to undertake scientific investigation, especially for something of such international significance.

Making data unavailable, or not reaching out for assistance in complicated analyses, only slows the process.

The resulting political to and fro by all countries, particularly the US and China, has meant that suspicion has deepened, and progress slowed even further.

Although WHO has been criticised for errors in how it managed the pandemic, and in collating data to understand the origins and progress future research, it remains the best international agency to foster open sharing of data.

Scientists, for the most part, want to do the right thing and find the answers to important questions. Facilitating this is crucial.

China’s huge quarantine camps standing months after ‘zero COVID’ [Al Jazeera English, 23 Mar 2023]

Satellite imagery shows facilities are still intact nearly four months after the end of Beijing’s draconian pandemic policy.
Taipei, Taiwan – Nearly four months after China abruptly scrapped its tough “zero-COVID” policies following rare mass protests, authorities have yet to dismantle sprawling quarantine facilities designed for isolating hundreds of thousands of people, an Al Jazeera investigation based on satellite imagery shows.

Mass quarantine facilities in three Chinese provinces appear fully intact with no visible changes to their structure, an analysis of the satellite images shows, raising questions about the Chinese government’s post-pandemic plans for the now-defunct structures.

China’s quarantine facilities, which were previously used to isolate, and at times treat, positive COVID-19 cases and close contacts, became a symbol of the human cost of Beijing’s “zero-COVID” policy, which was dropped in December amid mounting public frustration with the draconian measures.

Beiijng’s overarching plan for its now-defunct quarantine centres, if there is one, is not clear.
Provincial authorities in Guangdong, Shandong and Sichuan did not reply to Al Jazeera’s requests for comment. Efforts to reach the National Health Commission (NHC) were unsuccessful.

In December, however, the NHC called on local governments to “upgrade” quarantine centres into hospitals with facilities including intensive care. The NHC said local authorities should carry out the upgrades with local needs in mind but did not specify the ratio or number of facilities that should be refurbished.

Meanwhile, some local governments have announced plans for a variety of other uses for the centres – from temporary housing to elderly care.

The satellite images obtained and analysed by Al Jazeera’s Sanad investigation unit cover six quarantine centres: three in northern China’s Shandong province, two in Guangdong province on the southern coast, and one in Sichuan in the centre of the country.

The facilities include Guangzhou’s 80,000-person capacity Nansha Health Centre, which was only completed in November. The furthest distance between locations – from the outskirts of Jining in Shandong to Guangzhou in Guangdong – is more than 1,700km (1,056 miles).

Sanad geolocated the quarantine centres using drone footage circulated on social media and analysed satellite images of the facilities taken within the last few days.

The images of quarantine centres analysed by Al Jazeera do not show any structural changes or construction to suggest significant upgrades.

For China, upgrading defunct quarantine centres en masse could potentially be a potentially difficult and costly task.

“Quarantine hospitals are designed in a very different way from acute care hospitals because for quarantine, the main purpose of the facility is to quarantine, not treatment,” Chi Chunhuei, director of the centre for global health at Oregon State University, told Al Jazeera.

While the Chinese government has not published official figures, news reports and official statements suggest that a large number of makeshift structures were erected across the country during the pandemic.

As early as January and February 2020, the National Development and Reform Commission allocated 530 million yuan ($77m) to quickly build two prefabricated COVID-19 hospitals in Wuhan, the then epicentre of the pandemic. China State Construction allocated another 500 million yuan (72.6m) to the project, which was modelled after a makeshift hospital built during the SARS pandemic in 2003.

The two facilities were dismantled in April 2020 as China began to contain the first COVID wave but the model would be widely adapted again two years later in the midst of an even larger infection wave in the spring of 2022.

As authorities struggled to contain the virus once again, local and city governments got to work to flatten the curve and ultimately achieve zero cases.

Chinese health official Jiao Yahui said there were 33 prefabricated hospitals completed or under construction in March 2022 alone. In May, the director of the NHC, Ma Xiaowei, called for more quarantine facilities in an op-ed for the Communist Party’s Qiushi Magazine.

China’s “zero-Covid” is gone, but quarantine facilities remain

Shanghai, a large COVID hotspot in 2022, by itself allocated at least 16.77 billion yuan ($2.4bn) for COVID-19 infrastructure, services, staff salaries and other needs in its 2022 budget. Like those of other local governments, the budget did not break down how much was spent on quarantine facilities specifically.

“The funding for the COVID infrastructure is a little bit opaque but it seems to come from a variety of sources, including SPB [special purpose bonds], central government budget and municipal/provincial budgets,” Arendse Huld, an editor at the business-intelligence website and magazine China Briefing, told Al Jazeera.

In August 2022, an NHC directive called for more reserve quarantine facilities, while stipulating they should be built with normal day-to-day functions in mind. Construction continued across China, including in Guangzhou, where authorities announced plans to build 36 facilities with a total capacity of 110,000 beds as late as November 2022.

Discussions on the costs and future of the quarantine facilities are difficult to find in China’s heavily-censored media.

A critical article on the news platform 163.com, which questioned who would pay for Shandong to dismantle quarantine camps built at a cost of 23 billion yuan ($3.3bn), had its contents deleted, although its title remains visible online.Much of the cost of China’s quarantine centres was funded by debt.

Chinese financial news site Yicai reported that more than 100 local governments issued special purpose bonds, racking up debts of up to 440 million yuan ($63.9m).

Many of the local authorities said they planned to rent out the facilities after the pandemic to generate income and fund the debt.

Huld, the editor, said authorities may find it difficult to make the centres economically viable if converted to other uses, which could include hotels, office buildings, shopfronts, warehouses, expo centres and even parking lots.

“I think it’s reasonable to be sceptical of the viability of these facilities for long-term use and of whether they can really generate income in the future,” Huld said.

“These facilities were not made to be permanent and so it seems unlikely that they will really have much longevity. This sentiment is also being felt in China, as we can see from various social media posts [and] web articles.”

In Jinan, the capital of Shandong province, a 650-cabin quarantine camp – that spans more than 20,000 square metres (215,000 sq feet) – was converted into temporary housing for “skilled talent” to resolve a housing shortage for people working at a nearby tech complex, an official statement said. In Shandong, at least one quarantine facility has been designated to become an elderly care home.

Government authorities in remote Qinghai on the Tibetan Plateau said 29 quarantine camps with more than 10,000 beds in total would be kept open to provide reserve beds.

The NHC also recommended that some quarantine centres could be upgraded to medical facilities but Jin Dong-yan, a professor of medicine at the University of Hong Kong, questioned their suitability.

He said the facilities are typically in less-than-ideal locations, far from urban centres, while the buildings themselves would not meet medical standards.

“Even if you build a new hospital from the ground up, there may not be manpower to run it,” Jin told Al Jazeera.

China’s rural areas have just 2.4 practising physicians and 2.6 registered nurses per 1,000 people, according to data compiled by China Briefing, far fewer than urban areas, where the ratio is 3.7 practising physicians and 4.6 nurses.

Jin said authorities might try to save face by repurposing the centres regardless of their long-term viability or suitability.

“The money has already been spent, the best they can do is try to recycle the waste,” he said.
Despite the unresolved questions, Beijing has cast its handling of the pandemic as an unqualified success.

During China’s National People’s Congress earlier this month, newly-appointed Premier Li Qiang said China’s COVID-19 policies were “completely right” and “delivered highly effective outcomes”.

After praising China’s “remarkable” transition from “zero-COVID”, Li said China would continue to “strengthen medical and health services at all levels” and improve its early warning system for epidemics.

China’s official death toll is just 120,576, according to World Health Organization statistics. Health experts widely agree that figure greatly underestimates the actual toll, with some academic studies estimating 1-1.5 million deaths.

While some quarantine facilities may find other uses, others are likely to be consigned to the ash heap of history, said Chi, from Oregan State University, particularly if they are built on highly-sought urban land.

“If they are built in a more suburban area, the land value is not so high, they will probably not tear them down and they can convert them into other use,” he said. “But if some of the quarantine hospitals were built on high-value city land, there’s a high likelihood they will tear it down or modify them into commercial buildings because they desperately need to boost [economic] growth.”

For some Chinese, the centres stand as reminders of the draconian policies that upended the economy and their personal lives for the quixotic goal of zero infections.

For Guangzhou local Jenny, who asked not to be identified by her name, even the sight of kiosks built for PCR testing still haunts her.

“They remind me of painful memories, what else can there be?” Jenny told Al Jazeera.

Jenny, who vividly recalls images of police deploying batons, water cannons and tear gas against protesters during last year’s anti-lockdown protests, is not worried about what happens to the quarantine centres.

Like many Chinese, she just wants to move on from the pandemic.

“The average person does not care,” Jenny said.

Zoonotic Bird Flu News since 11 Mar 2023

BIRD SHOTS [Science, 6 Apr 2023]

By JON COHEN

As an avian influenza virus devastates the poultry industry, the United States considers an unprecedented step: vaccinating its flocks

LAKESIDE, CALIFORNIA—Hilliker’s Ranch Fresh Eggs in this San Diego suburb has 30,000 chickens in three “cage-free,” open-air barns, where birds crowd the floor like rush-hour riders on a big city subway. “A cage-free aviary is a very interesting science experiment,” says Frank Hilliker, who runs the farm his grandfather started in 1942. He worries mightily about infections spreading through the massed birds. On his iPhone, he pulls up a list of the vaccines his chickens get: against Newcastle disease, infectious laryngotracheitis, coryza, colibacillosis, salmonella, infectious bronchitis, and fowlpox.

There is one disease for which his chickens have not been vaccinated: a highly pathogenic avian influenza (HPAI) that’s now racing around the world, killing 90% or more of the poultry it infects. Endemic in migratory birds, this HPAI emerged in U.S. poultry in February 2022, and to date has killed or required the culling of a record 58 million chickens, turkeys, and ducks in commercial and backyard flocks.

Hilliker, who despite the unusually chilly February morning is wearing cargo shorts and a zip-up sweatshirt—this is San Diego—has a no-nonsense demeanor mixed with a tinge of superstition from years of worrying about his chickens. His farm has never detected an HPAI, he says, knocking on a wood wall. “We’re pretty isolated here,” he says, giving another rap. But he might well use an HPAI vaccine to protect his birds, he says, if it was priced right—and allowed.

The goal of vaccination is not just to protect poultry. Well before COVID-19, epidemiologists were nervously watching two kinds of highly pathogenic influenza viruses, H5 and H7, fearing they could erupt into a human pandemic reminiscent of the 1918 flu. HPAI can infect mammals, and the current, massive outbreak has killed seals, bears, and farmed mink and infected at least seven people, killing one. Thankfully, there is no evidence the virus can spread from mammal to mammal, let alone person to person—so far. But fears are growing that the more mammals it infects, the higher the odds that it will adapt to humans.

