Liam Davenport

It is becoming increasingly clear that obesity is one of the biggest risk factors for severe COVID-19 disease, particularly among younger patients.

Newly published data from New York show that, among those aged under 60 years, obesity was twice as likely to result in hospitalization for COVID-19 and also significantly increased the likelihood that a person would end up in intensive care.

“Obesity [in people younger than 60] appears to be a previously unrecognized risk factor for hospital admission and need for critical care. This has important and practical implications when nearly 40% of adults in the U.S. are obese with a body mass index [BMI] of [at least] 30,” wrote Jennifer Lighter, MD, of New York University Langone Health, and colleagues in their research letter published in Clinical Infectious Diseases.

Similar findings in a preprint publication, yet to be peer reviewed, from another New York hospital show that, with the exception of older age, obesity (BMI greater than 40 kg/m²) had the strongest association with hospitalization for COVID-19, increasing the risk more than 500%.

Meanwhile, a new French study shows a high frequency of obesity among patients admitted to one ICU for COVID-19; furthermore, disease severity increased with increasing BMI. One of the authors said in an interview that many of the presenting patients were younger, with their only risk factor being obesity.

“Patients with obesity should avoid any COVID-19 contamination by enforcing all prevention measures during the current pandemic,” wrote the authors, led by Arthur Simonnet, MD, Centre Hospitalier Universitaire de Lille (France).

They also stressed that COVID-19 patients “with severe obesity should be monitored more closely.”
 

Those with obesity are young and become very sick, very quickly

François Pattou, MD, PhD, coauthor of the French article published in Obesity said in an interview that, when patients with COVID-19 began to arrive at their ICU in Lille, there were young patients who did not have any other comorbidities.

“They were just obese,” he observed, adding that they seemed “to have a very specific disease, something different” from that seen before, with patients becoming very sick, very quickly.

In their study, they examined 124 consecutive patients admitted to intensive care with COVID-19 between Feb. 25 and April 5, 2020, and compared them with a historical control group of 306 patients admitted to the ICU at the same hospital for non–COVID-19-related severe acute respiratory disease in 2019.

By April 6, 60 patients with COVID-19 had been discharged from intensive care, 18 had died, and 46 remained in the unit. The majority (73%) were male, and their median age was 60 years. Obesity and severe obesity were significantly more prevalent among the patients with COVID-19, at 47.6% and 28.2% versus 25.2% and 10.8% among historical controls (P < .001 for trend).

A key finding was that those with a BMI greater than 35 had a more than 600% increased risk of requiring mechanical ventilation (odds ratio, 7.36; P = .021), compared with those with a BMI less than 25, even after adjusting for age, diabetes, and hypertension.
 

Obesity in under 60s at least doubles risk of admission in U.S.

The studies out of New York, one of which was stratified by age, paint a similar picture.

Dr. Lighter and colleagues found that, of the 3,615 individuals who tested positive for COVID-19 in their series, 775 (21%) had a BMI of 30-34 and 595 (16%) had a BMI of at least 35. Obesity wasn’t a predictor of admission to hospital or the ICU in those over the age of 60 years, but in those younger than 60 years, it was.

Those under age 60 with a BMI of 30-34 were twice as likely to be admitted to hospital (hazard ratio, 2.0; P < .0001) and critical care (HR, 1.8; P = .006), compared with those under age 60 with a BMI less than 30. Likewise, those under age 60 with a BMI of at least 35 were 2.2 (P < .0001) and 3.6 (P < .0001) times more likely to be admitted to acute and critical care.

“Unfortunately, obesity in people [less than] 60 years is a newly identified epidemiologic risk factor which may contribute to increased morbidity rates [with COVID-19] experienced in the U.S.,” they concluded.

And in the other U.S. study, Christopher M. Petrilli, MD, of New York University, and colleagues looked at 4,103 patients with COVID-19 treated between March 1 and April 2, 2020, and followed to April 7.

Just under half of patients (48.7%) were hospitalized, of whom 22.3% required mechanical ventilation and 14.6% died or were discharged to hospice. The research was published on medRxiv, showing that, apart from age, the strongest predictors of hospitalization were BMI greater than 40 (OR, 6.2) and heart failure (OR, 4.3).

“It is notable that the chronic condition with the strongest association with critical illness was obesity, with a substantially higher odds ratio than any cardiovascular or pulmonary disease,” they noted.
 

Inflammation is a possible culprit

Dr. Pattou believes that the culprit behind the increased risk of disease severity seen with obesity in COVID-19 is inflammation, mediated by fibrin deposits in the circulation, which his colleagues have seen on autopsy, and which “block oxygen passage through the blood.”

This may help explain why mechanical ventilation can be less successful in these patients. “The answer is to get rid of this inflammation,” Dr. Pattou observed.

Dr. Petrilli and colleagues also observed that obesity “is well-recognized to be a proinflammatory condition.”

And their findings showed “the importance of inflammatory markers in distinguishing future critical from noncritical illness,” they said, noting that, among these markers, early elevations in C-reactive protein and D-dimer “had the strongest association with mechanical ventilation or mortality.”

Livio Luzi, MD, of IRCCS MultiMedica, Milan, Italy, has previously written on the relationship between influenza and obesity, and discussed in an interview the potential lessons for the COVID-19 pandemic.

“Obesity is characterized by an impairment of immune response and by a low-grade chronic inflammation. Furthermore, obese subjects have an altered dynamic of pulmonary ventilation, with reduced diaphragmatic excursion,” Dr. Luzi said. These factors, alongside others, “may help to explain” the current results, and stress the importance of close monitoring of those with obesity and COVID-19.

No relevant financial relationships were declared.

This article first appeared on Medscape.com.

It is becoming increasingly clear that obesity is one of the biggest risk factors for severe COVID-19 disease, particularly among younger patients.

Newly published data from New York show that, among those aged under 60 years, obesity was twice as likely to result in hospitalization for COVID-19 and also significantly increased the likelihood that a person would end up in intensive care.

“Obesity [in people younger than 60] appears to be a previously unrecognized risk factor for hospital admission and need for critical care. This has important and practical implications when nearly 40% of adults in the U.S. are obese with a body mass index [BMI] of [at least] 30,” wrote Jennifer Lighter, MD, of New York University Langone Health, and colleagues in their research letter published in Clinical Infectious Diseases.

Similar findings in a preprint publication, yet to be peer reviewed, from another New York hospital show that, with the exception of older age, obesity (BMI greater than 40 kg/m²) had the strongest association with hospitalization for COVID-19, increasing the risk more than 500%.

Meanwhile, a new French study shows a high frequency of obesity among patients admitted to one ICU for COVID-19; furthermore, disease severity increased with increasing BMI. One of the authors said in an interview that many of the presenting patients were younger, with their only risk factor being obesity.

“Patients with obesity should avoid any COVID-19 contamination by enforcing all prevention measures during the current pandemic,” wrote the authors, led by Arthur Simonnet, MD, Centre Hospitalier Universitaire de Lille (France).

They also stressed that COVID-19 patients “with severe obesity should be monitored more closely.”
 

Those with obesity are young and become very sick, very quickly

François Pattou, MD, PhD, coauthor of the French article published in Obesity said in an interview that, when patients with COVID-19 began to arrive at their ICU in Lille, there were young patients who did not have any other comorbidities.

“They were just obese,” he observed, adding that they seemed “to have a very specific disease, something different” from that seen before, with patients becoming very sick, very quickly.

In their study, they examined 124 consecutive patients admitted to intensive care with COVID-19 between Feb. 25 and April 5, 2020, and compared them with a historical control group of 306 patients admitted to the ICU at the same hospital for non–COVID-19-related severe acute respiratory disease in 2019.

By April 6, 60 patients with COVID-19 had been discharged from intensive care, 18 had died, and 46 remained in the unit. The majority (73%) were male, and their median age was 60 years. Obesity and severe obesity were significantly more prevalent among the patients with COVID-19, at 47.6% and 28.2% versus 25.2% and 10.8% among historical controls (P < .001 for trend).

A key finding was that those with a BMI greater than 35 had a more than 600% increased risk of requiring mechanical ventilation (odds ratio, 7.36; P = .021), compared with those with a BMI less than 25, even after adjusting for age, diabetes, and hypertension.
 

Obesity in under 60s at least doubles risk of admission in U.S.

The studies out of New York, one of which was stratified by age, paint a similar picture.

Dr. Lighter and colleagues found that, of the 3,615 individuals who tested positive for COVID-19 in their series, 775 (21%) had a BMI of 30-34 and 595 (16%) had a BMI of at least 35. Obesity wasn’t a predictor of admission to hospital or the ICU in those over the age of 60 years, but in those younger than 60 years, it was.

