In a new paper published Feb. 4 in JAMA, Mayo Clinic
researchers describe the benefits of in-home noninvasive ventilation
therapy ? which includes a type referred to as bilevel positive airway
pressure, or BiPAP ? for many patients with chronic obstructive
pulmonary disease (COPD). The team identified a number of benefits,
including reduced mortality, fewer hospital admissions, lower risk of
intubation, improved shortness of breath, and fewer emergency department
visits.
COPD is a chronic lung disease that makes it difficult to breathe.
COPD is the third leading cause of death in the U.S., with more than 15
million people currently living with the disease, according to the
American Lung Association.
Many people who have COPD suffer from hypercapnia, the retention of
carbon dioxide — a waste product of metabolism normally expelled by the
lungs as a person breathes. This may lead to acute respiratory failure
and hospitalization. One treatment for chronic hypercapnia is
noninvasive ventilation, or a machine with a mask that helps to improve
breathing.
Michael Wilson, M.D., a pulmonary and critical care physician at Mayo
Clinic, led the study, which was funded by the Agency for Healthcare
Research and Quality under a contract with the Mayo Clinic
Evidence-Based Practice Center.
“Although there is ample evidence supporting in-hospital use of
breathing devices such as BiPAP, until now, we didn’t know which
benefits may be available when we send people home with a new piece of
equipment,” says Dr. Wilson. “There were indications that at-home
therapy might be beneficial, but there were conflicting studies and
guidelines as to what would be best for our patients.”
He and his colleagues wanted to determine the best practice,
collecting and summarizing all available medical knowledge surrounding
the topic.
To that end, the team conducted a meta-analysis, combing all
available peer-reviewed and other expert literature for relevant
randomized clinical trials and comparative observational studies.
After reviewing more than 6,300 citations, the researchers found 33
studies evaluating outcomes for 51,085 patients with COPD and
hypercapnia who were followed for at least one month while using a
noninvasive ventilator at home during nighttime sleeping hours.
Among these patients, use of a noninvasive ventilator device, such as
bilevel positive airway pressure, compared to no device was
significantly associated with lower mortality: 29.2% versus 22.3%. The
use of a noninvasive ventilator device also led to fewer emergency
department visits and hospitalizations, and lower rates of intubation if
patients were admitted to the hospital.
“While there does seem to be some clear benefits to using devices
such as BiPAP, we should be cautious as the studies included a lot of
different types of patients with COPD. And many of the studies we
evaluated were low or moderate in quality,” says Dr. Wilson. “We still
have a lot more to learn about which machine settings are best for
different types of patients. In addition, although many studies in our
review included quality of life measurements, we didn’t see an
improvement. While some studies showed better quality of life, other
studies showed no difference. Again, this points to the importance of
needing to more carefully evaluate which patients with COPD may receive
benefit.”
“Patients with COPD should talk with their physicians to determine
whether a breathing device such as a BiPAP machine might be a good
choice for them,” he says. “For many patients, such a device may offer
important benefits.”
###
The senior author of the study is Zhen Wang, Ph.D., associate
director of the Mayo Clinic Evidence-Based Practice Research Program.
This project also was supported by the Mayo Clinic Robert D. and
Patricia E. Kern Center for the Science of Health Care Delivery, in
which Dr. Wang holds a leadership role in knowledge synthesis research
and Dr. Wilson is a Kern Scholar Program alumnus. https://www.eurekalert.org/pub_releases/2020-02/mc-nhf020420.php
GW Pharmaceuticals PLC- ADR GWPH 1.07%, which derives a lion’s share of its revenues from its cannabinoid seizure drug Epidiolex,
provides value for investors due to the potential for the drug to have
wide utility over both orphan and non-orphan indications, according to
BofA Securities.
The GW Pharma Analyst
Tazeen Ahmad maintained a Buy rating on GW Pharma with a $224 price target.
The GW Pharma Thesis
The update came after a teleconference call with an epilepsy
specialist who treats about 260 patients, Ahmad said in a Tuesday note.
(See her track record here.)