Slowing the spread among birds could reduce the risk. “I think it is time to give serious consideration to vaccinating commercial poultry in the United States,” says Robert Webster, an emeritus influenza researcher at St. Jude Children’s Research Hospital. But despite strong evidence that HPAI vaccine programs can work—mainly from China, which has aggressively vaccinated poultry over the past 2 decades—the U.S. Department of Agriculture (USDA) does not give farmers like Hilliker the option. Instead, the country has fought HPAI by combining intensive surveillance, strict biosecurity at farms, and culling.

Skeptics of poultry vaccination say that’s the right approach. Immunizing flocks, they argue, could allow the virus to spread silently—not reducing the threat of an avian flu pandemic but simply making it more difficult to detect. And the current practice of “stamping out” outbreaks has worked: Before the current HPAI strain surfaced in U.S. flocks in February 2022, no HPAI had swept through since 2015. But in the face of the largest HPAI outbreak on record, both the United States and Europe are rethinking their hesitancy.

Many questions remain about how, exactly, to use a vaccine in countries that have relied on culling. And because of the uncertain U.S. market, companies are reluctant to invest in moving beyond the initial steps of making vaccines against the current variant and embarking on the rigorous and costly process of seeking regulatory approval. “There’s no incentive at all,” says microbiologist Mahesh Kumar, who heads global biologics R&D for Zoetis, which makes vaccines for pets and livestock and sells an HPAI vaccine outside the United States. “It’s very, very difficult for anybody to continue to invest in that space.”

And something else has kept the brakes on HPAI vaccination in both the United States and Europe: trade. Some countries—including the United States—won’t allow imports of meat or eggs from vaccinated birds.

Scientific evidence doesn’t support those bans. But as Nancy Reimer, a poultry veterinarian who provides care for Hilliker’s birds, puts it, “Some of this is political science, not poultry science.”

THE FIRST GLIMPSE of the HPAI strain now wreaking havoc came in 2010 in China’s Jiangsu province, when researchers from Yangzhou University isolated a new variant of a known subtype, H5N8, from a duck sold in a market. (The H and N refer to two viral surface proteins, hemagglutinin and neuraminidase.) Three years later, a similar virus was spotted in another duck, about 300 kilometers south in Zhejiang. When relatives surfaced a third time, in Korean breeder ducks the next year, a new clade was christened: 2.3.4.4b.

The march of 2.3.4.4b took an ominous turn at an island in Qinghai Lake on the Tibetan Plateau. The lake, the largest in China, provides a temporary home to some 150,000 migratory birds each year flying between Russia and India or Australia. On 1 May 2016, researchers discovered the carcass of a brown-headed gull, the first of some 150 gulls and geese at the lake found to have been infected with variants of 2.3.4.4b. The virus was evidently headed north.

That summer and fall some of the same variants turned up near the Ural mountains in Russia, and then the virus took hold in Western Europe. The resulting HPAI epidemic in poultry, researchers wrote in the Proceedings of the National Academy of Sciences, was “the largest and most widespread … ever recorded in Europe.”

By October 2020, the virus had undergone a significant genetic change, swapping N8 for N1, but the new H5N1 2.3.4.4b proved just as transmissible as its predecessor. It spread to Africa and back to Asia. Then, in November 2020, came evidence it had jumped the Atlantic Ocean: Researchers documented a sick great black-backed gull on Newfoundland. In the following weeks and months it established multiple beachheadsin North America.

By now, 2.3.4.4b has evolved a niche unlike any HPAI ever seen. Usually HPAI infections die out in a season, but the 2.3.4.4b clade is present year-round in migratory birds. It infects so many species in so many locales that no country’s poultry flocks are ever safe.

Despite their name, HPAIs can cause mild or no disease in some avian species, including ducks. But their arrival on an unvaccinated chicken farm can be devastating. Birds may become weak and listless, stop laying eggs, develop severe diarrhea, stumble, and struggle to breathe. An entire flock can die within 2 days. By USDA regulations, just a single bird infected with HPAI requires stamping out a flock, a gruesome procedure that entails cutting off ventilation in barns or suffocating the birds with carbon dioxide or fire-fighting foam. USDA has a program that compensates producers who are forced to cull, but rebuilding the business can still mean a major financial hit.

Globally the toll is enormous. The intergovernmental World Organisation for Animal Health has tracked stamp-outs triggered by H5 and H7 infections. Between January 2005 and 2022, more than 8500 H5 outbreaks led to the culling of nearly 400 million birds, with another 30 million sacrificed to fight more than 100 outbreaks of H7s.

IN 1995, MEXICO PIONEERED an alternative approach to combating HPAI, becoming the first country to use a vaccine as well as culling to stop a virus designated H5N2. The vaccine, which cost pennies per dose, was made like the human one, by growing the virus in eggs and then inactivating it with chemicals. The campaign eliminated the virus from Mexico’s flocks in short order.

China in November 2005 upped the ante in the face of a frightening H5N1 strain that spilled over to nearly 100 humans in Asia that year. In addition to culling, it set out to vaccinate all 14 billion chicken, geese, and ducks then consumed in the country each year—the largest single vaccination effort ever for any species, according to the Food and Agriculture Organization of the United Nations. The government provided the vaccine at no cost to farmers, who were required to use it. Thirteen other countries also used H5 vaccines in poultry by 2010, but China alone accounted for 91% of the total shots given to birds—nearly 100 billion doses.

Later, China faced a new threat: an H7N9 strain that spread through flocks in multiple waves starting in 2013. People caught it, too, mainly from farming or live poultry sold at markets, and by 2017 it had sickened 1500, killing 39% of them. The human tragedy and the economic loss led China in 2017 to introduce a bivalent H5/H7 vaccine for poultry.

This Iowa farm had to cull 56,000 birds in 2015 because of highly pathogenic avian influenza.

Culling flocks is a standard way to control the virus in the United States.SCOTT MORGAN/THE NEW YORK TIMES/REDUX

China’s HPAI vaccines have had limitations, says virologist Chen Hualan at the Harbin Veterinary Research Institute, who with her colleagues studied the country’s vaccination campaign. The evolution of new variants, which immune pressure from vaccines helped to speed up, forced repeated vaccine updates. And domestic ducks—which often did not get vaccinated—provided a haven for the virus.

China’s farmers rear about 4 billion ducks each year, mostly in open fields where they mingle with wild birds and are regularly exposed to flu and other viruses. But because ducks rarely become ill from HPAI, only about 30% of duck farmers vaccinated their birds. “This explains why even though the H5 vaccine has been used in poultry in China for over 10 years, H5 virus can still be detected in the live poultry markets, mainly from ducks,” Chen and her colleagues wrote in 2018.

Some Chinese farmers shunned HPAI vaccination because of worries that it could allow infections to spread without being detected by surveillance. Farms that raise chickens for their meat (the “broilers” that are slaughtered when they are about 6 to 8 weeks old) also had less financial incentive to vaccinate than farms with egg layers, which typically produce for a year or longer.

Still, Chen’s group found that about 70% of the chickens they sampled had antibodies from the H5N1 or the H5/H7 bivalent vaccines. As a result, she and her colleagues wrote in Emerging Microbes & Infections on 2 December 2022, “even though the globally circulating H5 viruses have been detected in many species of wild birds and occasionally in ducks or geese in recent years, they have never caused problems on routinely vaccinated poultry farms in China.”

China’s success in vaccinating against H7N9 is even more compelling. The Chen team sampled more than 50,000 poultry at some 1500 markets and farms before and after the H7N9 vaccine campaign began. They found the prevalence of the virus dropped by 93.3%, and the spread of H7N9 to humans stopped altogether. No human case of H7N9 has been reported since 2019.

The effort benefits both poultry and farmers, Chen told Science, because the government does not require culling an entire farm if the virus is found in one bird. “If it is in a farm with several barns, just birds in that barn will be destroyed,” she says.

Given that success, “We recommend that any unnecessary obstacles to vaccination strategies should be removed immediately and forever,” she and her colleagues wrote in a review paper this year.

Webster also sees lessons in China’s vaccination effort, which not only tamped down HPAI in China but likely kept H7N9 influenza viruses from spreading worldwide. “It is remarkable,” he says. “I believe that Chen is justified in believing that vaccination played an important role.”

The European Union in May 2022 conceded that vaccinating might make sense and is now testing candidates against 2.3.4.4b. At an October 2022 meeting in Paris, organized under the aegis of the International Alliance for Biological Standardization, participants called for “removing unnecessary barriers” for vaccination to control HPAI.

“We cannot keep doing the same thing over and over again,” said David Swayne, a veterinarian who for 28 years ran USDA’s main HPAI research group and co-organized the meeting, which brought together academic scientists, vaccinemakers, and representatives of European governments. “The virus has changed. We’ve got to change.”

IN THE UNITED STATES, the National Chicken Council is not convinced. The organization, which represents broiler farmers, has long argued that using HPAI vaccines would lead to trade restrictions, based in part on fears of silent infections that could contaminate chicken products.

Swayne dismisses that concern, which his own group’s experiments may have helped fuel.

They gave vaccinated birds extraordinarily high “challenge” doses of virus to see how well the vaccine prevented death and reduced viral shedding. The high doses meant that vaccinated birds sometimes got infected but showed no signs of illness. But the silent infection concern is “a misinterpretation of that data,” Swayne says. Vaccinated birds exposed to more realistic, real-world virus doses, he says, are unlikely to become infected.

Even if farms missed infections, the main U.S. export is meat, usually frozen—not live birds. No evidence exists that frozen meat can transmit influenza viruses. “When you look at risk analyses, they would say the chances of that happening are low or negligible,” Swayne says.

The bottom line is that business worries often trump science, says James Sumner, who served as president of the USA Poultry and Egg Export Council from 1990 to 2022 and remains a consultant there. “Many countries look for excuses to restrict trade,” he says—and many already have grievances against the United States. “The products that we export the most are the leg quarters, and we export those at a pretty low price because our industry makes its money on the upper half of the chicken, on the breast and the wings,” which Americans prefer, Sumner explains. Farmers in foreign countries “consider that unfair trade, and it is often classified as dumping,” he says. Refusing to import chicken meat from the United States if it vaccinates is a tempting retaliatory measure.

On the flip side, farmers who raise turkeys, another big branch of the U.S. poultry meat market, are more pro-vaccine because their birds are particularly susceptible to HPAI and they live for up to 6 months. “There are these divided camps,” Sumner says.

Still, the unprecedented H5N1 outbreak in the United States has altered the conversation.

Vaccination “is discussed much more widely now, and there are some people who are pushing for it,” Sumner says. “We all recognize that there are situations where vaccination would be beneficial.”