Those under age 60 with a BMI of 30-34 were twice as likely to be admitted to hospital (hazard ratio, 2.0; P < .0001) and critical care (HR, 1.8; P = .006), compared with those under age 60 with a BMI less than 30. Likewise, those under age 60 with a BMI of at least 35 were 2.2 (P < .0001) and 3.6 (P < .0001) times more likely to be admitted to acute and critical care.

“Unfortunately, obesity in people [less than] 60 years is a newly identified epidemiologic risk factor which may contribute to increased morbidity rates [with COVID-19] experienced in the U.S.,” they concluded.

And in the other U.S. study, Christopher M. Petrilli, MD, of New York University, and colleagues looked at 4,103 patients with COVID-19 treated between March 1 and April 2, 2020, and followed to April 7.

Just under half of patients (48.7%) were hospitalized, of whom 22.3% required mechanical ventilation and 14.6% died or were discharged to hospice. The research was published on medRxiv, showing that, apart from age, the strongest predictors of hospitalization were BMI greater than 40 (OR, 6.2) and heart failure (OR, 4.3).

“It is notable that the chronic condition with the strongest association with critical illness was obesity, with a substantially higher odds ratio than any cardiovascular or pulmonary disease,” they noted.
 

Inflammation is a possible culprit

Dr. Pattou believes that the culprit behind the increased risk of disease severity seen with obesity in COVID-19 is inflammation, mediated by fibrin deposits in the circulation, which his colleagues have seen on autopsy, and which “block oxygen passage through the blood.”

This may help explain why mechanical ventilation can be less successful in these patients. “The answer is to get rid of this inflammation,” Dr. Pattou observed.

Dr. Petrilli and colleagues also observed that obesity “is well-recognized to be a proinflammatory condition.”

And their findings showed “the importance of inflammatory markers in distinguishing future critical from noncritical illness,” they said, noting that, among these markers, early elevations in C-reactive protein and D-dimer “had the strongest association with mechanical ventilation or mortality.”

Livio Luzi, MD, of IRCCS MultiMedica, Milan, Italy, has previously written on the relationship between influenza and obesity, and discussed in an interview the potential lessons for the COVID-19 pandemic.

“Obesity is characterized by an impairment of immune response and by a low-grade chronic inflammation. Furthermore, obese subjects have an altered dynamic of pulmonary ventilation, with reduced diaphragmatic excursion,” Dr. Luzi said. These factors, alongside others, “may help to explain” the current results, and stress the importance of close monitoring of those with obesity and COVID-19.

No relevant financial relationships were declared.

This article first appeared on Medscape.com.

It is becoming increasingly clear that obesity is one of the biggest risk factors for severe COVID-19 disease, particularly among younger patients.

Newly published data from New York show that, among those aged under 60 years, obesity was twice as likely to result in hospitalization for COVID-19 and also significantly increased the likelihood that a person would end up in intensive care.

“Obesity [in people younger than 60] appears to be a previously unrecognized risk factor for hospital admission and need for critical care. This has important and practical implications when nearly 40% of adults in the U.S. are obese with a body mass index [BMI] of [at least] 30,” wrote Jennifer Lighter, MD, of New York University Langone Health, and colleagues in their research letter published in Clinical Infectious Diseases.

Similar findings in a preprint publication, yet to be peer reviewed, from another New York hospital show that, with the exception of older age, obesity (BMI greater than 40 kg/m²) had the strongest association with hospitalization for COVID-19, increasing the risk more than 500%.

Meanwhile, a new French study shows a high frequency of obesity among patients admitted to one ICU for COVID-19; furthermore, disease severity increased with increasing BMI. One of the authors said in an interview that many of the presenting patients were younger, with their only risk factor being obesity.

“Patients with obesity should avoid any COVID-19 contamination by enforcing all prevention measures during the current pandemic,” wrote the authors, led by Arthur Simonnet, MD, Centre Hospitalier Universitaire de Lille (France).

They also stressed that COVID-19 patients “with severe obesity should be monitored more closely.”
 

Those with obesity are young and become very sick, very quickly

François Pattou, MD, PhD, coauthor of the French article published in Obesity said in an interview that, when patients with COVID-19 began to arrive at their ICU in Lille, there were young patients who did not have any other comorbidities.

“They were just obese,” he observed, adding that they seemed “to have a very specific disease, something different” from that seen before, with patients becoming very sick, very quickly.

In their study, they examined 124 consecutive patients admitted to intensive care with COVID-19 between Feb. 25 and April 5, 2020, and compared them with a historical control group of 306 patients admitted to the ICU at the same hospital for non–COVID-19-related severe acute respiratory disease in 2019.

By April 6, 60 patients with COVID-19 had been discharged from intensive care, 18 had died, and 46 remained in the unit. The majority (73%) were male, and their median age was 60 years. Obesity and severe obesity were significantly more prevalent among the patients with COVID-19, at 47.6% and 28.2% versus 25.2% and 10.8% among historical controls (P < .001 for trend).

A key finding was that those with a BMI greater than 35 had a more than 600% increased risk of requiring mechanical ventilation (odds ratio, 7.36; P = .021), compared with those with a BMI less than 25, even after adjusting for age, diabetes, and hypertension.
 

Obesity in under 60s at least doubles risk of admission in U.S.

The studies out of New York, one of which was stratified by age, paint a similar picture.

Dr. Lighter and colleagues found that, of the 3,615 individuals who tested positive for COVID-19 in their series, 775 (21%) had a BMI of 30-34 and 595 (16%) had a BMI of at least 35. Obesity wasn’t a predictor of admission to hospital or the ICU in those over the age of 60 years, but in those younger than 60 years, it was.

Those under age 60 with a BMI of 30-34 were twice as likely to be admitted to hospital (hazard ratio, 2.0; P < .0001) and critical care (HR, 1.8; P = .006), compared with those under age 60 with a BMI less than 30. Likewise, those under age 60 with a BMI of at least 35 were 2.2 (P < .0001) and 3.6 (P < .0001) times more likely to be admitted to acute and critical care.

“Unfortunately, obesity in people [less than] 60 years is a newly identified epidemiologic risk factor which may contribute to increased morbidity rates [with COVID-19] experienced in the U.S.,” they concluded.

And in the other U.S. study, Christopher M. Petrilli, MD, of New York University, and colleagues looked at 4,103 patients with COVID-19 treated between March 1 and April 2, 2020, and followed to April 7.

Just under half of patients (48.7%) were hospitalized, of whom 22.3% required mechanical ventilation and 14.6% died or were discharged to hospice. The research was published on medRxiv, showing that, apart from age, the strongest predictors of hospitalization were BMI greater than 40 (OR, 6.2) and heart failure (OR, 4.3).

“It is notable that the chronic condition with the strongest association with critical illness was obesity, with a substantially higher odds ratio than any cardiovascular or pulmonary disease,” they noted.
 

Inflammation is a possible culprit

Dr. Pattou believes that the culprit behind the increased risk of disease severity seen with obesity in COVID-19 is inflammation, mediated by fibrin deposits in the circulation, which his colleagues have seen on autopsy, and which “block oxygen passage through the blood.”

This may help explain why mechanical ventilation can be less successful in these patients. “The answer is to get rid of this inflammation,” Dr. Pattou observed.

Dr. Petrilli and colleagues also observed that obesity “is well-recognized to be a proinflammatory condition.”

And their findings showed “the importance of inflammatory markers in distinguishing future critical from noncritical illness,” they said, noting that, among these markers, early elevations in C-reactive protein and D-dimer “had the strongest association with mechanical ventilation or mortality.”

Livio Luzi, MD, of IRCCS MultiMedica, Milan, Italy, has previously written on the relationship between influenza and obesity, and discussed in an interview the potential lessons for the COVID-19 pandemic.

“Obesity is characterized by an impairment of immune response and by a low-grade chronic inflammation. Furthermore, obese subjects have an altered dynamic of pulmonary ventilation, with reduced diaphragmatic excursion,” Dr. Luzi said. These factors, alongside others, “may help to explain” the current results, and stress the importance of close monitoring of those with obesity and COVID-19.

No relevant financial relationships were declared.

This article first appeared on Medscape.com.

The first protocol for the use of lung ultrasound to quantitatively and reproducibly assess the degree of lung involvement in patients suspected of having COVID-19 infection has been published by a team of Italian experts with experience using the technology on the front line.

Particularly in Spain and Italy — where the pandemic has struck hardest in Europe — hard-pressed clinicians seeking to quickly understand whether patients with seemingly mild disease could be harboring more serious lung involvement have increasingly relied upon lung ultrasound in the emergency room.