Out of 45 patients on Epidiolex, four to five patients have dropped
off the treatment, translating to a 10% discontinuation rate, the
analyst said.
The discontinuations had more to do with parental requests or adverse
events, including diarrhea and liver enzyme elevations, rather than to a
lack of efficacy, she said.
The specialist indicated that about 40-50% of patients were
well-controlled on a dose regimen of 10mg/kg twice daily, although for
non-responders, a dose above 20mg/kg was administered, Ahmad said.
The doctor reported comparable or slightly higher response rates
compared to published data, according to BofA. About one-third of
the patients showed improvement in sleep, adding to their quality of
life.
The doctor suggested that out of the 10 tuberous sclerosis complex
patients he follows, he is likely to treat three to five with Epidiolex
after the sNDA for an expanded labeling to use it for TSC is approved,
the analyst said.
GW Pharma announced Monday it has submitted the sNDA for TSC.
BofA estimates Epidiolex
risk-adjusted peak sales of $2.5 billion in 2027 across Dravet
syndrome, Lennox-Gastaut syndrome, TSC and off-label indications. https://www.benzinga.com/analyst-ratings/analyst-color/20/02/15247312/bofa-sees-blockbuster-sales-potential-for-gw-pharmas-cbd-drug-epidiolex
Reports out of China indicate ten passengers on Carnival’s (NYSE:CCL) Diamond Princess cruise ship currently sitting at the Yokohama port tested positive for novel coronavirus.
Japan’s Health Ministry tested a total of 133
passengers who showed symptoms of fever or had close contact with people
with coronavirus.
Princess Cruises is quarantining 3.7K passengers for two weeks due to the positive tests of the ten passengers.
With the new coronavirus
spreading from person to person (possibly including from people without
symptoms), reaching four continents, and traveling faster than SARS,
driving it out of existence is looking increasingly unlikely.
It’s still possible that quarantines and travel bans will first halt
the outbreak and then eradicate the microbe, and the world will never
see 2019-nCoV again, as epidemiologist Dr. Mike Ryan, head of health emergencies at the World Health Organization, told STAT on Saturday. That’s what happened with SARS in 2003.
Many experts, however, view that happy outcome as increasingly
unlikely. “Independent self-sustaining outbreaks [of 2019-nCoV] in major
cities globally could become inevitable because of substantial
exportation of pre-symptomatic cases,” scientists at the University of
Hong Kong concluded in a paper published in The Lancet last week.
Researchers are therefore asking what seems like a defeatist question
but whose answer has huge implications for public policy: What will a
world with endemic 2019-nCoV — circulating permanently in the human
population — be like?
“It’s not too soon to talk about this,” said Dr. Amesh Adalja, an
infectious disease specialist at the Johns Hopkins Center for Health
Security. “We know that respiratory viruses are especially difficult to
control, so I think it’s very possible that the current outbreak ends
with the virus becoming endemic.”
Experts see two possibilities, each with unique consequences:
Just another coronavirus
2019-nCoV joins the four coronaviruses now circulating in people. “I
can imagine a scenario where this becomes a fifth endemic human
coronavirus,” said Stephen Morse of Columbia University’s Mailman School
of Public Health, an epidemiologist and expert on emerging infectious
diseases. “We don’t pay much attention to them because they’re so
mundane,” especially compared to seasonal flu.
Although little-known outside health care and virology circles, the
current four “are already part of the winter-spring seasonal landscape
of respiratory disease,” Adalja said. Two of them, OC43 and 229E, were discovered in the 1960s but had circulated in cows and bats, respectively, for centuries. The others, HKU1 and NL63, were discovered
after the 2003-2004 SARS outbreak, also after circulating in animals.
It’s not known how long they’d existed in people before scientists
noticed, but since they jumped from animals to people before the era of
virology, it isn’t known whether that initial jump triggered widespread
disease.
OC43 and 229E are more prevalent than other endemic human coronaviruses, especially
in children and the elderly. Together, the four are responsible for an
estimated one-quarter of all colds. “For the most part they cause
common-cold-type symptoms,” said Richard Webby, an influenza expert at
St. Jude Children’s Research Hospital. “Maybe that is the most likely
end scenario if this thing becomes entrenched.”