Poultry vaccinemakers say they stand ready to develop products if the market exists. Kumar says it would be wise for the government to at least order doses for USDA’s National Veterinary Stockpile now, as it did in 2016 to prepare for a variant of an H5N1 strain that had devastated poultry flocks the year before. (In response to a Freedom of Information Act request, USDA told Science that the stockpile currently contains no HPAI vaccines.)

Zoetis has produced what’s known as a master seed to make vaccine against 2.3.4.4b, Kumar says, and done initial safety and efficacy studies. Boehringer Ingelheim told Science that it, too, had “completed efficacy tests against clade 2.3.4.4b.” But both companies are waiting for a signal from USDA that it will allow use of the vaccines. “It’s not like you just turn on the button, and you have vaccine ready, right? It takes time to get it done,” Kumar says.

In March, USDA began to test four different HPAI vaccines made by agency scientists, Zoetis, and Merck. Erica Spackman, acting director of USDA’s Exotic and Emerging Avian Viral Diseases unit, says her team will challenge vaccinated chickens to see how well they’re protected against the 2.3.4.4b strain. The commercial vaccines target earlier H5 strains, but Spackman says a mismatch between a genome used to make a vaccine and the virus in circulation sometimes doesn’t matter. “Some strains are very immunogenic and that overcomes the mismatches,” she says. Spackman has little concern about vaccines creating silent infections. “Within the context of a population monitored by a surveillance program, as would be the case here, infection is not silent,” she says.

In a statement to Science, USDA said if the vaccines work, which the agency should know by June, it will look for manufacturers to produce them. (It will also consider data from European labs now testing vaccines against 2.3.4.4b, Spackman says.) Then, “there are 20 discrete stages to complete” before companies can submit data for regulatory approval, the statement says. It typically takes 2.5 to 3 years to complete that process, the agency said, but “in emergency situations manufacturers may expedite development, resulting in a shortened timeframe to licensure.”

Reimer, the veterinarian who cares for the birds at Hilliker’s farm, does not expect to be vaccinating chickens soon enough to protect them from the current HPAI wave. “I’ve had these discussions before,” Reimer says. “With this particular outbreak, I’m guessing we won’t resolve anything.” But by the time the next HPAI outbreak hits, she says, her charges may not have to face the virus unprotected.

BIRD FLU, HUMAN CASES AND THE RISK TO AUSTRALIA [ealth & Medicine, 20 Mar 2023]

By Dr Michelle Wille and Professor Ian Barr

Avian flu is continuing to spread throughout the world, infecting some mammals as it goes – but what’s the risk to Australia? Avian flu is continuing to spread throughout the world, killing wild birds and poultry en masse across the northern hemisphere, Africa and South America.

Not only is this strain of bird flu wreaking havoc on wild birds and poultry, it is responsible for numerous cases in mammals, including humans.

But what is the threat to Australia?

WHAT IS BIRD FLU?
Bird flu is a form of avian influenza that’s highly pathogenic for poultry and many wild birds.

Since 2021, we have seen the unfolding of an enormous panzootic of a particular strain of this highly pathogenic avian influenza, known as HPAI clade 2.3.4.4b H5N1.


There are current outbreaks on all continents except, for now, the Antarctic and Australia.

These outbreaks have been responsible for the deaths of more than half a billion poultry as of 28 Feb 2023, either due to the virus itself or in attempts to stop the virus spread through culling.

The number of wild bird deaths is unknown, but the scale is potentially in the millions across a great diversity of birds. So far, deaths have been recorded in some 303 different bird species.

For example, a recent outbreak in Peru reported more than 50,000 dead wild birdsacross the country’s protected areas. These outbreaks are of substantial conservation concern for wild birds, with potential population effects and, in some cases, a risk of extinction.

Of note, is that while HPAI viruses usually cause very high mortality in chickens and other poultry, with varying mortality in wild birds, there is an enormous diversity of avian influenza strains that cause no disease and circulate naturally in wild birds. These are called low pathogenic avian influenza (or LPAI) viruses.

WHAT IS THE RISK FOR HUMANS?
In addition to the avian outbreaks, numerous cases have been detected in mammals. These include outbreaks in a large Spanish mink farm, in sea lions in South Americaand a variety of human cases, most recently, a child in Cambodia.

These outbreaks have caused global concern about any potential mammal-to-mammal transmission.

Currently, this virus is still a bird adapted virus – meaning there are no confirmed cases of mammal-to-mammal transmission. The vast majority of cases reported in mammals have been in predators and scavengers that have been infected by the dead or dying birds that they’ve eaten.

So, perhaps it’s not surprising to see an increase in the number of mainly carnivorous mammalian cases given the scale of wild-bird outbreaks.

From experimental studies, we have a good idea which mutations are required for mammal-to-mammal transmission.

One of these mutations is currently widely detected in mammalian cases and occurs at lower mammalian body temperatures instead of the hotter avian body temperatures.

The other mutations of concern, which could make avian influenza viruses more transmissible in mammals, have not yet been found in the wild, but continued genomic surveillance and mutation mapping is critical to track the ongoing evolution of this virus.

To date, all human cases have been in people exposed to sick or dead birds (mainly poultry) infected with HPAI and there have been no confirmed instances of human-to-human transmission.

HPAI H5Nx has caused around 900 human infections since 2003, with an overall case fatality rate of approximately 60 per cent.

Given the large number of avian outbreaks, it’s reassuring that the number of human cases is very few. Even some of the human cases that have been initially recorded as infections with the 2.3.4.4b H5N1 viruses may have been due to carriage of the virus in the nose rather than a true infection.

This is often referred to as “environmental contamination”, resulting in a positive test for H5N1 virus in nasal swabs but the person shows no symptoms of a true infection, as has been suggested in two recent cases in Spain.

The World Health Organization (WHO) states that the risk for humans remains low, but is elevated for people occupationally exposed to infected birds. However, the WHO also indicates that the zoonotic risk is elevated.

Importantly, there are a number of therapeutics, like specific influenza antiviral drugs, which work well against all avian influenza viruses including H5N1 if taken early enough.

The WHO also evaluates avian influenza viruses at its bi-annual vaccine strain meeting in preparation for a potential pandemic and prepares seed viruses that could be used to produce vaccines if required.

GLOBAL RESPONSE AND RISK TO AUSTRALIA
Avian influenza is clearly a OneHealth disease – that is it affects wildlife, domestic animals and humans. So a multi-pronged OneHealth response is critical; we cannot wait until signs of human-to-human transmission occur.

Strong biosecurity is key to preventing viral incursion into poultry production and subsequent spill-over into wild birds – there’s certainly capacity for continued improvements.

More recently, vaccination has been considered as an additional tool to control spread.

Some countries, like Mexico, Vietnam and China have been vaccinating flocks for some time to try to control HPAI.

The US, UK, European Union (EU) and Australia do not vaccinate, however EU legislation has recently been changed to accommodate vaccination, but strict conditions must be met to ensure that vaccination efforts are effective and do not further drive virus evolution or cause “silent spread” (diminishes disease but does not stop infection).

These measures include making sure the vaccine is well matched to the circulating HPAI and that vaccination actually prevents infection with HPAI.

While not a silver bullet, vaccination has the potential to alleviate the burden of HPAI H5Nx on poultry when done appropriately and in combination with other exisiting approaches.

This will likely help prevent human spillover infections and would also hopefully reduce the impact on wild birds by lowering the overall environmental viral load.

Currently, Australia remains free from HPAI H5N1.

While avian influenza outbreaks have occurred here previously, they have always been caused by domestic strains that have evolved to become highly pathogenic rather than an incursion from globally circulating HPAI strains.

However, just because it hasn’t happened before, doesn’t mean this particular virus (that has become increasingly capable to also infect wild birds) will not arrive in Australia.

Millions of wild birds migrate between Asia and Australia each year, arriving from their northern hemisphere breeding grounds between September and November.

The main reason why this virus has not yet reached Australia is likely because there are no migratory duck species, which are the main movers of influenza viruses, migrating between East Asia and Australia.

However, we do know that shorebirds and seabirds are hosts for influenza, so if HPAI H5N1 were to arrive in Australia, it would most likely arrive with them.

In response to this risk, our team has performed enhanced surveillance on wild migratory birds as they arrived in Australia between September and December last year.

Thankfully all birds tested negative and there have been no indications of outbreaks in Australia since.

We will again enter a risk period of viral introduction when the migratory birds return in the second half of this year, and our teams will again be on the front lines to provide state and federal agencies rapid information to help them respond to any outbreaks – if they occur.

HPAI looks like it will continue to circulate for many years to come, so we need to maintain our long-term vigilance in Australia and work with others to try and eradicate or control this global threat.

Two dolphins die from bird flu in UK waters for the first time [inews, 16 Mar 2023]

The highly infectious H5N1 variant has previously been found in otters, foxes and grey seals in the UK
Two dolphins have died from bird flu in UK waters for the first time, the government has announced.

The sea mammals were found in separate locations, on beaches in Devon and in Pembrokeshire, last month.

Both dolphins were confirmed to have been infected with the highly infectious H5N1 variant of avian influenza which has spread around the globe during the past 18 months.

Millions of birds have died from bird flu in the latest outbreak, either from the virus itself or from culling, but scientists are concerned that it is spreading to mammals.

The virus has now been confirmed in 23 mammals in the UK. Bird flu has been discovered in dolphins in other parts of the world but these are the first cases in the UK. It has previously been found in foxes, otters and grey seals around the British Isles.

There has not so far been confirmation that the virus can spread between mammals in the wild, and most wildlife who contract avian flu are believed to have caught it from scavenging infected birds.

However there are concerns that H5N1 could potentially be spreading between mammals after the mass deaths of seals and sea lions elsewhere in the world.

The findings have been passed to the World Organisation for Animal Health.

The risk to humans from avian flu is classed as very low and the only cases have been in people who came into close contact with infected birds. There is no evidence of human to human transmission.

A spokesperson for the Animal and Plant Health Agency said: “Samples taken as part of routine wildlife surveillance have detected the presence of influenza of avian origin in two dolphins and one porpoise.

“The animals were found dead, and it is very likely they had predated on infected wild birds.

“The presence of influenza of avian origin in mammals is not new, although it is uncommon, and the risk of the H5N1 strain to non-avian UK wildlife remains low.”

The government says there is no evidence of an increased risk to non-avian wildlife following the deaths of the dolphins.

People are advised not to touch any sick or dead wild animals or birds and to wash hands thoroughly with soap after contact with any animal.

Bird flu: Nigeria is on major migratory bird routes, new strains keep appearing [The Conversation Indonesia, 16 Mar 2023]

Avian influenza is a highly contagious viral infection of birds, commonly called “bird flu”, which has been recurring in Nigeria since 2006. It has resulted in the loss of millions of birds and income for people who rely on the poultry industry. Nigeria is currently grappling with another outbreak which started in 2021.