Now Libertario Demi, PhD, head of the ultrasound laboratory, University of Trento, Italy, and colleagues have developed a protocol, published online March 30 in the Journal of Ultrasound Medicine, to standardize practice.

Their research, which builds on previous work by the team, offers broad agreement with industry-led algorithms and emphasizes the use of wireless, handheld ultrasound devices, ideally consisting of a separate probe and tablet, to make sterilization easy.

Firms such as the Butterfly Network, Phillips, Clarius, GE Healthcare, and Siemens are among numerous companies that produce one or more such devices, including some that are completely integrated.
 

Not Universally Accepted

However, lung ultrasound is not yet universally accepted as a tool for diagnosing pneumonia in the context of COVID-19 and triaging patients.

The National Health Service in England does not even mention lung ultrasound in its radiology decision tool for suspected COVID-19, specifying instead chest X-ray as the first-line diagnostic imaging tool, with CT scanning in equivocal cases.

But Giovanni Volpicelli, MD, University Hospital San Luigi Gonzaga, Turin, Italy, who has previously described his experience to Medscape Medical News, says many patients with COVID-19 in his hospital presented with a negative chest X-ray but were found to have interstitial pneumonia on lung ultrasound.

Moreover, while CT scan remains the gold standard, the risk of nosocomial infection is more easily controlled if patients do not have to be transported to the radiology department but remain in the emergency room and instead undergo lung ultrasound there, he stressed.
 

Experts Share Experience of Lung Ultrasound in COVID-19

In developing and publishing their protocol, Demi, senior author of the article, and other colleagues from the heavily affected cities of Northern Italy, say their aim is “to share our experience and to propose a standardization with respect to the use of lung ultrasound in the management of COVID-19 patients.”

They reviewed an anonymized database of around 60,000 ultrasound images of confirmed COVID-19 cases and reviewers were blinded to patients’ clinical backgrounds.

For image acquisition, the authors recommend scanning 14 areas in each patient for 10 seconds, making the scans intercostal to cover the widest possible surface area.

They advise the use of a single focal point on the pleural line, which they write, optimizes the beam shape for observing the lung surface.

The authors also urge that the mechanical index (MI) be kept low because high MIs sustained for long periods “may result in damaging the lung.”

They also stress that cosmetic filters and modalities such as harmonic imaging, contrast, doppler, and compounding should be avoided, alongside saturation phenomena.
 

What Constitutes Intermediate Disease?

Once the images have been taken, they are scored on a 0-3 scale for each of the 14 areas, with no weighting on any individual area.

A score of 0 is given when the pleural line is continuous and regular, with the presence of A-lines, denoting that the lungs are unaffected.

An area is given a score of 3 when the scan shows dense and largely extended white lung tissue, with or without consolidations, indicating severe disease.

At both ends of this spectrum, there is agreement between the Italian protocol and an algorithm developed by the Butterfly Network.

However, the two differ when it comes to scoring intermediate cases. On the Butterfly algorithm, the suggestion is to look for B-lines, caused by fluid and cellular infiltration into the interstitium, and to weigh that against the need for supplementary oxygen.

The Italian team, in contrast, says a score of 1 is given when the pleural line is indented, with vertical areas of white visible below.

A score of 2 is given when the pleural line is broken, with small to large areas of consolidation and associated areas of white below.

Demi told Medscape Medical News that they did not refer to B-lines in their protocol as their visibility depends entirely on the imaging frequency and the probe used.

“This means that scoring on B-lines, people with different machines would give completely different scores for the same patient.”

He continued: “We prefer to refer to horizontal and vertical artifacts, and provide an analysis of the patterns, which is related to the physics of the interactions between the ultrasound waves and lung surface.”

In response, Mike Stone, MD, Legacy Emanuel Medical Center, Portland, Oregon, and director of education at Butterfly, said there appears to be wide variation in lung findings that “may or may not correlate with the severity of symptoms.”

He told Medscape Medical News it is “hard to know exactly if someone with pure B-lines will progress to serious illness or if someone with some subpleural consolidations will do well.”
 

A Negative Ultrasound Is the Most Useful

Volpicelli believes that, in any case, any patient with an intermediate pattern will require further diagnosis, such as other imaging modalities and blood exams, and the real role of lung ultrasound is in assessing patients at either end of the spectrum.

“In other words, there are situations where lung ultrasound can be considered definitive,” he told Medscape Medical News. “For instance, if I see a patient with mild signs of the disease, just fever, and I perform lung ultrasound and see nothing, lung ultrasound rules out pneumonia.”

“This patient may have COVID-19 of course, but they do not have pneumonia, and they can be treated at home, awaiting the result of the swab test. And this is useful because you can reduce the burden in the emergency department.”

Volpicelli continued: “On the other hand, there are patients with acute respiratory failure in respiratory distress. If the lung ultrasound is normal, you can rule out COVID-19 and you need to use other diagnostic procedures to understand the problem.”

“This is also very important for us because it’s crucial to be able to remove the patient from the isolation area and perform CT scan, chest radiography, and all the other diagnostic tools that we need.”
 

Are Wireless Machines Needed? Not Necessarily

With regard to the use of wireless technology, the Italian team says that “in the setting of COVID-19, wireless probes and tablets represent the most appropriate ultrasound equipment” because they can “easily be wrapped in single-use plastic covers, reducing the risk of contamination,” and making sterilization easy.

Stone suggests that integrated portable devices, however, are no more likely to cause cross-contamination than separate probes and tablets, as they can fit within a sterile sheath as a single unit.

Volpicelli, for his part, doesn’t like what he sees as undue focus on wireless devices for lung ultrasound in the COVID-19 protocols.

He is concerned that recommending them as the best approach may be sending out the wrong message, which could be very “dangerous” as people may then think they cannot perform this screening with standard ultrasound machines.

For him, the issue of cross contamination with standard lung ultrasound machines is “nonexistent. Cleaning the machine is quite easy and I do it hundreds of times per week.”

He does acknowledge, however, that if the lung ultrasound is performed under certain circumstances, for example when a patient is using a continuous positive airway pressure (CPAP) machine, “the risk of having the machine contaminated is a little bit higher.”

“In these situations...we have a more intensive cleaning procedure to avoid cross-contamination.”

He stressed: “Not all centers have wireless machines, whereas a normal machine is usually in all hospitals.”

“The advantages of using lung ultrasound [in COVID-19] are too great to be limited by something that is not important in my opinion,” he concluded.

Stone is director of education at the Butterfly Network. No other conflicts of interest were declared.

This article first appeared on Medscape.com.

The first protocol for the use of lung ultrasound to quantitatively and reproducibly assess the degree of lung involvement in patients suspected of having COVID-19 infection has been published by a team of Italian experts with experience using the technology on the front line.

Particularly in Spain and Italy — where the pandemic has struck hardest in Europe — hard-pressed clinicians seeking to quickly understand whether patients with seemingly mild disease could be harboring more serious lung involvement have increasingly relied upon lung ultrasound in the emergency room.

Now Libertario Demi, PhD, head of the ultrasound laboratory, University of Trento, Italy, and colleagues have developed a protocol, published online March 30 in the Journal of Ultrasound Medicine, to standardize practice.

Their research, which builds on previous work by the team, offers broad agreement with industry-led algorithms and emphasizes the use of wireless, handheld ultrasound devices, ideally consisting of a separate probe and tablet, to make sterilization easy.

Firms such as the Butterfly Network, Phillips, Clarius, GE Healthcare, and Siemens are among numerous companies that produce one or more such devices, including some that are completely integrated.
 

Not Universally Accepted

However, lung ultrasound is not yet universally accepted as a tool for diagnosing pneumonia in the context of COVID-19 and triaging patients.

The National Health Service in England does not even mention lung ultrasound in its radiology decision tool for suspected COVID-19, specifying instead chest X-ray as the first-line diagnostic imaging tool, with CT scanning in equivocal cases.

But Giovanni Volpicelli, MD, University Hospital San Luigi Gonzaga, Turin, Italy, who has previously described his experience to Medscape Medical News, says many patients with COVID-19 in his hospital presented with a negative chest X-ray but were found to have interstitial pneumonia on lung ultrasound.

Moreover, while CT scan remains the gold standard, the risk of nosocomial infection is more easily controlled if patients do not have to be transported to the radiology department but remain in the emergency room and instead undergo lung ultrasound there, he stressed.
 

Experts Share Experience of Lung Ultrasound in COVID-19

In developing and publishing their protocol, Demi, senior author of the article, and other colleagues from the heavily affected cities of Northern Italy, say their aim is “to share our experience and to propose a standardization with respect to the use of lung ultrasound in the management of COVID-19 patients.”

They reviewed an anonymized database of around 60,000 ultrasound images of confirmed COVID-19 cases and reviewers were blinded to patients’ clinical backgrounds.