All four, in particular HKU1, can cause pneumonia, and sometimes
death. It is rare enough that researchers do not have good estimates of
its prevalence or virulence, but two of the others have been better
studied. In one of the few close looks at OC43 and 229E, researchers measured
their infection rates during four winters (1999-2003) in Rochester,
N.Y., among 2,897 healthy outpatients, adults with cardiopulmonary
disease, and patients hospitalized with acute respiratory illnesses.
They identified 398 coronavirus infections (four people had both OC43
or 229E). Infection rates ran from 0.5% among healthy elderly adults to
15% among healthy young adults (where “healthy” means they had no viral
symptoms), with the highest rates coming in the winter of 2000-2001,
for no obvious reason — suggesting that coronavirus infection rates will
rise and fall unpredictably, much like seasonal flu, and that its
consequences will also be similar: some serious illness, some mild, and a
lot of asymptomatic infections.
The most common symptoms were runny nose, cough, and congestion, for
about 10 days; no one even ran a fever. All told, 35% of infections with
229E and 18% with OC43 were asymptomatic. “Asymptomatic infection …
[meaning] without respiratory symptoms was fairly common,” the authors
concluded.
But sometimes symptoms were nothing to sneeze at. There were 96
coronavirus infections among the 1,388 hospitalized patients. OC43
caused more severe disease than 229E, requiring intensive care for 15%
of those infected. About one-third of the patients admitted to the
hospital with either coronavirus developed pneumonia; one of the 229E
patients and two of the OC43 patients died.
On the bright side, if a coronavirus infects enough people regularly
there will be greater business incentive to develop a vaccine and other
countermeasures. That never happened with SARS because it died out,
leaving no market for such products.
On the decidedly darker side, a fifth endemic coronavirus means more sickness and death from respiratory infections. Odds: Moderate. “I think there is a reasonable
probability that this becomes the fifth community-acquired coronavirus,”
Adalja said, something he expanded on in his blog.
Webby agreed: “I have a little bit of hope that, OK, we’ll put up with a
couple of years of heightened [2019-nCoV] activity before settling down
to something like the other four coronaviruses.”
2019-nCoV returns repeatedly like seasonal flu
The “seasonal” reflects the fact that viruses can’t tolerate high
heat and humidity, preferring the cool and dry conditions of winter and
spring, Webby said. That’s why flu, as well as the four coronaviruses,
are less prevalent in warm, humid months. If the new coronavirus follows
suit, then containment efforts plus the arrival of summer should drive
infections to near zero.
But also like flu viruses, that doesn’t mean it’s gone.
The “bad” reflects the fact that the number of 2019-nCoV cases and
deaths so far suggests that the new coronavirus has a fatality rate
around 2%. That’s almost certainly an overestimate, since mild cases aren’t all being counted. But even 2% is less than SARS’ 10% and nowhere near the 37%
of MERS (Middle East respiratory syndrome coronavirus). On the other
hand, seasonal flu kills fewer than 0.1% of those it infects, though
that’s still tens of thousands of deaths a year just in the U.S. The
global disaster that was the 1917 “Spanish flu” pandemic killed 2.5%.
“One scenario is that we go through a pandemic,” as the current
outbreak may become, said Columbia’s Morse. “Then, depending what the
virus does, it could quite possibly settle down into a respiratory
illness that comes back seasonally.”
The toll that would take depends on how many people it infects and how virulent it is. Virulence reflects the viruses’ genetics.
The genome of the novel coronavirus consists of a single stand of
RNA. Microbes with that kind of genome mutate “notoriously quickly,”
said biologist Michael Farzan of Scripps Research, who in 2005 was part
of the team that identified the structure of the “spike protein” by which SARS enters human cells.
But SARS has a molecular proofreading system that reduces its
mutation rate, and the new coronavirus’s similarity to SARS at the
genomic level suggests it does, too. “That makes the mutation rate much,
much lower than for flu or HIV,” Farzan said. That lowers the chance
that the virus will evolve in some catastrophic way to, say, become
significantly more lethal.