The Conversation Africa asked Clement Meseko, a virologist and expert on animal influenza, to explain the disease’s re-occurrences.

What is bird flu? How does it spread? Is it dangerous to humans?

Bird flu is scientifically known as avian influenza and the pathogenic form as highly pathogenic avian influenza. It is a disease in birds (specifically poultry) caused by an influenza virus. It is highly pathogenic, meaning it causes tissue and organ damage in the host, and can kill more than 75% of the infected flock.

Waterfowls like ducks are natural reservoirs of the disease. They can harbour avian flu without showing any symptoms. Many waterfowls and other wild birds are migratory, moving across and between continents – this brings them into contact with resident birds and domestic poultry. Their body secretions and excretions may contain virus that can then infect other birds and poultry.

The symptoms in infected poultry include sudden death, respiratory distress, cough and haemorrhages in tissue and organs. Other animals, including pigs, horses and dogs can also be infected – and so can humans. In fact, it is zoonotic and therefore can be fatal for humans too.

Highly pathogenic avian influenza H5N1 virus infections have infected more than 880 people with about 50% case fatality globally.

The virus also has the capacity to cause a pandemic: an influenza virus of avian origin, but not the currently circulating strain, caused the 1918 pandemic that ultimately killed about 50 million people – worse than the current COVID-19 pandemic .

How many outbreaks have there been in Nigeria since 2006?
Nigeria’s first outbreak of bird flu was confirmed in January 2006, the first epidemic in poultry in Africa. It killed millions of birds and millions more were culled to contain its spread. The economic and livelihood loss was huge as the disease spread all over the country with 100% mortality in many cases. The estimate of the economic cost of bird flu outbreak in Nigeria was over nine billion Nigerian naira (about US$32 million) – with people losing investment, livelihood and jobs.

The disease was brought under control by 2008 thanks to stringent biosecurity measures like depopulation (culling), decontamination and control of poultry movement. In 2015 another strain emerged in Nigeria. Since then, new strains keep appearing.

Live bird markets, common across Nigeria, are the main points of spread of bird flu while wetlands are the points of initial transmissions. Local waterfowls and other birds that may harbour avian flu come into contact with other bird species and with people. In 2006, 312 cases and in 2015, 256 outbreaks of highly pathogenic avian influenza were recorded.

What should Nigeria be doing differently?
The disease may become endemic in Nigeria if circulation continuous and detection of the same strain is established. If a disease is constantly circulating in reservoir hosts it will lead to spill over to poultry and humans.

If that’s the case, biosecurity measures must be stepped up. For instance, the government may consider other measures in addition to biosecurity. This may include controlled and regulated vaccination. There are vaccines. They have been used in Egypt, China, Indonesia with a mixture of failure and success. Vaccines only reduce the impact of the disease but do not prevent infection or re-infection.

Those in the agricultural sector also need to introduce effective control measures at live bird markets and in the way poultry is traded more broadly. Measures would include restructuring the live bird markets, discouraging the mixing of species, the introduction of plastic cages and crates that can be easily cleaned and disinfected. Frequent cleaning, disinfection and decontamination of live bird market environments is very important for disease containment.

You’ve described as Nigeria was an “ecological sink” for such viruses. Please explain
In the research that examined the outbreak of the 2015-2016 bird flu, we found that west Africa was the epicentre of the virus that was later found in other sub-Saharan African regions – the central, eastern and southern African countries. In particular, within west Africa, Nigeria was the most important point of virus introduction and a central hub in the virus spread.

Bird flu is mostly introduced into Nigeria through the presence and activities of wild birds. For instance, in the 2015-2016 outbreak we identified four virus introductions into Nigeria likely from east Europe.

These birds travel across continents and countries through multiple international migratory routes, in much the same way that airlines move across the world on designated routes. Three major wild bird migratory routes from Asia and Europe transverse Nigeria. That’s good news for biodiversity but bad news for disease control.

Bird watchers and ornithologists have found that migratory birds from Europe move into Nigeria every year during the cold harmattan season (November - February). This is the peak time for avian flu outbreaks.

Nigeria is the most affected African country in terms of the frequency and burden of avian flu.

This makes it the destination “sink” of the strains that may be circulating in Europe at any given time.

Because we can’t change birds’ routes or habits, it would be up to Nigerian authorities to make sure it keeps its local birds and people as safe as possible. This would include surveillance of wild birds at wetlands and the monitoring of viral infections. Early detection is vital for early warning, risk analysis and control of infection.

'Like no outbreak we've seen': Will spring migration spike often-deadly bird flu cases? [Star Tribune, 16 Mar 2023]

By Bob Timmons

A year after a new outbreak took a toll on wild birds, wildlife health specialists are remaining cautious.

Minnesota wildlife health specialists have learned something from a year ago when a deadly bird flu outbreak began killing wild birds like bald eagles, hawks and owls: the virus remains a serious threat even if signs of its presence ebbs at times.

Now, with spring migration ahead and reports of new cases in Central and South America, attention is heightened. Migratory waterfowl, which naturally host some form of the virus, are known drivers of transmission.

"This outbreak continues to unfold like no other outbreak we have ever seen," said Victoria Hall, executive director of the Raptor Center at the University of Minnesota. Each year the center treats upward of 1,000 sick and injured birds.

The three most common species treated are great horned owls, bald eagles and red-tailed hawks. All were seen exponentially more in 2022, said Hall, attributed to an outbreak that originated in Europe. As of March 6, the center has tested 1,051 birds, with 215 positive cases. All but one raptor with bird flu died.

Great horned owls especially have been hard-hit by several factors, Hall said. They are cagey hunters and more likely to eat an infected waterfowl, or hunt in areas where geese and ducks live and are shedding the virus through bodily secretions and feces. The virus is endemic to swans, ducks and geese, some of which show no signs of illness. Plus, Minnesota has a significant waterfowl population that overwinters.

The owls in some cases were bringing the virus back to their nests — and their young, which already had hatched when the outbreak was peaking last spring.

"Entire family units would come in sick at one time, which we did not see with other species," said Hall, recalling a case of four or five owls together. Since last March, 92 of 215 positive cases have been great horned owls. Only one survived and was released back into the wild.

"Any time you are taking out breeding pairs, you have to think about population impact," she added.

As the virus shifts, specialists have shifted tactics, too, Hall said.

The center is working with the Center for Disease Control and wildlife managers with the Department of Agriculture, in addition to the Minnesota Department of Natural Resources, dialing in on how to respond and sharing knowledge.

The Raptor Center is testing for antibody levels in birds arriving at the center for reasons other than the flu to learn if raptors are surviving infection in the wild, Hall said.

"There is so much about wildife we are learning in real time, how this virus is working its way through," Hall said. "We can generate some of the science and tell the community what we are seeing."

For its part, the DNR partners with federal wildlife officials to test waterfowl seasonally for HPAI and has for several years. DNR staff were out last week in the south metro capturing dabbling ducks like mallards, with a goal of 110 swab samples this winter, said Wildlife Health Program Supervisor Erik Hildebrand.

The agency also investigates when there are reports of five or more sick or dead birds over a short period of time in a localized area. Carcasses are collected for testing at the University of Minnesota Veterinary Diagnostic Laboratory. Bird flu was confirmed in the deaths of American crows found in Hennepin County in mid-to-late January.

The Wildlife Health Program has to be mindful of all wildlife. Last May, DNR specialists investigated and confirmed the first case of bird flu in a mammal in Minnesota, when a sick fox kit was found in Anoka County. Sporadic infections have been reported, too, in foxes, skunks, bears and sea lions in the United States, Canada and other countries. Most recently, the World Organization for Animal Health reported six more U.S. cases, including a river otter in Wisconsin.

Hildebrand said people who see dead or dying birds or other wildlife should call the DNR's hotline at 888-646-6367.

"I hope we don't see what we saw last spring," he added.

Bird flu associated with hundreds of seal deaths in New England in 2022 [Science Daily, 15 Mar 2023]

Highly pathogenic avian influenza connected to a large scale mortality event in wild mammals
Summary:
Researchers have found that an outbreak of highly pathogenic avian influenza (HPAI) was associated with the deaths of more than 330 New England harbor and gray seals along the North Atlantic coast in June and July 2022, and the outbreak was connected to a wave of avian influenza in birds in the region.

Researchers at Cummings School of Veterinary Medicine at Tufts University found that an outbreak of highly pathogenic avian influenza (HPAI) was associated with the deaths of more than 330 New England harbor and gray seals along the North Atlantic coast in June and July 2022, and the outbreak was connected to a wave of avian influenza in birds in the region.

HPAI is more commonly known as bird flu, and the H5N1 strain has been responsible for about 60 million poultry deaths in the U.S. since October 2020, with similar numbers in Europe. The virus was known to have spilled over from birds into mammals, such as mink, foxes, skunk, and bears, but those were mostly small, localized events. This study is among the first to directly connect HPAI to a larger scale mortality event in wild mammals.

The co-first authors on the paper -- virologist and senior scientist Wendy Puryear and post-doctoral researcher Kaitlin Sawatzki, who both work in the Runstadler Lab at Cummings School -- have been researching viruses in seals for years. They credit their findings in the new study to a unique and robust data set made possible by a collaboration with wildlife clinics and rehabilitation and response organizations in the region, in particular with Tufts Wildlife Clinic and director Maureen Murray, V03, associate clinical professor at Cummings School, and an author on the paper.

"We have a better resolution and greater depth of detail on this virus than before because we were able to sequence it and detect changes almost in real time," said Puryear. "And we have pairings of samples, sometimes literally from a bird and a seal on the same beach."

The clinic has been conducting avian influenza surveillance on birds and some mammals since January 2022, shortly after this strain of avian influenza took a trans-Atlantic journey from Europe into the U.S. Through this testing, the team found a wide range of flu viruses, including at least three strains that crossed the Atlantic, and they witnessed consistent waves of infection in birds.

At the same time, in collaboration with NOAA's Greater Atlantic Region Marine Mammal Stranding Network, they were able to screen nearly all seals that came through the network, whether or not the animal appeared sick. The stranding network is composed of experts from state and federal wildlife and fisheries agencies, non-profit rehabilitation and response facilities, aquariums, and academic institutions who respond to strandings.

"Because of the genetic data that we gathered, we were the first to see a strain of the virus that's unique to New England. The data set will allow us to more meaningfully address questions of which animals are passing the virus to which animals and how the virus is changing," said Sawatzki.

How HPAI Is Transmitted
In addition to poultry, H5N1 also has had a huge impact on wild birds, especially sea birds. Multiple locations around the globe have experienced large die-offs, such as recently in Peru, where the virus killed 60,000 pelicans, penguins, and gulls.