For image acquisition, the authors recommend scanning 14 areas in each patient for 10 seconds, making the scans intercostal to cover the widest possible surface area.

They advise the use of a single focal point on the pleural line, which they write, optimizes the beam shape for observing the lung surface.

The authors also urge that the mechanical index (MI) be kept low because high MIs sustained for long periods “may result in damaging the lung.”

They also stress that cosmetic filters and modalities such as harmonic imaging, contrast, doppler, and compounding should be avoided, alongside saturation phenomena.
 

What Constitutes Intermediate Disease?

Once the images have been taken, they are scored on a 0-3 scale for each of the 14 areas, with no weighting on any individual area.

A score of 0 is given when the pleural line is continuous and regular, with the presence of A-lines, denoting that the lungs are unaffected.

An area is given a score of 3 when the scan shows dense and largely extended white lung tissue, with or without consolidations, indicating severe disease.

At both ends of this spectrum, there is agreement between the Italian protocol and an algorithm developed by the Butterfly Network.

However, the two differ when it comes to scoring intermediate cases. On the Butterfly algorithm, the suggestion is to look for B-lines, caused by fluid and cellular infiltration into the interstitium, and to weigh that against the need for supplementary oxygen.

The Italian team, in contrast, says a score of 1 is given when the pleural line is indented, with vertical areas of white visible below.

A score of 2 is given when the pleural line is broken, with small to large areas of consolidation and associated areas of white below.

Demi told Medscape Medical News that they did not refer to B-lines in their protocol as their visibility depends entirely on the imaging frequency and the probe used.

“This means that scoring on B-lines, people with different machines would give completely different scores for the same patient.”

He continued: “We prefer to refer to horizontal and vertical artifacts, and provide an analysis of the patterns, which is related to the physics of the interactions between the ultrasound waves and lung surface.”

In response, Mike Stone, MD, Legacy Emanuel Medical Center, Portland, Oregon, and director of education at Butterfly, said there appears to be wide variation in lung findings that “may or may not correlate with the severity of symptoms.”

He told Medscape Medical News it is “hard to know exactly if someone with pure B-lines will progress to serious illness or if someone with some subpleural consolidations will do well.”
 

A Negative Ultrasound Is the Most Useful

Volpicelli believes that, in any case, any patient with an intermediate pattern will require further diagnosis, such as other imaging modalities and blood exams, and the real role of lung ultrasound is in assessing patients at either end of the spectrum.

“In other words, there are situations where lung ultrasound can be considered definitive,” he told Medscape Medical News. “For instance, if I see a patient with mild signs of the disease, just fever, and I perform lung ultrasound and see nothing, lung ultrasound rules out pneumonia.”

“This patient may have COVID-19 of course, but they do not have pneumonia, and they can be treated at home, awaiting the result of the swab test. And this is useful because you can reduce the burden in the emergency department.”

Volpicelli continued: “On the other hand, there are patients with acute respiratory failure in respiratory distress. If the lung ultrasound is normal, you can rule out COVID-19 and you need to use other diagnostic procedures to understand the problem.”

“This is also very important for us because it’s crucial to be able to remove the patient from the isolation area and perform CT scan, chest radiography, and all the other diagnostic tools that we need.”
 

Are Wireless Machines Needed? Not Necessarily

With regard to the use of wireless technology, the Italian team says that “in the setting of COVID-19, wireless probes and tablets represent the most appropriate ultrasound equipment” because they can “easily be wrapped in single-use plastic covers, reducing the risk of contamination,” and making sterilization easy.

Stone suggests that integrated portable devices, however, are no more likely to cause cross-contamination than separate probes and tablets, as they can fit within a sterile sheath as a single unit.

Volpicelli, for his part, doesn’t like what he sees as undue focus on wireless devices for lung ultrasound in the COVID-19 protocols.

He is concerned that recommending them as the best approach may be sending out the wrong message, which could be very “dangerous” as people may then think they cannot perform this screening with standard ultrasound machines.

For him, the issue of cross contamination with standard lung ultrasound machines is “nonexistent. Cleaning the machine is quite easy and I do it hundreds of times per week.”

He does acknowledge, however, that if the lung ultrasound is performed under certain circumstances, for example when a patient is using a continuous positive airway pressure (CPAP) machine, “the risk of having the machine contaminated is a little bit higher.”

“In these situations...we have a more intensive cleaning procedure to avoid cross-contamination.”

He stressed: “Not all centers have wireless machines, whereas a normal machine is usually in all hospitals.”

“The advantages of using lung ultrasound [in COVID-19] are too great to be limited by something that is not important in my opinion,” he concluded.

Stone is director of education at the Butterfly Network. No other conflicts of interest were declared.

This article first appeared on Medscape.com.

The first protocol for the use of lung ultrasound to quantitatively and reproducibly assess the degree of lung involvement in patients suspected of having COVID-19 infection has been published by a team of Italian experts with experience using the technology on the front line.

Particularly in Spain and Italy — where the pandemic has struck hardest in Europe — hard-pressed clinicians seeking to quickly understand whether patients with seemingly mild disease could be harboring more serious lung involvement have increasingly relied upon lung ultrasound in the emergency room.

Now Libertario Demi, PhD, head of the ultrasound laboratory, University of Trento, Italy, and colleagues have developed a protocol, published online March 30 in the Journal of Ultrasound Medicine, to standardize practice.

Their research, which builds on previous work by the team, offers broad agreement with industry-led algorithms and emphasizes the use of wireless, handheld ultrasound devices, ideally consisting of a separate probe and tablet, to make sterilization easy.

Firms such as the Butterfly Network, Phillips, Clarius, GE Healthcare, and Siemens are among numerous companies that produce one or more such devices, including some that are completely integrated.
 

Not Universally Accepted

However, lung ultrasound is not yet universally accepted as a tool for diagnosing pneumonia in the context of COVID-19 and triaging patients.

The National Health Service in England does not even mention lung ultrasound in its radiology decision tool for suspected COVID-19, specifying instead chest X-ray as the first-line diagnostic imaging tool, with CT scanning in equivocal cases.

But Giovanni Volpicelli, MD, University Hospital San Luigi Gonzaga, Turin, Italy, who has previously described his experience to Medscape Medical News, says many patients with COVID-19 in his hospital presented with a negative chest X-ray but were found to have interstitial pneumonia on lung ultrasound.

Moreover, while CT scan remains the gold standard, the risk of nosocomial infection is more easily controlled if patients do not have to be transported to the radiology department but remain in the emergency room and instead undergo lung ultrasound there, he stressed.
 

Experts Share Experience of Lung Ultrasound in COVID-19

In developing and publishing their protocol, Demi, senior author of the article, and other colleagues from the heavily affected cities of Northern Italy, say their aim is “to share our experience and to propose a standardization with respect to the use of lung ultrasound in the management of COVID-19 patients.”

They reviewed an anonymized database of around 60,000 ultrasound images of confirmed COVID-19 cases and reviewers were blinded to patients’ clinical backgrounds.

For image acquisition, the authors recommend scanning 14 areas in each patient for 10 seconds, making the scans intercostal to cover the widest possible surface area.

They advise the use of a single focal point on the pleural line, which they write, optimizes the beam shape for observing the lung surface.

The authors also urge that the mechanical index (MI) be kept low because high MIs sustained for long periods “may result in damaging the lung.”

They also stress that cosmetic filters and modalities such as harmonic imaging, contrast, doppler, and compounding should be avoided, alongside saturation phenomena.
 

What Constitutes Intermediate Disease?

Once the images have been taken, they are scored on a 0-3 scale for each of the 14 areas, with no weighting on any individual area.

A score of 0 is given when the pleural line is continuous and regular, with the presence of A-lines, denoting that the lungs are unaffected.

An area is given a score of 3 when the scan shows dense and largely extended white lung tissue, with or without consolidations, indicating severe disease.

At both ends of this spectrum, there is agreement between the Italian protocol and an algorithm developed by the Butterfly Network.

However, the two differ when it comes to scoring intermediate cases. On the Butterfly algorithm, the suggestion is to look for B-lines, caused by fluid and cellular infiltration into the interstitium, and to weigh that against the need for supplementary oxygen.

The Italian team, in contrast, says a score of 1 is given when the pleural line is indented, with vertical areas of white visible below.

A score of 2 is given when the pleural line is broken, with small to large areas of consolidation and associated areas of white below.

Demi told Medscape Medical News that they did not refer to B-lines in their protocol as their visibility depends entirely on the imaging frequency and the probe used.

“This means that scoring on B-lines, people with different machines would give completely different scores for the same patient.”