The coronavirus “may not change [genetically] at all” in a way that
alters function, said biologist Andrew Rambaut of the University of
Edinburgh, who has been analyzing the genomes of the 2019-nCoV’s from
dozens of patients. “It is transmitting quite well already so it may not
have to ‘evolve’ to be endemic.”
Any evolution that does take place in an endemic coronavirus,
including one that spikes seasonally, might well be toward less
virulence. “It doesn’t want to kill you before you transmit it,” Farzan
said. “One would therefore expect a slow attenuation” of virulence if
the virus becomes like seasonal flu. Dead people don’t transmit viruses,
“and even people sitting in their beds and shivering” because they are
seriously ill “don’t transmit that well,” he said.
The toll of a seasonal-flu-like coronavirus also depends on immunity —
which is also scientifically uncertain. Exposure to the four endemic
coronaviruses produces immunity that lasts longer than that to
influenza, Webby said, but not permanent immunity. Like respiratory
syncytial virus, which can re-infect adults who had it in childhood,
coronavirus immunity wanes.
“Everyone, by the time they reach adulthood, should have some
immunity to some coronavirus,” said Tim Sheahan, a coronavirus
researcher at University of North Carolina’s Gillings School of Global
Public Health. But because it doesn’t last, older people can get
reinfected. The elderly also have a higher death rate from coronaviruses
such as SARS and MERS, a pattern 2019-nCoV is following.
“There is some evidence that people can be reinfected with the four
coronaviruses and that there is no long-lasting immunity,” Dr. Susan
Kline, an infectious disease specialist at of the University of
Minnesota. “Like rhinoviruses [which cause the common cold], you could
be infected multiple times over your life. You can mount an antibody
response, but it wanes, so on subsequent exposure you don’t have
protection.” Subsequent infections often produce milder illness,
however.
The common-cold-causing coronaviruses are different enough that an
infection from one won’t produce immunity to another. But the novel
coronavirus overlaps enough with SARS that survivors of the 2002-3003
outbreak might have some immunity to the new arrival, Sheahan said: “Is
it enough to prevent infection? I don’t know.”
How widespread even limited immunity would be, and therefore how many
people would become ill from the next go-round of 2019-nCoV, also
“depends on how many people get infected the first time around,” Webby
said. That number is certainly higher than the more than 20,000
identified cases, since people with no or mild symptoms escape the
attention of health care systems.
Since 2019-nCoV is new, “this first wave will be particularly bad
because we have an immunologically naïve population,” Adalja said.
Future waves should pass by people who were exposed (but not necessarily
sickened) this time around, Morse said, “but that assumes this virus
doesn’t develop the tricks of flu,” which famously tweaks the surface
molecules that the immune system can see, making itself invisible to
antibodies from previous exposures. Odds: Pretty good. What we may be seeing “is the
emergence of a new coronavirus … that could very well become another
seasonal pathogen that causes pneumonia,” said infectious disease expert
Michael Osterholm of the University of Minnesota. It would be “more
than a cold” and less than SARS: “The only other pathogen I can compare
it to is seasonal influenza.”
Infectious disease researchers at The University of Texas at Austin
and other institutions in Hong Kong, mainland China and France have
concluded there is a high probability that the deadly Wuhan coronavirus
spread beyond Wuhan and other quarantined cities before Chinese
officials were able to put a quarantine in place. At least 128 cities in
China outside of the quarantine zone, including cities with no reported
cases to date, had a greater than even risk of exposure, according to a
paper currently in press with Emerging Infectious Diseases, a journal of the U.S. Centers for Disease Control and Prevention.
Based on comprehensive travel data from location-based services and
modeling of the disease done at UT Austin’s Texas Advanced Computing
Center, 128 cities in China had a 50% chance or greater risk that
someone exposed to the virus traveled there before the quarantine began.
The team also estimated there were 11,213 cases of the coronavirus in
Wuhan by the time of the quarantine on Jan. 22—a rate 10 times higher
than the reported cases.