At the time of the seal mortality event in New England, the virus was hitting gulls particularly hard, the researchers found. There are lots of ways gulls and other birds may transmit the virus to seals, they said. Seals and sea birds are coastal animals living in the same areas that have environmental contact, if not direct contact, since they share the same water and shoreline. A seal may contract the virus if it comes in contact with a sick bird's excrement or water contaminated by that excrement, or if it preys upon an infected bird.

The accepted knowledge is that H5N1 is nearly 100% fatal for domestic and wild birds other than waterfowl, and the same is proving true when it comes to spillover in wild mammals. All the seals that tested positive for HPAI were deceased at the time of sampling or succumbed shortly after. None of the animals that tested positive recovered. However, it's possible some asymptomatic or recovered cases never came into the stranding networks.

In addition to the seal mortality event in New England, which was the first time H5N1 was detected in marine mammals in the wild, other locations have lost marine mammals to the virus. Peru announced about 3,500 sea lions died from the virus, Canada reported a seal mortality event along the St. Lawrence Estuary, and there was a similar event with seals in the Caspian Sea, according to news reports from Russia.

A hotly debated topic among scientists is whether there has been mammal-to-mammal transmission of HPAI between seals.

"It's not surprising that you might have transmission between the seals, because it has happened with low pathogenic avian influenza," said Puryear. "However, we can't say definitively whether or not there has been mammal-to-mammal transmission of HPAI."

"To get strong evidence of mammal-to-mammal transmission, you need two things: lots of infected animals and time," explained Sawatzki. "Time for the virus to mutate, and time for the mutated virus to be transmitted to another seal. As the virus acquires mutations, we can see shared mutations in the sequences that are specific only to mammals and that haven't been seen in a bird before. We had the numbers, but this outbreak didn't last long enough to provide evidence for seal-to-seal transmission."

The research team found evidence that the virus mutated in a small number of seals. But fortunately, they have not seen a case of bird flu in seals along the Atlantic coast since the end of last summer. However, stranding season is about to start for harbor seals and gray seals, so they are bracing themselves for what might happen.

Prevention and Risk to Humans
The risk to the public remains low, according to the Centers for Disease Control and Prevention. Since December 2021, less than 10 human cases of H5N1 have been reported globally, and those cases occurred in people with direct exposure to infected poultry. There are no documented cases of human transmission for this variant.

However, there is the possibility it could become a larger issue for human health. Avian influenza emerged in 1996, and since 2003, 868 cases of human infection with H5N1 have been reported worldwide, according to the World Health Organization. Of those, 457 were fatal, roughly a 50% fatality rate.

"And that's why people get nervous about it," Puryear said.

There is a single-dose vaccine available for poultry, but it's not currently administered on a large scale -- in part because of cost and logistics, and in part because there's some concern it may make future surveillance of the virus more difficult. There's not much that can be done in terms of responding to the virus for wildlife, particularly given the scale at which infection is occurring.

Biosecurity is important in limiting the ways in which the virus can spread between and within species, the researchers said. For example, wild birds should be kept separate from domestic birds, such as backyard chickens. In addition, thorough and timely surveillance of domestic animals and wildlife is key to understanding how the virus is evolving to prepare the best possible vaccines and treatments.

Citation: Research reported in this article was supported by the National Institutes of Health's National Institute of Allergy and Infectious Disease under award 75N93021C00014. Complete information on authors, funders, and conflicts of interest is available in the published paper.

Story Source:
Materials provided by Tufts University. Original written by Angela Nelson. Note: Content may be edited for style and length.

Journal Reference:
1. Puryear W, Sawatzki K, Hill N, Foss A, Stone JJ, Doughty L, et al. Highly pathogenic avian influenza A(H5N1) virus outbreak in New England seals, United States. Emerg Infect Dis., 2023 DOI: 10.3201/eid2904.221538

Scientists Investigate a Bird Flu Outbreak in Seals [The New York Times, 15 Mar 2023]

By Emily Anthes

Wild birds passed the virus to seals in New England at least twice last summer, a new study suggests.

Last summer, the highly contagious strain of avian influenza that had been spreading through North American birds made its way into marine mammals, causing a spike in seal strandings along the coast of Maine. In June and July, more than 150 dead or ailing seals washed ashore.

Now, a study provides new insight into the outbreak. Of the 41 stranded seals tested for the virus, nearly half were infected with it, scientists reported on Wednesday in the journal Emerging Infectious Diseases. It is likely that wild birds introduced the virus to seals at least twice, the researchers concluded. In several seals, the virus had mutations that are associated with adaptation to mammals.

The risk to humans remains low, and the seal outbreak waned quickly, the scientists said.

“It was a dead-end event, as far as we can tell,” said Kaitlin Sawatzki, a postdoctoral researcher at the Cummings School of Veterinary Medicine at Tufts University and an author of the new paper. “The virus that entered into those seals has not persisted.”

But the report comes amid growing concerns that the virus, which has already caused the largest bird flu outbreak in the nation’s history, could adapt to spread more efficiently among mammals, potentially sparking a new pandemic.

It remains unclear whether the seals were spreading the virus to one another or primarily picking it up from birds. But the number of affected seals suggests that either the virus spreads easily among the marine mammals or that the barrier for bird-to-seal transmission is low.

“We truly don’t know if it’s transmitting from bird to seal, bird to seal, bird to seal 100 times over or if it’s going into a couple of seals and then spreading,” said Wendy Puryear, a virologist at the Tufts veterinary school and an author of the new paper. “Both are possible,” she added. “Neither are great.”

Either scenario calls for closer monitoring of seals, said David Stallknecht, an expert on wildlife diseases and influenza at the University of Georgia, who was not involved in the research.

“We need to just keep our eyes on them,” he said. “The easiest way to tell if this persists in seals is to keep testing them.”

The current version of H5N1 has become unusually widespread in wild birds and has spilled over repeatedly into mammals, including bobcats, raccoons and foxes. Scientists believe that most wild mammals are contracting the virus directly from birds.

But a bird flu outbreak on a Spanish mink farm last fall suggested that the virus could spread efficiently among some mammalian species. And a mass die-off of sea lions in Peru has raised concerns that marine mammals might be spreading the virus to one another, too.

Seals are known to be susceptible to avian influenza, and other versions of the virus have previously caused outbreaks in the animals.

The new study is a collaboration between researchers at several academic institutions and wildlife organizations, including Marine Mammals of Maine and New England Wildlife Centers, as well as federal scientists.

The researchers collected samples from 1,079 wild birds and 132 gray seals and harbor seals stranded along the North Atlantic coast from Jan. 20 to July 31, 2022. “That gave us a really powerful ability to see what is happening in the birds and the seals in the same time in the same region,” Dr. Puryear said.

There were two waves of flu in wild birds, the researchers found. The first, which peaked in March 2022, primarily affected raptors, while the second, which began in June, hit gulls and sea ducks known as eiders.

No seals tested positive for avian influenza during the first wave of bird infections. But during the summer stranding event, 19 of 41 seals tested positive.

The researchers found two slightly different versions of the virus in the seals. One matched what was circulating in terns, while the other resembled what was circulating in a broader array of birds, including gulls and eiders. The finding suggests that the virus spilled over at least twice.

Because these seals do not typically eat birds, the scientists suspect that the animals are picking up the virus from the environment, perhaps through contact with bird droppings.
Viral samples from the seals also had mutations that were rare or absent in birds. Three seal samples had mutations that have been shown to improve viral replication or increase virulence in mammals.

Such mutations are not unique. In another recent study, a team of Canadian scientists found the same mutations in some viral samples taken from bird-flu-infected foxes. “When there’s a bird-to-mammalian spillover event, they seem to be acquired to pretty quickly,” Dr. Sawatzki said.

The presence of these mutations is not, in and of itself, a reason to “sound the alarm,” Dr. Stallknecht said. But continued surveillance is necessary not only to safeguard human health but also to protect wild animals from a virus that has already proved devastating.

“These emerging diseases need to be looked at on a bigger scale than just ‘pandemic potential,’” he said, “because they affect a lot of other species on the globe.”

Europe's Bird Flu Outbreak Raises Concerns [Precision Vaccinations, 14 Mar 2023]

by Robert Carlson

Avian influenza is spreading in birds, mammals, and infecting people.

Since late 2021, a global shift has occurred in the ecology of highly pathogenic avian influenza (HPAI) of the H5 subtype. The continual spread of H5 HPAI (bird flu) is cause for concern, given the high mortality in birds, mammals, and some humans.

'Because past influenza pandemics originated from animal reservoirs, we argue that it is crucial to step up actions both to prevent H5 HPAI from becoming a future pandemic,' wrote Marion P G Koopmans. Viroscience Department, Erasmus University Medical Centre, Netherlands and colleagues in The Lancet Infectious Diseases on March 7, 2023.

To visualize the current impact across Europe, the European Food Safety Agency, the European Centre for Disease Prevention and Control (ECDC), and the European Union published an assessment of bird flu data collected from December 2022 to March 1, 2023.

This analysis found HAPI clade 2.3.4.4b was reported in domestic (522) and wild (1,138) birds in 24 countries.

An unexpected number of HPAI virus detections in sea birds were observed, mainly in gull species, particularly in black-headed gulls in France, Belgium, the Netherlands, and Italy.

The close genetic relationship among viruses collected from black-headed gulls suggests a southward spread of the HAPI virus.

Moreover, the genetic analyses indicate that the virus persisted in Europe in residential wild birds during and after the summer months.

And might increase during the coming months as breeding bird colonies move inland with possible overlap with poultry production areas.

Worldwide, the bird flu virus continued to spread southward in the Americas, from Mexico to southern Chile.

The Peruvian pelican was the most frequently reported infected species, with thousands of deaths reported.

The reporting of bird flu in mammals (sea lions) also continued, probably linked to feeding on infected wild birds.

Since October 2022, six A(H5N1) detections in humans were reported from Cambodia (a family cluster with two people, clade 2.3.2.1c), China (2, clade 2.3.4.4b), Ecuador (1, clade 2.3.4.4b), and Vietnam (1, clade 2.3.4.4b), as well as two A(H5N6) human infections from China.

This 43-page ECDC report says the risk of bird flu infection in Europe is assessed as low for the general population and low to moderate for occupationally or otherwise exposed people.
However, the number of mammals infected with A(H5N1) viruses and the detection of viruses carrying markers for mammalian adaptation in other genes, such as the PB2 that correlated with increased replication and virulence in mammals in Canada, South America, and the U.S. is of concern for humans.

Currently, the U.S. Food and Drug Administration, and other agencies, have approved bird flu vaccines for people.

In the U.S., the Audenza vaccine was approved in 2020 and would become available during an outbreak.

Furthermore, the U.S. government has funded initiatives to develop new bird flu vaccines.