He continued: “We prefer to refer to horizontal and vertical artifacts, and provide an analysis of the patterns, which is related to the physics of the interactions between the ultrasound waves and lung surface.”

In response, Mike Stone, MD, Legacy Emanuel Medical Center, Portland, Oregon, and director of education at Butterfly, said there appears to be wide variation in lung findings that “may or may not correlate with the severity of symptoms.”

He told Medscape Medical News it is “hard to know exactly if someone with pure B-lines will progress to serious illness or if someone with some subpleural consolidations will do well.”
 

A Negative Ultrasound Is the Most Useful

Volpicelli believes that, in any case, any patient with an intermediate pattern will require further diagnosis, such as other imaging modalities and blood exams, and the real role of lung ultrasound is in assessing patients at either end of the spectrum.

“In other words, there are situations where lung ultrasound can be considered definitive,” he told Medscape Medical News. “For instance, if I see a patient with mild signs of the disease, just fever, and I perform lung ultrasound and see nothing, lung ultrasound rules out pneumonia.”

“This patient may have COVID-19 of course, but they do not have pneumonia, and they can be treated at home, awaiting the result of the swab test. And this is useful because you can reduce the burden in the emergency department.”

Volpicelli continued: “On the other hand, there are patients with acute respiratory failure in respiratory distress. If the lung ultrasound is normal, you can rule out COVID-19 and you need to use other diagnostic procedures to understand the problem.”

“This is also very important for us because it’s crucial to be able to remove the patient from the isolation area and perform CT scan, chest radiography, and all the other diagnostic tools that we need.”
 

Are Wireless Machines Needed? Not Necessarily

With regard to the use of wireless technology, the Italian team says that “in the setting of COVID-19, wireless probes and tablets represent the most appropriate ultrasound equipment” because they can “easily be wrapped in single-use plastic covers, reducing the risk of contamination,” and making sterilization easy.

Stone suggests that integrated portable devices, however, are no more likely to cause cross-contamination than separate probes and tablets, as they can fit within a sterile sheath as a single unit.

Volpicelli, for his part, doesn’t like what he sees as undue focus on wireless devices for lung ultrasound in the COVID-19 protocols.

He is concerned that recommending them as the best approach may be sending out the wrong message, which could be very “dangerous” as people may then think they cannot perform this screening with standard ultrasound machines.

For him, the issue of cross contamination with standard lung ultrasound machines is “nonexistent. Cleaning the machine is quite easy and I do it hundreds of times per week.”

He does acknowledge, however, that if the lung ultrasound is performed under certain circumstances, for example when a patient is using a continuous positive airway pressure (CPAP) machine, “the risk of having the machine contaminated is a little bit higher.”

“In these situations...we have a more intensive cleaning procedure to avoid cross-contamination.”

He stressed: “Not all centers have wireless machines, whereas a normal machine is usually in all hospitals.”

“The advantages of using lung ultrasound [in COVID-19] are too great to be limited by something that is not important in my opinion,” he concluded.

Stone is director of education at the Butterfly Network. No other conflicts of interest were declared.

This article first appeared on Medscape.com.

As the first international guidelines on the management of critically ill patients with COVID-19 are understandably comprehensive, one expert involved in their development highlights the essential recommendations and explains the rationale behind prone ventilation.

A panel of 39 experts from 12 countries from across the globe developed the 50 recommendations within four domains, under the auspices of the Surviving Sepsis Campaign. They are issued by the European Society of Intensive Care Medicine (ESICM), and will subsequently be published in the journal Intensive Care Medicine.

A central aspect of the guidance is what works, and what does not, in treating critically ill patients with COVID-19 in intensive care.

Ten of the recommendations cover potential pharmacotherapies, most of which have only weak or no evidence of benefit, as discussed in a recent perspective on Medscape. All 50 recommendations, along with the associated level of evidence, are detailed in table 2 in the paper.

There is also an algorithm for the management of patients with acute hypoxemic respiratory failure secondary to COVID-19 (figure 2) and a summary of clinical practice recommendations (figure 3).

In an editorial in the Journal of the American Medical Association issued just days after these new guidelines, Francois Lamontagne, MD, MSc, and Derek C. Angus, MD, MPH, say they “represent an excellent first step toward optimal, evidence-informed care for patients with COVID-19.” Lamontagne is from Universitaire de Sherbrooke, Canada, and Angus is from University of Pittsburgh School of Medicine, Pennsylvania, and is an associate editor with JAMA.
 

Dealing With Tide of COVID-19 Patients, Protecting Healthcare Workers

Editor in chief of Intensive Care Medicine Giuseppe Citerio, MD, from University of Milano-Bicocca, Monza, Italy, said: “COVID-19 cases are rising rapidly worldwide, and so we are increasingly seeing that intensive care units [ICUs] have difficulty in dealing with the tide of patients.”

“We need more resource in ICUs, and quickly. This means more ventilators and more trained personnel. In the meantime, this guidance aims to rationalize our approach and to avoid unproven strategies,” he explains in a press release from ESICM.

“This is the first guidance to lay out what works and what doesn’t in treating coronavirus-infected patients in intensive care. It’s based on decades of research on acute respiratory infection being applied to COVID-19 patients,” added ESICM President-Elect Maurizio Cecconi, MD, from Humanitas University, Milan, Italy.

“At the same time as caring for patients, we need to make sure that health workers are following procedures which will allow themselves to be protected against infection,” he stressed.

“We must protect them, they are in the frontline. We cannot allow our healthcare workers to be at risk. On top of that, if they get infected they could also spread the disease further.”

Top-10 Recommendations

While all 50 recommendations are key to the successful management of COVID-19 patients, busy clinicians on the frontline need to zone in on those indispensable practical recommendations that they should implement immediately.

Medscape Medical News therefore asked lead author Waleed Alhazzani, MD, MSc, from the Division of Critical Care, McMaster University, Hamilton, Canada, to give his personal top 10, the first three of which are focused on limiting the spread of infection.

1. For healthcare workers performing aerosol-generating procedures¹ on patients with COVID-19 in the ICU, we recommend using fitted respirator masks (N95 respirators, FFP2, or equivalent), as compared to surgical/medical masks, in addition to other personal protective equipment (eg, gloves, gown, and eye protection such as a face shield or safety goggles.

2. We recommend performing aerosol-generating procedures on ICU patients with COVID-19 in a negative-pressure room.

3. For healthcare workers providing usual care for nonventilated COVID-19 patients, we suggest using surgical/medical masks, as compared to respirator masks in addition to other personal protective equipment.

4. For healthcare workers performing endotracheal intubation on patients with COVID-19, we suggest using video guided laryngoscopy, over direct laryngoscopy, if available.

5. We recommend endotracheal intubation in patients with COVID-19, performed by healthcare workers experienced with airway management, to minimize the number of attempts and risk of transmission.

6. For intubated and mechanically ventilated adults with suspicion of COVID-19, we suggest obtaining endotracheal aspirates, over bronchial wash or bronchoalveolar lavage samples.

7. For adults with COVID-19 and acute hypoxemic respiratory failure, we suggest using high-flow nasal cannula [HFNC] over noninvasive positive pressure ventilation [NIPPV].

8. For adults with COVID-19 receiving NIPPV or HFNC, we recommend close monitoring for worsening of respiratory status and early intubation in a controlled setting if worsening occurs.

9. For mechanically ventilated adults with COVID-19 and moderate to severe acute respiratory distress syndrome [ARDS], we suggest prone ventilation for 12 to 16 hours over no prone ventilation.

10. For mechanically ventilated adults with COVID-19 and respiratory failure (without ARDS), we don’t recommend routine use of systemic corticosteroids.

¹ This includes endotracheal intubation, bronchoscopy, open suctioning, administration of nebulized treatment, manual ventilation before intubation, physical proning of the patient, disconnecting the patient from the ventilator, noninvasive positive pressure ventilation, tracheostomy, and cardiopulmonary resuscitation.
 

These choices are in broad agreement with those selected by Jason T. Poston, MD, University of Chicago, Illinois, and colleagues in their synopsis of these guidelines, published online March 26 in JAMA, although they also highlight another recommendation on infection control:

• For healthcare workers who are performing non-aerosol-generating procedures on mechanically ventilated (closed circuit) patients with COVID-19, we suggest using surgical/medical masks, as opposed to respirator masks, in addition to other personal protective equipment.

Importance of Prone Ventilation, Perhaps for Many Days

One recommendation singled out by both Alhazzani and coauthors, and Poston and colleagues, relates to prone ventilation for 12 to 16 hours in adults with moderate to severe ARDS receiving mechanical ventilation.

Michelle N. Gong, MD, MS, chief of critical care medicine at Montefiore Medical Center, New York City, also highlighted this practice in a live-stream interview with JAMA editor in chief Howard Bauchner, MD.