“This risk assessment identified several cities throughout China
likely to be harboring yet undetected cases of [Wuhan coronavirus] and
suggests that early 2020 ground and rail travel seeded cases far beyond the Wuhan region quarantine,” write the authors.
As of Feb. 4, officials have confirmed 425 fatalities from the virus,
all but two in mainland China, and more than 20,000 confirmed cases
spread across the world.
The paper shows there is a 99% chance that at least one patient
carrying the virus traveled to the cities of Beijing, Guangzhou,
Shenzhen and Shanghai by the time the quarantine was put in place for
the city
of Wuhan on Jan. 23. The quarantine has since expanded to include
cities with populations totaling 60 million people. Beijing reported its
first fatality from the virus on Jan. 27.
The team estimated new cases of the virus doubled roughly every week,
and on average, that every infected person transmitted the disease to
approximately two other people.
Lauren Ancel Meyers, a mathematical epidemiologist and professor of
integrative biology and statistics and data sciences at UT Austin; and
Zhanwei Du, a computer scientist working at UT Austin, along with a team
of scientists from France, China and Hong Kong, used historical travel
data for the busy Spring Festival season to chart human movements
between 371 cities in China. The team used road, train and air travel
data to yield results more accurate than those of other models.
“Given that 98% of all trips during this period are taken by train or
car, our analysis of air, rail and road travel data yields more
granular risk estimates than possible with air passenger data alone,”
said Meyers, who specializes in modeling the spread of infectious diseases.
“The quarantine will probably prevent future transmission out of Wuhan.
However, introductions of the novel coronavirus had already occurred
throughout China and the world by the time the quarantine started.”
The model also takes into account the reported cases of the disease outside of China to estimate the rates of epidemic growth.
Based on the team’s estimates, there are at least 128 cities and as
many as 186 cities in China that had at least a 50% chance of an
infected visitor from Wuhan arriving sometime in the three weeks before
the quarantine was enacted. Several cities reporting no cases had a 99%
probability that an infected person visited. Those cities—each with a
population of more than 2 million people—include Fushun, Laibin and
Chuxiong. https://medicalxpress.com/news/2020-02-early-coronavirus-china-quarantine-zone.html
Significantly reducing dietary levels of the amino acid methionine
could slow onset and progression of inflammatory and autoimmune
disorders such as multiple sclerosis in high-risk individuals, according
to findings published today in Cell Metabolism.
While many cell types in the body produce methionine, the immune cells
responsible for responding to threats like pathogens do not. Instead,
the methionine that fuels these specialized cells, called T cells, must
be ingested through food consumption. Although methionine is found in
most foods, animal products such as meat and eggs contain particularly
high levels.
“Methionine is critical for a healthy immune system. Our results suggest, for people predisposed to inflammatory and autoimmune disorders
like multiple sclerosis, reducing methionine intake can actually dampen
the immune cells that cause disease, leading to better outcomes,” said
Russell Jones, Ph.D., the study’s senior author and program leader of
Van Andel Institute’s Metabolic and Nutritional Programming group.
“These findings provide further basis for dietary interventions as
future treatments for these disorders.”
Autoimmune disorders occur when the immune system mistakenly attacks
and destroys healthy tissue. For example, in multiple sclerosis—the most
common inflammatory disease of the central nervous system—the myelin
sheath that protects nerve cells in the brain and spinal cord is
targeted by the immune system. The subsequent damage impedes messages
traveling to and from the brain, resulting in progressively worsening
symptoms like numbness, muscle weakness, coordination and balance
problems, and cognitive decline. There currently are no treatments that
significantly slow or stop multiple sclerosis without greatly increasing
the risk of infection or cancer.
“What causes multiple sclerosis is still not completely understood.
We know that genes related to the immune system are implicated but environmental factors
also have a role to play,” said Catherine Larochelle, M.D., Ph.D.,
study co-author, and a clinician-scientist in neuroimmunology and
neurologist at the Multiple Sclerosis Clinic at the Centre Hospitalier
de l’Université de Montréal. “The fact that metabolic factors like
obesity increase the risk of developing multiple sclerosis makes the
idea of dietary intervention to calm down the immune system particularly
appealing.”