Over 10% of Japan's Chickens to be Killed This Season as Avian Influenza Rages, Chicken Farmers [Mainichi Shimbun, 13 Mar 2023]

by Toru Morinaga

Since October 2022, highly pathogenic avian influenza has been raging across Japan, killing a record number of chickens and other animals. The price of chicken eggs is also at an all-time high. Koichi Tanaka, 78, who has supported the Tokyo metropolitan area for half a century in Ibaraki, the "chicken and egg kingdom," had his chicken coop emptied after the first round of culls.

The poultry farm he had spent half a century building was...
It was around 10:00 a.m. on December 20, 2010. The employee reported that 170 adult chickens had died in one of the six chicken coops at Tanaka Egg Farm, an egg-laying and poultry farm in Kasama City, Ibaraki Prefecture. The thought crossed my mind, "Could it be ......? In the afternoon, another 80 birds died, and on the following day, the simple test confirmed that they were positive. There was nothing Mr. Tanaka could do while prefectural officials in protective clothing spent two days disposing of all 106,000 birds on the farm with carbon dioxide gas.

Born and raised on a poultry farm, he started his own business around 1970 with 2,000 birds. Over the course of half a century, he has grown to employ nine employees and ship 90,000 to 100,000 eggs per day.

As a veteran poultry farmer, he also served as vice president of the Prefectural Poultry Farmers Association, and thought he had taken sufficient measures to prevent infection. He drew curtains over the skylights of his chicken coops to keep out wild birds and their droppings, and changed his boots when entering the coop. Vehicles entering and leaving the premises were disinfected, and rodents were regularly exterminated and slaked lime was sprayed to prevent small animals from entering. The Ministry of Agriculture, Forestry, and Fisheries is currently analyzing the cause of the outbreak. I thought we had prevented the outbreak because of the measures we had taken, but it may have just been a coincidence that there were no outbreaks," he muses. He has not been attending meetings of the association for some time because he feels uncomfortable.

A chicken coop where an outbreak of avian influenza was confirmed. A curtain was drawn over the skylight at Tanaka Egg in Ikenobe, Kasama City, Ibaraki Prefecture, at 0:09 p.m. on February 16, 2023.

A chicken coop where an outbreak of avian influenza was confirmed. A curtain was drawn over the skylight at Tanaka Chicken Egg in Ikenobe, Kasama City, Ibaraki Prefecture, at 0:09 p.m. on February 16, 2023 (photo by Toru Morinaga).

In mid-February, employees at Tanaka Chicken Egg were busy disinfecting chicken coops. All buildings had been disinfected three times, with several more scheduled. For a while, they were in a state of despair, but encouraged by their eldest son, who serves as managing director, they changed their mind, saying, "We intend to resume operations once we pass an inspection (by the Livestock Health and Sanitation Department) to see if the virus is detected in the walls and other parts of the poultry house.

With the advice of the Livestock Health Center, the company has set up "front rooms" in all the buildings where the poultry are changed before entering the coops in preparation for the reopening, which is expected in April. The plan is to install pipes to spray disinfectant on the roofs of the chicken coops by the fall, when migratory birds are expected to fly in.

Invisible root cause of the outbreak
The reason why the fear of another outbreak of avian influenza persists is that no fundamental solution is in sight, even though it has been nearly 20 years since 2004, when the first outbreak of avian influenza occurred in Japan in 79 years.

The number of birds killed this season has exceeded 15 million nationwide, a record high. The majority of these were egg-laying hens, which accounted for more than 10% of the approximately 137.29 million hens kept nationwide (as of February 2010). In Ibaraki alone, which had the largest number of egg-laying hens in Japan at approximately 15.14 million (as of February 2010), approximately 4.28 million, or nearly 30%, have already been disposed of. In March, the wholesale price of eggs, which had been kept low for many years, reached an average of 337 yen per kilogram of medium-size eggs (Tokyo area, as of March 9), the highest price since 1993, when statistics were first published.

The stable supply of "price superiority" is wavering. Mr. Tanaka says, "I hope they will allow the use of vaccines," but according to the Animal Health Division of the Ministry of Agriculture, Forestry and Fisheries, there is still no vaccine that can prevent the infection itself. Although four types of vaccines that are effective in suppressing the onset of the disease have been approved, the quarantine guidelines do not permit their use because "if symptoms are suppressed, detection may be delayed, and the infection may spread.

The Japan Poultry Farmers Association, a group of poultry farmers from across the country, has begun to request that the government take the lead in conducting research and studies on vaccines. In fact, calls for vaccination and development of a vaccine were also raised in 2004, mainly by the industry. The association sought approval for the use of a vaccine on the grounds that it could significantly reduce the amount of virus produced by infected people and could be effective in preventing the spread of infectious diseases. However, nearly 20 years have passed without any progress in the debate.

We have been making efforts to ensure a stable supply of safe eggs, but there are still concerns. We want consumers to know what is going on. The soil on the site where the hens and eggs were buried remains heaped up like a tomb.

Bird Flu Continues Decimating Mammals [Precision Vaccinations, 12 Mar 2023]

By Karen McClorey Hackett

The U.K. National History Museum recently reported sea lions in Peru are among the latest victims of a version of the highly pathogenic avian influenza (HPAI) known as bird flu.

The HAPI virus has killed about 3,500 South American sea lions in Peru as of March 9, 2023.
The Peruvian government has reported that since November 2022, around 3% of the country's sea lions have died due to HPAI infections.

Peru, like many South American countries, believes HAPI was brought south by pelicans before jumping into the marine mammals.

In the Northern Hemisphere, Canada and the United States have reported multiple mammalian fatalities related to bird flu infections.

The United States Department of Agriculture and the World Animal Health Information System reported during March 2023, over 131 HAPI H5N1 detections of wild striped skunks, black bears, raccoons, and red foxes.

? The California Department of Fish and Wildlife received confirmation on February 15, 2023, that an adult bobcat died from the Eurasian strain of HPAI H5N1.
? The Colorado Parks and Wildlife confirmed on February 9, 2023, several cases of HPAI in free-ranging wildlife (black bear, skunk, mountain lion).
? The Montana Department of Fish, Wildlife, and Parks confirmed on January 17, 2023, three juvenile grizzly bears tested positive for HAPI.

While there are no vaccines that protect birds or mammals from H5N1 infections, there are bird flu vaccines for humans.

In the U.S., the Food and Drug Administration authorized CSL Seqirus' Audenz vaccine on January 31, 2020, and RAPIVAB in 2022.

And the U.S. government has financially supported the development of newer bird flu vaccines for people.

Furthermore, the government reminds everyone that annual flu shots are effective against certain types of influenza, but they are not effective against bord flu viruses.

Tainai City Poultry Farm Confirmed Infected with Avian Influenza by Simple Inspection [NHK, 11 Mar 2023]

It has been confirmed that dead chickens at a poultry farm in Tainai City, Niigata Prefecture, were infected with avian influenza.

The prefectural government plans to begin the disposal of approximately 330,000 chickens being raised if the highly pathogenic virus, which has a high fatality rate, is detected.

On the morning of the 11th, a poultry farm in Tainai City reported to the prefectural government that it had noticed an increase in the number of dead chickens and other abnormalities, and as a result of a simple test, it was confirmed that the dead chickens were infected with avian influenza.

As a result, the prefectural government ordered the poultry farm to restrict the movement of the chickens and to thoroughly disinfect them.

If the highly pathogenic avian influenza virus, which has a high mortality rate, is detected in the ongoing genetic testing, the prefecture plans to begin the disposal of approximately 330,000 chickens raised for egg production at this poultry farm.

The prefectural government held a task force meeting at 5:00 p.m. on November 11, attended by Governor Hanazumi, to discuss future measures.

In Tainai City, highly pathogenic avian influenza virus was detected at another poultry farm this month, and the disposal of approximately 680,000 chickens was completed on November 11.

The prefectural government is calling for a calm response, saying that there have been no confirmed cases of avian influenza infection in Japan from eating chicken meat or eggs.

According to the prefectural government, if the highly pathogenic avian influenza virus is confirmed by genetic testing, this will be the fifth case of avian influenza at poultry farms and other facilities in the prefecture this season, following 13 cases in Kagoshima, 6 in Ibaraki, Chiba, and Hiroshima prefectures.

In response to the successive confirmations of avian influenza, the prefectural government has requested poultry farm operators to take extra precautions by thoroughly changing their boots when entering farms, and by checking again for holes where small animals can enter, such as ventilation fans and air vents, and other out-of-sight areas.

(translated by M.Y.)

New Coronavirus News from 1 Mar 2023

Long COVID Now Looks like a Neurological Disease, Helping Doctors to Focus Treatments [Scientific American, 1 Mar 2023]

By Stephani Sutherland

Tara Ghormley has always been an overachiever. She finished at the top of her class in high school, graduated summa cum laude from college and earned top honors in veterinary school. She went on to complete a rigorous training program and build a successful career as a veterinary internal medicine specialist. But in March 2020 she got infected with the SARS-CoV-2 virus—just the 24th case in the small, coastal central California town she lived in at the time, near the site of an early outbreak in the COVID pandemic. “I could have done without being first at this,” she says.

Almost three years after apparently clearing the virus from her body, Ghormley is still suffering. She gets exhausted quickly, her heartbeat suddenly races, and she goes through periods where she can't concentrate or think clearly. Ghormley and her husband, who have relocated to a Los Angeles suburb, once spent their free time visiting their “happiest place on Earth”—Disneyland—but her health prevented that for more than a year. She still spends most of her days off resting in the dark or going to her many doctors' appointments. Her early infection and ongoing symptoms make her one of the first people in the country with “long COVID,” a condition where symptoms persist for at least three months after the infection and can last for years. The syndrome is known by medical professionals as postacute sequelae of COVID-19, or PASC.

People with long COVID have symptoms such as pain, extreme fatigue and “brain fog,” or difficulty concentrating or remembering things. As of February 2022, the syndrome was estimated to affect about 16 million adults in the U.S. and had forced between two million and four million Americans out of the workforce, many of whom have yet to return. Long COVID often arises in otherwise healthy young people, and it can follow even a mild initial infection.

The risk appears at least slightly higher in people who were hospitalized for COVID and in older adults (who end up in the hospital more often). Women and those at socioeconomic disadvantage also face higher risk, as do people who smoke, are obese, or have any of an array of health conditions, particularly autoimmune disease. Vaccination appears to reduce the danger but does not entirely prevent long COVID.