She explained that, in her institution, they have been “very aggressive about proning these patients as early as possible, but unlike some of the past ARDS patients…they tend to require many, many days of proning in order to get a response”.

Gong added that patients “may improve very rapidly when they are proned, but when we supinate them, they lose [the improvement] and then they get proned for upwards of 10 days or more, if need be.”

Alhazzani told Medscape Medical News that prone ventilation “is a simple intervention that requires training of healthcare providers but can be applied in most contexts.”

He explained that the recommendation “is driven by indirect evidence from ARDS,” not specifically those in COVID-19, with recent studies having shown that COVID-19 “can affect lung bases and may cause significant atelectasis and reduced lung compliance in the context of ARDS.”

“Prone ventilation has been shown to reduce mortality in patients with moderate to severe ARDS. Therefore, we issued a suggestion for clinicians to consider prone ventilation in this population.”

‘Impressively Thorough’ Recommendations, With Some Caveats

In their JAMA editorial, Lamontagne and Angus describe the recommendations as “impressively thorough and expansive.”

They note that they address resource scarcity, which “is likely to be a critical issue in low- and middle-income countries experiencing any reasonably large number of cases and in high-income countries experiencing a surge in the demand for critical care.”

The authors say, however, that a “weakness” of the guidelines is that they make recommendations for interventions that “lack supporting evidence.”

Consequently, “when prioritizing scarce resources, clinicians and healthcare systems will have to choose among options that have limited evidence to support them.”

“In future iterations of the guidelines, there should be more detailed recommendations for how clinicians should prioritize scarce resources, or include more recommendations against the use of unproven therapies.”

“The tasks ahead for the dissemination and uptake of optimal critical care are herculean,” Lamontagne and Angus say.

They include “a need to generate more robust evidence, consider carefully the application of that evidence across a wide variety of clinical circumstances, and generate supporting materials to ensure effective implementation of the guideline recommendations,” they conclude.

ESICM recommendations coauthor Yaseen Arabi is the principal investigator on a clinical trial for lopinavir/ritonavir and interferon in Middle East respiratory syndrome (MERS) and he was a nonpaid consultant on antiviral active for MERS- coronavirus (CoV) for Gilead Sciences and SAB Biotherapeutics. He is an investigator on REMAP-CAP trial and is a Board Members of the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC). Coauthor Eddy Fan declared receiving consultancy fees from ALung Technologies and MC3 Cardiopulmonary. Coauthor Maurizio Cecconi declared consultancy work with Edwards Lifesciences, Directed Systems, and Cheetah Medical.

JAMA Clinical Guidelines Synopsis coauthor Poston declares receiving honoraria for the CHEST Critical Care Board Review Course.

Editorialist Lamontagne reported receiving grants from the National Institute for Health Research (NIHR), Fonds de recherche du Québec-Santé, and the Lotte & John Hecht Foundation, unrelated to this work. Editorialist Angus participated in the development of Surviving Sepsis Campaign guidelines for sepsis, but had no role in the creation of the current COVID-19 guidelines, nor the decision to create these guidelines.

This article first appeared on Medscape.com.

As the first international guidelines on the management of critically ill patients with COVID-19 are understandably comprehensive, one expert involved in their development highlights the essential recommendations and explains the rationale behind prone ventilation.

A panel of 39 experts from 12 countries from across the globe developed the 50 recommendations within four domains, under the auspices of the Surviving Sepsis Campaign. They are issued by the European Society of Intensive Care Medicine (ESICM), and will subsequently be published in the journal Intensive Care Medicine.

A central aspect of the guidance is what works, and what does not, in treating critically ill patients with COVID-19 in intensive care.

Ten of the recommendations cover potential pharmacotherapies, most of which have only weak or no evidence of benefit, as discussed in a recent perspective on Medscape. All 50 recommendations, along with the associated level of evidence, are detailed in table 2 in the paper.

There is also an algorithm for the management of patients with acute hypoxemic respiratory failure secondary to COVID-19 (figure 2) and a summary of clinical practice recommendations (figure 3).

In an editorial in the Journal of the American Medical Association issued just days after these new guidelines, Francois Lamontagne, MD, MSc, and Derek C. Angus, MD, MPH, say they “represent an excellent first step toward optimal, evidence-informed care for patients with COVID-19.” Lamontagne is from Universitaire de Sherbrooke, Canada, and Angus is from University of Pittsburgh School of Medicine, Pennsylvania, and is an associate editor with JAMA.
 

Dealing With Tide of COVID-19 Patients, Protecting Healthcare Workers

Editor in chief of Intensive Care Medicine Giuseppe Citerio, MD, from University of Milano-Bicocca, Monza, Italy, said: “COVID-19 cases are rising rapidly worldwide, and so we are increasingly seeing that intensive care units [ICUs] have difficulty in dealing with the tide of patients.”

“We need more resource in ICUs, and quickly. This means more ventilators and more trained personnel. In the meantime, this guidance aims to rationalize our approach and to avoid unproven strategies,” he explains in a press release from ESICM.

“This is the first guidance to lay out what works and what doesn’t in treating coronavirus-infected patients in intensive care. It’s based on decades of research on acute respiratory infection being applied to COVID-19 patients,” added ESICM President-Elect Maurizio Cecconi, MD, from Humanitas University, Milan, Italy.

“At the same time as caring for patients, we need to make sure that health workers are following procedures which will allow themselves to be protected against infection,” he stressed.

“We must protect them, they are in the frontline. We cannot allow our healthcare workers to be at risk. On top of that, if they get infected they could also spread the disease further.”

Top-10 Recommendations

While all 50 recommendations are key to the successful management of COVID-19 patients, busy clinicians on the frontline need to zone in on those indispensable practical recommendations that they should implement immediately.

Medscape Medical News therefore asked lead author Waleed Alhazzani, MD, MSc, from the Division of Critical Care, McMaster University, Hamilton, Canada, to give his personal top 10, the first three of which are focused on limiting the spread of infection.

1. For healthcare workers performing aerosol-generating procedures¹ on patients with COVID-19 in the ICU, we recommend using fitted respirator masks (N95 respirators, FFP2, or equivalent), as compared to surgical/medical masks, in addition to other personal protective equipment (eg, gloves, gown, and eye protection such as a face shield or safety goggles.

2. We recommend performing aerosol-generating procedures on ICU patients with COVID-19 in a negative-pressure room.

3. For healthcare workers providing usual care for nonventilated COVID-19 patients, we suggest using surgical/medical masks, as compared to respirator masks in addition to other personal protective equipment.

4. For healthcare workers performing endotracheal intubation on patients with COVID-19, we suggest using video guided laryngoscopy, over direct laryngoscopy, if available.

5. We recommend endotracheal intubation in patients with COVID-19, performed by healthcare workers experienced with airway management, to minimize the number of attempts and risk of transmission.

6. For intubated and mechanically ventilated adults with suspicion of COVID-19, we suggest obtaining endotracheal aspirates, over bronchial wash or bronchoalveolar lavage samples.

7. For adults with COVID-19 and acute hypoxemic respiratory failure, we suggest using high-flow nasal cannula [HFNC] over noninvasive positive pressure ventilation [NIPPV].

8. For adults with COVID-19 receiving NIPPV or HFNC, we recommend close monitoring for worsening of respiratory status and early intubation in a controlled setting if worsening occurs.

9. For mechanically ventilated adults with COVID-19 and moderate to severe acute respiratory distress syndrome [ARDS], we suggest prone ventilation for 12 to 16 hours over no prone ventilation.

10. For mechanically ventilated adults with COVID-19 and respiratory failure (without ARDS), we don’t recommend routine use of systemic corticosteroids.

¹ This includes endotracheal intubation, bronchoscopy, open suctioning, administration of nebulized treatment, manual ventilation before intubation, physical proning of the patient, disconnecting the patient from the ventilator, noninvasive positive pressure ventilation, tracheostomy, and cardiopulmonary resuscitation.
 

These choices are in broad agreement with those selected by Jason T. Poston, MD, University of Chicago, Illinois, and colleagues in their synopsis of these guidelines, published online March 26 in JAMA, although they also highlight another recommendation on infection control:

• For healthcare workers who are performing non-aerosol-generating procedures on mechanically ventilated (closed circuit) patients with COVID-19, we suggest using surgical/medical masks, as opposed to respirator masks, in addition to other personal protective equipment.

Importance of Prone Ventilation, Perhaps for Many Days

One recommendation singled out by both Alhazzani and coauthors, and Poston and colleagues, relates to prone ventilation for 12 to 16 hours in adults with moderate to severe ARDS receiving mechanical ventilation.