During an immune response,
T cells flood the affected area to help the body fend off pathogens.
Jones, Larochelle and their teams found dietary methionine fuels this
process by helping “reprogram” T cells to respond to the threat by more
quickly replicating and differentiating into specialized subtypes. Some
of these reprogrammed T cells cause inflammation, which is a normal part
of an immune response but can cause damage if it lingers, such as the
nerve damage that occurs in multiple sclerosis.
The researchers also found that significantly reducing methionine in the diets of mouse models of multiple sclerosis altered the reprogramming of T cells,
limiting their ability to cause inflammation in the brain and spinal
cord. The result was a delay in the disease’s onset and slowed
progression.
“By restricting methionine in the diet, you’re essentially removing
the fuel for this over-active inflammatory response without compromising
the rest of the immune system,” Jones said.
He cautions that the findings must be verified in humans before
dietary guidelines can be developed. The team also plans to investigate
whether new medications can be designed that target methionine
metabolism.
The study is the latest to spotlight methionine-restricted diets as
possible treatments for disease. A 2019 study from the Locasale Lab at
Duke University demonstrated that reducing methionine could improve the
effects of chemotherapy and radiation in fighting cancer.
More information: Dominic G. Roy et al. Methionine Metabolism Shapes T Helper Cell Responses through Regulation of Epigenetic Reprogramming. Cell MetablolismDOI: 10.1016/j.cmet.2020.01.006
In a pair of related studies, a team of Yale researchers has found a
way to reverse type-2 diabetes and liver fibrosis in mice, and has shown
that the underlying processes are conserved in humans.
The studies appear in the Feb. 4 edition of Cell Reports and in the Jan. 17 edition of Nature Communications.
In the earlier study, researchers found an important connection
between how the body responds to fasting and type-2 diabetes. Fasting
“switches on” a process in the body in which two particular proteins,
TET3 and HNF4α increase in the liver,
driving up production of blood glucose. In type-2 diabetes, this
“switch” fails to turn off when fasting ends, as it would in a
non-diabetic person.
Researchers hypothesized that if they could “knock down” the levels
of these two proteins, they could stop diabetes from developing. Huang
and team injected mice with genetic material
known as small interfering RNAs (siRNAs) packaged inside viruses that
targeted TET3 or HNF4β. They found that blood glucose and insulin
dropped significantly—effectively stopping diabetes in its tracks.
In the Feb. 4 Cell Reports study, researchers looked at how
TET3 contributed to the development of fibrosis in the liver, and found
that the protein was involved in fibrosis on multiple levels. Almost all
fibrosis, regardless of the organ involved, starts from abnormal
protein signaling, Huang said.
She and colleagues discovered that TET3 plays a role in the fibrosis
signaling pathway in three different locations—and acts as an important
regulator in fibrosis development. This means there are likely
opportunities to develop drugs that inhibit TET3 to slow or reverse
fibrosis, said Da Li, associate research scientist in genetics and
co-author on both studies.
Both diseases—type-2 diabetes and fibrosis of the liver and other
organs—are common, but have few treatment options. Around 28 million
people in the U.S. have type-2 diabetes, characterized by high blood
sugar levels, a condition that can lead to many other health problems, including heart disease, stroke, and kidney failure.
Cirrhosis is one of the leading causes of death worldwide and is marked by liver fibrosis—a
buildup of scar tissue on the liver, said co-author James Boyer, M.D.,
professor and emeritus director of the Yale Liver Center.
Researchers noted that several drugs, such as metformin, are currently available to control blood sugar levels in patients with diabetes. But these have a range of unpleasant side effects, and patients can develop resistance to these drugs.
And there is little medical relief for fibrosis sufferers.
“Right now, there are no effective drugs for the treatment of
fibrosis,” said Xuchen Zhang, M.D., associate professor in pathology and
co-author on the fibrosis study.
Huang has filed for a patent related to her discoveries with support from the Yale Office of Cooperative Research.
The next step, she said, will be to identify where to best target TET3 and HNF4α and to develop the most effective siRNAs or small molecules to treat type-2 diabetes or fibrosis.