The most common, persistent and disabling symptoms of long COVID are neurological. Some are easily recognized as brain- or nerve-related: many people experience cognitive dysfunction in the form of difficulty with memory, attention, sleep and mood. Others may seem rooted more in the body than the brain, such as pain and postexertional malaise (PEM), a kind of “energy crash” that people experience after even mild exercise. But those, too, result from nerve dysfunction, often in the autonomic nervous system, which directs our bodies to breathe and digest food and generally runs our organs on autopilot. This so-called dysautonomia can lead to dizziness, a racing heart, high or low blood pressure, and gut disturbances, sometimes leaving people unable to work or even function independently.

The SARS-CoV-2 virus is new, but postviral syndromes are not. Research on other viruses, and on neurological damage from the human immunodeficiency virus (HIV) in particular, is guiding work on long COVID. And the recognition that the syndrome may cause its many effects through the brain and the nervous system is beginning to shape approaches to medical treatment. “I now think of COVID as a neurological disease as much as I think of it as a pulmonary disease, and that's definitely true in long COVID,” says William Pittman, a physician at UCLA Health in Los Angeles, who treats Ghormley and many similar patients.

Although 16 million U.S. sufferers is a reasonable estimate of the condition's toll, there are other, more dire assessments. A meta-analysis of 41 studies conducted in 2021 concluded that worldwide, 43 percent of people infected with SARS-CoV-2 may develop long COVID, with about 30 percent—translating to approximately 30 million people—affected in the U.S. Some studies have offered more conservative numbers. A June 2022 survey reported by the U.S. National Center for Health Statistics found that among adults who had had COVID, one in five was experiencing long COVID three months later; the U.K. Office for National Statistics put the estimate at one in 10. Even if only a small share of infections result in long COVID, experts say, they will add up to millions more people affected—and potentially disabled.

Most of the first recognized cases of long COVID were in patients who needed extended respiratory therapy or who had obvious organ damage that caused lasting symptoms. People reporting neurological symptoms were often overlooked or dismissed as traumatized by their initial illness and hospitalization. But as 2020 came to an end, says Helen Lavretsky, a psychiatrist at the University of California, Los Angeles, “we started getting to a place of sorting through what was really going on ... and it became very evident at that time that neuropsychiatric symptoms were quite prevalent,” most commonly fatigue, malaise, brain fog, smell loss and post-traumatic stress disorder, as well as cognitive problems and even psychosis.

Ghormley was in her late 30s and relatively healthy when she caught the virus, but she had underlying conditions—including rheumatoid arthritis and asthma—that put her at risk for severe COVID. She spent several days at home, struggling to breathe, and then she went to the hospital, where her blood pressure soared and her blood glucose dropped precipitously. She mostly recovered from this acute phase within a few weeks, but, she says, “I never really got better.”

Soon after coming home from the hospital, Ghormley developed what her husband called “goldfish brain.” “I'd put something down and have no idea where I put it,” she recalls. “It kept happening over and over. I was thinking, ‘This is getting weird.’ My husband said I was not remembering anything. I'd try to talk, and I knew what I wanted to say, but I couldn't think of the word.”

“Everything fell apart for me,” says Tara Ghormley, who has been struggling with long COVID since 2020. Credit: Ewan Burns

She also experienced tremors, dramatic mood swings and painful hypersensitivity to sounds. “My husband opening a paper bag felt like knives stabbing me in the ear,” she recounts. Any exertion—physical or mental—left her exhausted and in pain. The changes were jarring to Ghormley, who prided herself on her sharp mind. “The thing that bothered me the most was that I was really having trouble thinking, speaking, remembering—trying to complete a task and having no idea what it was. Suddenly I had quite profound neurological deficits. Everything fell apart for me at that time. That was horribly traumatic ... it kind of broke me. I didn't feel like me.”

ROOTS OF DYSFUNCTION
As a veterinary internist, Ghormley says, it's her job to problem solve when mysterious symptoms arise, including her own. “I was actively trying to find reasons and find what I could do.” She theorized that some of her neurological symptoms might be the result of thrombotic events, blood clots that can cause ministrokes. Several early studies showed that COVID attacks endothelial cells, which line blood vessels. That can lead to clotting and oxygen deprivation in multiple organs, including the brain. Even subtle disruption of endothelial cells in the brain could contribute to cognitive dysfunction.

One study found that in people with neurological COVID symptoms, the immune system seems to be activated specifically in the central nervous system, creating inflammation. But brain inflammation is probably not caused by the virus infecting that organ directly. Avindra Nath, who has long studied postviral neurological syndromes at the National Institutes of Health, found something similar in an autopsy study of people who died of COVID. “When you look at the COVID brain, you don't actually find [huge amounts of virus, but] we found a lot of immune activation,” he says, particularly around blood vessels. The examinations suggested that immune cells called macrophages had been stirred up. “Macrophages are not that precise in their attack,” Nath says. “They come and start chewing things up; they produce all kinds of free radicals, cytokines. It's almost like blanket bombing—it ends up causing a lot of damage.

And they're very hard to shut down, so they persist for a long time. These are the unwelcome guests” that may be causing persistent inflammation in the brain.

Determining which patients have ongoing inflammation could help inform treatments. Early research identified markers that often are elevated in people with the condition, says Troy Torgerson, an immunologist at the Allen Institute in Seattle. Three cell-signaling molecules—tumor necrosis factor alpha, interleukin 6 and interferon beta—stood out in long COVID patients. But this pattern wasn't found in absolutely everyone. “We're trying to sort through long COVID patients and say, ‘This would be a good group to take to trials of an anti-inflammatory drug, whereas this group may need to focus more on rehabilitation,’” Torgerson says. He led a study (currently released as a preprint, without formal scientific review by a journal) in which his team measured proteins from the blood of 55 patients. The researchers found that a subset had persistent inflammation. Among those people, they saw a distinct immune pathway linked to a lasting response to infection. “One subset of patients does appear to have an ongoing response to some virus,” Torgerson says.

Isolated pockets of SARS-CoV-2 or even pieces of viral proteins may remain in the body well after the initial infection and continue to elicit an immune attack. The first solid evidence for “viral persistence” outside the lungs came in 2021 from researchers in Singapore who found viral proteins throughout the gut in five patients who had recovered from COVID as much as six months earlier. A study conducted at the University of California, San Francisco, found evidence for viral particles in the brains of people with long COVID. Scientists collected exosomes, or tiny packets of cellular material, released specifically from cells of the central nervous system. The exosomes contained pieces of viral proteins as well as mitochondrial proteins, which may indicate an immune attack on those vital cellular organelles. Amounts of such suspicious proteins were higher in patients with neuropsychiatric symptoms than in those without them.

The virus could linger in the brain for months, according to research conducted at the NIH and reported in Nature in December 2022. The autopsy study of 44 people who died of COVID found rampant inflammation mainly in the respiratory tract, but viral RNA was detected throughout the body, even in the brain, as long as 230 days after infection. Two other studies, both published last year in the Proceedings of the National Academy of Sciences USA, showed evidence that SARS-CoV-2 may infect astrocytes, a type of neural support cell, gaining entrance via neurons in the skin lining the nose.

Researchers are examining inflammatory signals in patients with long COVID in increasingly fine detail. A small study led by Joanna Hellmuth, a neurologist at U.C.S.F., found that patients with cognitive symptoms had immune-related abnormalities in their cerebrospinal fluid, whereas none of the patients without cognitive symptoms did. At the 2022 meeting of the Society for Neuroscience, Hellmuth reported that she had looked at more specific immune markers in people with cognitive symptoms and found that some patients had an elevated level of VEGF-C, a marker of endothelial dysfunction. Higher VEGF-C concentrations are associated with higher levels of immune cells getting into the brain, she says, and “they're not doing their normal function of maintaining the blood-brain barrier; they're distracted and perhaps activated.” Although the studies are small, Hellmuth adds, they reveal “real biological distinctions and inflammation in the brain. This is not a psychological or psychosomatic disorder; this is a neuroimmune disorder.”

What keeps the immune system in attack mode? According to Torgerson, “one option is that you've developed autoimmunity,” in which antibodies produced by the immune system to fight the virus also mark a person's own cells for immune attack. The response to the virus “turns the autoimmunity on, and that doesn't get better even when the virus goes away,” he says. Several studies have found evidence of autoimmune components called autoantibodies that interact with nerve cells in people with long COVID.

Clues about the inflammatory processes at work could point toward treatments for neurological symptoms. “If it's a macrophage-mediated inflammatory process ... intravenous immunoglobulin could make a difference [to] dampen the macrophages,” Nath says. The treatment, referred to as IVIg, contains a cocktail of proteins and antibodies that can mitigate an overactive immune response.

IVIg can also be used to block autoantibodies. And a therapy called rituximab that targets antibody-producing B cells provides “a time-tested therapy for a lot of autoantibody-mediated syndromes,” Nath says. Another strategy is to use corticosteroids to dampen immune activity altogether, although those drugs can be used for only a limited time. “That's a sledgehammer approach, and you can see if it makes a difference. At least it gives you an idea that, yes, it's an immune-mediated phenomenon, and now we need to find a better way to target it,” Nath says.

If the virus does hang around in some form, antiviral medications could potentially clear it, which might help resolve neurological symptoms. That's the hope of scientists running a clinical trial of Paxlovid, Pfizer's antiviral drug for acute COVID.

A CHRONIC FATIGUE CONNECTION?
Postviral syndromes have been documented for more than a century, arising after infection with viruses from HIV to the flu. Epstein-Barr virus, which causes mononucleosis, is one of several viruses linked to a condition called myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), which is estimated to affect at least one and a half million people in the U.S. ME/CFS bears striking resemblances to long COVID, with symptoms such as immune system dysregulation, fatigue and cognitive dysfunction. “One of the patterns we see is patients who definitely meet the criteria for ME/CFS. This is something we are seeing and treating all the time” in long COVID patients, Pittman says. ME/CFS can be severe, with some people losing mobility and becoming bedbound.

Nath, who also studies ME/CFS, says that “we think mechanistically they are going to be related.” Researchers suspect that ME/CFS, like some cases of long COVID, could be autoimmune in nature, with autoantibodies keeping the immune system activated. ME/CFS has been difficult to study because it often arises long after a mild infection, making it hard to identify a viral trigger. But with long COVID, Nath says, “the advantage is that we know exactly what started the process, and you can catch cases early in the [development of] ME/CFS-like symptoms.” In people who have had ME/CFS for years, “it's done damage, and it's hard to reverse that.” Nath speculates that for long COVID, if doctors could study people early in the illness, they would have a better chance of reversing the process.

Torgerson hopes that researchers will ultimately come to better understand ME/CFS because of COVID. “COVID has been more carefully studied with better technology in the time we've had it than any other infectious disease ever. I think we'll learn things that will be applicable to other inflammatory diseases driven by infection followed by an autoimmune process.”