Michelle N. Gong, MD, MS, chief of critical care medicine at Montefiore Medical Center, New York City, also highlighted this practice in a live-stream interview with JAMA editor in chief Howard Bauchner, MD.

She explained that, in her institution, they have been “very aggressive about proning these patients as early as possible, but unlike some of the past ARDS patients…they tend to require many, many days of proning in order to get a response”.

Gong added that patients “may improve very rapidly when they are proned, but when we supinate them, they lose [the improvement] and then they get proned for upwards of 10 days or more, if need be.”

Alhazzani told Medscape Medical News that prone ventilation “is a simple intervention that requires training of healthcare providers but can be applied in most contexts.”

He explained that the recommendation “is driven by indirect evidence from ARDS,” not specifically those in COVID-19, with recent studies having shown that COVID-19 “can affect lung bases and may cause significant atelectasis and reduced lung compliance in the context of ARDS.”

“Prone ventilation has been shown to reduce mortality in patients with moderate to severe ARDS. Therefore, we issued a suggestion for clinicians to consider prone ventilation in this population.”

‘Impressively Thorough’ Recommendations, With Some Caveats

In their JAMA editorial, Lamontagne and Angus describe the recommendations as “impressively thorough and expansive.”

They note that they address resource scarcity, which “is likely to be a critical issue in low- and middle-income countries experiencing any reasonably large number of cases and in high-income countries experiencing a surge in the demand for critical care.”

The authors say, however, that a “weakness” of the guidelines is that they make recommendations for interventions that “lack supporting evidence.”

Consequently, “when prioritizing scarce resources, clinicians and healthcare systems will have to choose among options that have limited evidence to support them.”

“In future iterations of the guidelines, there should be more detailed recommendations for how clinicians should prioritize scarce resources, or include more recommendations against the use of unproven therapies.”

“The tasks ahead for the dissemination and uptake of optimal critical care are herculean,” Lamontagne and Angus say.

They include “a need to generate more robust evidence, consider carefully the application of that evidence across a wide variety of clinical circumstances, and generate supporting materials to ensure effective implementation of the guideline recommendations,” they conclude.

ESICM recommendations coauthor Yaseen Arabi is the principal investigator on a clinical trial for lopinavir/ritonavir and interferon in Middle East respiratory syndrome (MERS) and he was a nonpaid consultant on antiviral active for MERS- coronavirus (CoV) for Gilead Sciences and SAB Biotherapeutics. He is an investigator on REMAP-CAP trial and is a Board Members of the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC). Coauthor Eddy Fan declared receiving consultancy fees from ALung Technologies and MC3 Cardiopulmonary. Coauthor Maurizio Cecconi declared consultancy work with Edwards Lifesciences, Directed Systems, and Cheetah Medical.

JAMA Clinical Guidelines Synopsis coauthor Poston declares receiving honoraria for the CHEST Critical Care Board Review Course.

Editorialist Lamontagne reported receiving grants from the National Institute for Health Research (NIHR), Fonds de recherche du Québec-Santé, and the Lotte & John Hecht Foundation, unrelated to this work. Editorialist Angus participated in the development of Surviving Sepsis Campaign guidelines for sepsis, but had no role in the creation of the current COVID-19 guidelines, nor the decision to create these guidelines.

This article first appeared on Medscape.com.

As the first international guidelines on the management of critically ill patients with COVID-19 are understandably comprehensive, one expert involved in their development highlights the essential recommendations and explains the rationale behind prone ventilation.

A panel of 39 experts from 12 countries from across the globe developed the 50 recommendations within four domains, under the auspices of the Surviving Sepsis Campaign. They are issued by the European Society of Intensive Care Medicine (ESICM), and will subsequently be published in the journal Intensive Care Medicine.

A central aspect of the guidance is what works, and what does not, in treating critically ill patients with COVID-19 in intensive care.

Ten of the recommendations cover potential pharmacotherapies, most of which have only weak or no evidence of benefit, as discussed in a recent perspective on Medscape. All 50 recommendations, along with the associated level of evidence, are detailed in table 2 in the paper.

There is also an algorithm for the management of patients with acute hypoxemic respiratory failure secondary to COVID-19 (figure 2) and a summary of clinical practice recommendations (figure 3).

In an editorial in the Journal of the American Medical Association issued just days after these new guidelines, Francois Lamontagne, MD, MSc, and Derek C. Angus, MD, MPH, say they “represent an excellent first step toward optimal, evidence-informed care for patients with COVID-19.” Lamontagne is from Universitaire de Sherbrooke, Canada, and Angus is from University of Pittsburgh School of Medicine, Pennsylvania, and is an associate editor with JAMA.
 

Dealing With Tide of COVID-19 Patients, Protecting Healthcare Workers

Editor in chief of Intensive Care Medicine Giuseppe Citerio, MD, from University of Milano-Bicocca, Monza, Italy, said: “COVID-19 cases are rising rapidly worldwide, and so we are increasingly seeing that intensive care units [ICUs] have difficulty in dealing with the tide of patients.”

“We need more resource in ICUs, and quickly. This means more ventilators and more trained personnel. In the meantime, this guidance aims to rationalize our approach and to avoid unproven strategies,” he explains in a press release from ESICM.

“This is the first guidance to lay out what works and what doesn’t in treating coronavirus-infected patients in intensive care. It’s based on decades of research on acute respiratory infection being applied to COVID-19 patients,” added ESICM President-Elect Maurizio Cecconi, MD, from Humanitas University, Milan, Italy.

“At the same time as caring for patients, we need to make sure that health workers are following procedures which will allow themselves to be protected against infection,” he stressed.

“We must protect them, they are in the frontline. We cannot allow our healthcare workers to be at risk. On top of that, if they get infected they could also spread the disease further.”

Top-10 Recommendations

While all 50 recommendations are key to the successful management of COVID-19 patients, busy clinicians on the frontline need to zone in on those indispensable practical recommendations that they should implement immediately.

Medscape Medical News therefore asked lead author Waleed Alhazzani, MD, MSc, from the Division of Critical Care, McMaster University, Hamilton, Canada, to give his personal top 10, the first three of which are focused on limiting the spread of infection.

1. For healthcare workers performing aerosol-generating procedures¹ on patients with COVID-19 in the ICU, we recommend using fitted respirator masks (N95 respirators, FFP2, or equivalent), as compared to surgical/medical masks, in addition to other personal protective equipment (eg, gloves, gown, and eye protection such as a face shield or safety goggles.

2. We recommend performing aerosol-generating procedures on ICU patients with COVID-19 in a negative-pressure room.

3. For healthcare workers providing usual care for nonventilated COVID-19 patients, we suggest using surgical/medical masks, as compared to respirator masks in addition to other personal protective equipment.

4. For healthcare workers performing endotracheal intubation on patients with COVID-19, we suggest using video guided laryngoscopy, over direct laryngoscopy, if available.

5. We recommend endotracheal intubation in patients with COVID-19, performed by healthcare workers experienced with airway management, to minimize the number of attempts and risk of transmission.

6. For intubated and mechanically ventilated adults with suspicion of COVID-19, we suggest obtaining endotracheal aspirates, over bronchial wash or bronchoalveolar lavage samples.

7. For adults with COVID-19 and acute hypoxemic respiratory failure, we suggest using high-flow nasal cannula [HFNC] over noninvasive positive pressure ventilation [NIPPV].

8. For adults with COVID-19 receiving NIPPV or HFNC, we recommend close monitoring for worsening of respiratory status and early intubation in a controlled setting if worsening occurs.

9. For mechanically ventilated adults with COVID-19 and moderate to severe acute respiratory distress syndrome [ARDS], we suggest prone ventilation for 12 to 16 hours over no prone ventilation.

10. For mechanically ventilated adults with COVID-19 and respiratory failure (without ARDS), we don’t recommend routine use of systemic corticosteroids.

¹ This includes endotracheal intubation, bronchoscopy, open suctioning, administration of nebulized treatment, manual ventilation before intubation, physical proning of the patient, disconnecting the patient from the ventilator, noninvasive positive pressure ventilation, tracheostomy, and cardiopulmonary resuscitation.
 

These choices are in broad agreement with those selected by Jason T. Poston, MD, University of Chicago, Illinois, and colleagues in their synopsis of these guidelines, published online March 26 in JAMA, although they also highlight another recommendation on infection control:

• For healthcare workers who are performing non-aerosol-generating procedures on mechanically ventilated (closed circuit) patients with COVID-19, we suggest using surgical/medical masks, as opposed to respirator masks, in addition to other personal protective equipment.