TEAM TREATMENT
Ghormley, after months of illness, sought care at UCLA Health's long COVID clinic, among the country's few comprehensive, multidisciplinary programs for people with this syndrome. Even though her symptoms are rooted in nervous system dysfunction, she needed an array of medical specialists to treat them. The clinic grew out of a program aimed at coordinating care for medically complex COVID patients, says its director Nisha Viswanathan, an internist and primary care physician. In following up with COVID patients after several months, she realized that “we had a group of patients who still had symptoms. There was no understanding around the condition; we were just trying to see what we could offer them.” Viswanathan and others convened a biweekly meeting of UCLA Health doctors in pulmonology, cardiology, neurology, psychiatry and other specialties to discuss individual cases and overall trends.

At UCLA Health, Pittman coordinates Ghormley's treatment. He says the interdisciplinary team is crucial to getting patients the best possible care. “Oftentimes there are so many symptoms,” and some patients have seen multiple specialists before arriving, but not necessarily the right ones. As long COVID primary care providers, he says, “we do the initial testing and get them to the right person.” For Ghormley, that list of providers includes Pittman, along with a neurologist, a pulmonologist, a cardiologist, a psychiatrist, a trauma counselor, a rheumatologist and a gynecologist.

The team approach has also been critical for doctors trying to understand a brand-new disease, Pittman says. “It's been a very interesting journey from knowing almost nothing to knowing a little bit now, and we're learning more every day, every week, every month,” he says.

The term “long COVID” “is an umbrella, and I think there are multiple diseases under that umbrella.” Although each long COVID patient is unique, Pittman says, “we start to see patterns developing. And with Ghormley, we saw a pattern of dysautonomia, which we see frequently.”

Dysautonomia impairs the autonomic nervous system, a network of nerves that branch out from the brain or spinal cord and extend through the body, controlling unconscious functions such as heartbeat, breathing, sweating and blood vessel dilation. For Ghormley, like many people with long COVID, dysautonomia takes the form of postural orthostatic tachycardia syndrome, or POTS. The syndrome encompasses a collection of symptoms that include a racing heart rate—particularly on standing—and fatigue, and it can cause bowel and bladder irregularities. POTS can also be a component of the exhaustion that comes with PEM. Although the symptoms may seem to affect the body, they stem from nervous system dysfunction.
Ghormley's dysautonomia led her to see cardiologist Megha Agarwal at a UCLA clinic near her home. Many physicians are not familiar with POTS, but Agarwal is particularly attuned to it, having seen it in some of her patients before COVID hit. “There's dysregulation of the nervous system, and so many things can cause it: some cancer therapies, viruses, autoimmune conditions.” Agarwal recognized POTS in Ghormley in the fall of 2020, when very little was known about long COVID. Now she believes “POTS is really what long-haul COVID is causing” in many patients. Luckily, Agarwal says, there are medical interventions that can help.

Tachycardia—the T in POTS—causes the heartbeat to speed up, contributing to exhaustion and fatigue in addition to stressing the heart itself. Drugs called beta-blockers (for the beta-adrenergic receptors they shut off in the heart) can lower the heart rate and improve symptoms. “When heart rate is controlled, not only does the pump improve,” Agarwal says, “[but people's] energy improves, their fatigue is gone, and sometimes there's better mental clarity.” For some patients like Ghormley, beta-blockers are not enough, so Agarwal adds a medication called ivabradine. “It's a bit off-label, but it's currently being aggressively studied” for POTS. For Ghormley, the combination led to real improvements, “so now she doesn't feel like she ran the Boston Marathon when all she did was sit down and stand up at work or take a shower,” Agarwal says.

Among Ghormley's toughest symptoms is her brain fog, a catchall term for a slew of cognitive problems that make it hard for her to function. For days when Ghormley works, her psychiatrist prescribes Adderall, a stimulant used to treat attention deficit hyperactivity disorder that helps her concentrate and stay focused. That has “helped immensely,” Ghormley says.

Ghormley credits her doctors and Agarwal in particular with doing the detective work to dig into her symptoms. “Nobody knew anything about it, but everyone listened to me,” Ghormley says. Perhaps because she was a professional from a medical field, no one “brushed me aside.”

That's unusual for people with long COVID, many of them women, who are often dismissed by physicians who doubt their complaints are real. “Patients just don't feel heard,” Viswanathan says. “I had a patient who told me everything, and after, I just said, ‘This must be so hard for you. I want you to know that everything you're feeling is real, and I've seen so many patients like you.’ And she started crying. She said, ‘No one has told me that. I can't tell you the number of times I was told it was in my head.’”

Credit: Now Medical Studio; Sources: “Postural Orthostatic Tachycardia Syndrome as a Sequela of COVID-19,” by Cameron K. Ormiston et al., in Heart Rhythm, Vol. 19; November 2022; “Long COVID-19 and Postural Orthostatic Tachycardia Syndrome—Is Dysautonomia to Be Blamed?” by Karan R. Chadda et al., in Frontiers in Cardiovascular Medicine; March 2022 (references)
In addition to drugs, other types of therapies, including physical therapy, can help improve some symptoms. But people who experience PEM face a particular challenge when using movement therapies. Pittman says the exertion can make these patients feel worse. “We don't want patients to go to not moving at all, but sometimes the type of movement they're doing may be flaring their symptoms.” He notes that often PEM strikes young, previously healthy people who will say, “‘I need to push myself,’ and then they go way too far and get worse. Our job is to try to find that middle ground and then make that consistent over time, so they're not getting further deconditioned but they don't have the PEM, which has been shown to set them back.”

THE LONG HAUL
Some patients, Pittman says, “have the expectation that they're going to come in, and within a month they're going to be back to normal. And resetting those expectations can be really challenging. You have to be really empathetic because people's lives have completely changed.”

But sometimes patients' quality of life can improve noticeably when they are able to adjust to a new normal. Still, he says, “patients have so many questions, and I can't lead them down a physiological pathway. I can tell them there's neuroinflammation, maybe there's autoimmunity, but we still don't have the answers. Sometimes it's really tough for us to accept and for the patient to accept that we just have to try our best.”

A number of people, Viswanathan says, benefit from reducing various treatments they have accumulated. Some people become so desperate that they will try anything from supplements to off-label medications to untested potions from the Internet. Stopping those sometimes leads to improved symptoms, she says.

Psychological care and support groups can help. Lavretsky adds that “lifestyle choices can play a huge role in improvement,” particularly better sleep habits and the use of breathing exercises to control anxiety. She tells people their bodies can heal themselves if the patients and clinicians find the right tools.

Whether that's true for everyone remains to be seen, Viswanathan says. “We see many patients who have gotten better with time. I have patients whose symptoms have disappeared in the course of a year, or they disappear and occasionally flare up again.” But for some, she says, “it could last many years.”

“We're going to be addressing this for probably decades,” Viswanathan says. “COVID is not going to go away so much as we're just going to get used to living with it, but part of [that] means that people will continue to develop long COVID.”

Vaccination appears to reduce the risk of long COVID. But a study published in May 2022 in Nature Medicine suggests the protection, though real, is not as good as one might hope. The survey of electronic health records from the U.S. Department of Veterans Affairs looked at the relatively small portion of vaccinated people who subsequently became infected. They developed long COVID only 15 percent less often than unvaccinated people. “These patients can have symptoms for one to two years or longer, and so every month you're racking up more patients. Even if it's 15 percent less, the total population of patients is still growing and exploding,” Pittman says. The best way to avoid getting long COVID, experts all agree, is to avoid getting COVID at all.

The syndrome is still mired in a lot of medical uncertainty. Patients might have one or a combination of the problems investigated so far: Long COVID might be caused by viral particles that persist in the brain or other parts of the nervous system. Or it might be an autoimmune disorder that lasts long after the virus has disappeared. Maybe overactive immune cells continue to perturb the nervous system and nearby blood vessels. Fortunately, the increasing ability to recognize specific problems is helping clinicians hone treatments that give patients the best chance of recovery.

Although Ghormley says her care has dramatically improved her symptoms and allowed her to “do some normal things again,” she continues to experience flare-ups that make it impossible for her to work for weeks at a time. One day last year she skipped a dose of her heart medication and made a Target run in the southern California heat. “I got home and basically collapsed in the hallway. Since then, everything has been out of whack. If I try to move around, my legs give out.” Most frustrating—and scary—to Ghormley is the unpredictability of her symptoms. “They have changed so much; some are manageable, some debilitating. One thing will get better, and another thing comes back. I'm always hopeful that it's going to get better, but I just don't know.”

New Coronavirus News from 4 Mar 2023

WHO calls on US to share information on Covid-19 origins after China lab claims [The Guardian, 4 Mar 2023]

World Health Organization’s director general says the politicisation of research into Covid’s origins was making the scientific work harder

The World Health Organization has urged all countries to reveal what they know about the origins of Covid-19, after claims from several US government agencies that a Chinese lab leak was behind the disease were furiously denied by Beijing.

“If any country has information about the origins of the pandemic, it’s essential for that information to be shared with WHO and the international scientific community,” the WHO director general, Tedros Adhanom Ghebreyesus, said on Friday.

The FBI director, Christopher Wray, told Fox News on Tuesday that his agency had now assessed the source of the Covid-19 pandemic was “most likely a potential lab incident in Wuhan”.

The first infections from coronavirus were recorded in late 2019 in the Chinese city, which hosts a virus research laboratory. Chinese officials have denied the FBI claim, calling it a smear campaign against Beijing.

Tedros stressed that the WHO did not wish to apportion blame, but wanted to “advance our understanding of how this pandemic started so we can prevent, prepare for and respond to future epidemics and pandemics”.

He said the politicisation of the origins research was making the scientific work harder and the world less safe as a result.

In 2021, the UN’s health agency set up the Scientific Advisory Group for the Origins of Novel Pathogens (Sago) to look into the origins of the pandemic.

“WHO continues to call for China to be transparent in sharing data and to conduct the necessary investigations and share the results,” said Tedros, adding that he had written and spoken to top Chinese leaders on multiple occasions.

“Until then, all hypotheses on the origins of the virus remain on the table.”

The comments from Wray came after a report earlier this week said the US Department of Energy had determined that a Chinese lab leak was the most likely cause of the Covid-19 outbreak. However, this assessment was made with “low confidence”.

Other agencies within the US intelligence community believe the virus emerged naturally.

Maria Van Kerkhove, the WHO’s Covid-19 technical lead, said the organisation had reached out to the US mission in Geneva for more information.

So far, however, they did not have access to the data on which the US reports were based, said Van Kerkhove.

“It remains vital that that information is shared”, to help move the scientific studies forward, she added.

Tedros said there was a moral imperative to find out how the pandemic started, for the sake of the millions who lost their lives to Covid-19 and those living with long Covid.

More than 6.8m Covid-19 deaths and more than 758m confirmed cases have been recorded by the WHO. The organisation acknowledges that the true toll is far higher.