Importance of Prone Ventilation, Perhaps for Many Days

One recommendation singled out by both Alhazzani and coauthors, and Poston and colleagues, relates to prone ventilation for 12 to 16 hours in adults with moderate to severe ARDS receiving mechanical ventilation.

Michelle N. Gong, MD, MS, chief of critical care medicine at Montefiore Medical Center, New York City, also highlighted this practice in a live-stream interview with JAMA editor in chief Howard Bauchner, MD.

She explained that, in her institution, they have been “very aggressive about proning these patients as early as possible, but unlike some of the past ARDS patients…they tend to require many, many days of proning in order to get a response”.

Gong added that patients “may improve very rapidly when they are proned, but when we supinate them, they lose [the improvement] and then they get proned for upwards of 10 days or more, if need be.”

Alhazzani told Medscape Medical News that prone ventilation “is a simple intervention that requires training of healthcare providers but can be applied in most contexts.”

He explained that the recommendation “is driven by indirect evidence from ARDS,” not specifically those in COVID-19, with recent studies having shown that COVID-19 “can affect lung bases and may cause significant atelectasis and reduced lung compliance in the context of ARDS.”

“Prone ventilation has been shown to reduce mortality in patients with moderate to severe ARDS. Therefore, we issued a suggestion for clinicians to consider prone ventilation in this population.”

‘Impressively Thorough’ Recommendations, With Some Caveats

In their JAMA editorial, Lamontagne and Angus describe the recommendations as “impressively thorough and expansive.”

They note that they address resource scarcity, which “is likely to be a critical issue in low- and middle-income countries experiencing any reasonably large number of cases and in high-income countries experiencing a surge in the demand for critical care.”

The authors say, however, that a “weakness” of the guidelines is that they make recommendations for interventions that “lack supporting evidence.”

Consequently, “when prioritizing scarce resources, clinicians and healthcare systems will have to choose among options that have limited evidence to support them.”

“In future iterations of the guidelines, there should be more detailed recommendations for how clinicians should prioritize scarce resources, or include more recommendations against the use of unproven therapies.”

“The tasks ahead for the dissemination and uptake of optimal critical care are herculean,” Lamontagne and Angus say.

They include “a need to generate more robust evidence, consider carefully the application of that evidence across a wide variety of clinical circumstances, and generate supporting materials to ensure effective implementation of the guideline recommendations,” they conclude.

ESICM recommendations coauthor Yaseen Arabi is the principal investigator on a clinical trial for lopinavir/ritonavir and interferon in Middle East respiratory syndrome (MERS) and he was a nonpaid consultant on antiviral active for MERS- coronavirus (CoV) for Gilead Sciences and SAB Biotherapeutics. He is an investigator on REMAP-CAP trial and is a Board Members of the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC). Coauthor Eddy Fan declared receiving consultancy fees from ALung Technologies and MC3 Cardiopulmonary. Coauthor Maurizio Cecconi declared consultancy work with Edwards Lifesciences, Directed Systems, and Cheetah Medical.

JAMA Clinical Guidelines Synopsis coauthor Poston declares receiving honoraria for the CHEST Critical Care Board Review Course.

Editorialist Lamontagne reported receiving grants from the National Institute for Health Research (NIHR), Fonds de recherche du Québec-Santé, and the Lotte & John Hecht Foundation, unrelated to this work. Editorialist Angus participated in the development of Surviving Sepsis Campaign guidelines for sepsis, but had no role in the creation of the current COVID-19 guidelines, nor the decision to create these guidelines.

This article first appeared on Medscape.com.

More than a third (35%) of patients with relapsed non–small cell lung cancer (NSCLC) treated with pembrolizumab (Keytruda, Merck) were still alive at 3 years, according to long-term results from a pivotal clinical trial.

The results also showed that, among the 10% of patients who completed all 35 cycles of pembrolizumab, the 3-year overall survival was approximately 99%, with progression-free survival (PFS) at around 70%.

“It is too soon to say that pembrolizumab is a potential cure...and we know that it doesn’t work for all patients, but the agent remains very, very promising,” said lead investigator Roy Herbst, MD, PhD, Department of Medical Oncology, Yale Comprehensive Cancer Center, New Haven, Connecticut.

These new results come from the KEYNOTE-010 trial, conducted in more than 1000 patients with NSCLC who had progressed on chemotherapy, randomized to receive immunotherapy with pembrolizumab or chemotherapy with docetaxel.

The results were published online on February 20 in the Journal of Clinical Oncology and were previously presented at the 2018 annual meeting of the European Society of Medical Oncology.

Overall survival at 3 years was 35% in patients with PD-L1 expression ≥ 50% in the tumor, and 23% in those with PD-L1 ≥ 1%.

This compares with 3-year overall survival of 11-13% with docetaxel.

These results are “really extraordinary,” Herbst commented to Medscape Medical News.

The 3-year overall survival rate of 35% in patients with PD-L1 ≥ 50% “is huge,” he said. “It really shows the durability of the response.”

Herbst commented that the “almost 100%” survival at 3 years among patients who completed 35 cycles of pembrolizumab shows that this treatment period (of about 2 years) is “probably about the right time to treat.”

“Currently, the agent is being used in all potential settings, before any other treatment, after other treatment, and with other treatments,” he said.

“Our hope is to find the very best way to use pembrolizumab to treat individual lung cancer patients, assessing how much PD-L1 a tumor expresses, what stage the patient is in, as well as other variables and biomarkers we are working on. This is the story of tailored therapy,” Herbst said.

Approached for comment, Solange Peters, MD, PhD, Oncology Department, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, said that the results are “very good” and “confirm the paradigms we have been seeing in melanoma,” with good long-term control, which is “very reassuring.”

However, she told Medscape Medical News that the trial raises an important question: «How long do you need to expose your patient with lung cancer to immunotherapy in order to get this long-term control?»

She said the “good news” is that, for the 10% of patients who completed 2 years of treatment per protocol, almost all of them are still alive at 3 years, “which is not observed with chemotherapy.”

The question for Peters is “more about the definition of long-term control,” as it was seen that almost one in three patients nevertheless had some form of progression.

This suggests that you have a group of people “who are nicely controlled, you stop the drug, and 1 year later a third of them have progressed.”

Peters said: “So how long do you need to treat these patients? I would say I still don’t know.”

“If I were one of these patients probably I would still want to continue [on the drug]. Of course, some might have progressed even while remaining on the drug, but the proportion who would have progressed is probably smaller than this one.”
 

Responses on Re-introduction of Therapy

The study also allowed patients who had completed 35 cycles of pembrolizumab to be restarted on the drug if they experienced progression.

The team found that, among 14 patients, 43% had a partial response and 36% had stable disease.

Herbst highlighted this finding and told Medscape Medical News that this «could be very important to physicians because they might want to think about using the drug again» in patients who have progressed on it.

He believes that the progression was not because of any resistance per se but rather a slowing down of the adaptive immune response.

“It’s just that it needs a boost,” he said, while noting that tissue specimens will nevertheless be required to demonstrate the theory.

Peters agreed that these results are “very promising,” but questioned their overall significance, as it is “a very small number of patients” from a subset whose disease was controlled while on treatment and then progressed after stopping.

She also pointed out that, in another study in patients with lung cancer (CheckMate-153), some patients were rechallenged with immunotherapy after having stopped treatment at 1 year “with very poor results.”

Peters said studies in melanoma have shown “rechallenge can be useful in a significant proportion of patients, but still you have not demonstrated that stopping and rechallenging is the same as not stopping.”

Study Details

KEYNOTE-010 involved patients with NSCLC from 202 centers in 24 countries with stage IIIB/IV disease expressing PD-L1 who had experienced disease progression after at least two cycles of platinum-based chemotherapy.

They were randomized 1:1:1 to open-label pembrolizumab 2 mg/kg, pembrolizumab 10 mg/kg, or docetaxel 75 mg/m² every 3 weeks.

Pembrolizumab was continued for 35 treatment cycles over 2 years and docetaxel was continued for the maximum duration allowed by local regulators.

Patients who stopped pembrolizumab after a complete response or completing all 35 cycles, and who subsequently experienced disease progression, could receive up to 17 additional cycles over 1 year if they had not received another anticancer therapy in the meantime.

Among the 1,034 patients originally recruited between August 2013 and February 2015, 691 were assigned to pembrolizumab at 3 mg/kg or 10 mg/kg and 343 to docetaxel.

For the intention-to-treat analysis in 1033 patients, the mean duration of follow-up was 42.6 months, with a median treatment duration of 3.5 months in the pembrolizumab group and 2.0 months in the docetaxel group.

Compared with docetaxel, pembrolizumab was associated with a significant reduction in the risk of death, at a hazard ratio of 0.53 in patients with PD-L1 ≥ 50% and 0.69 in those with PD-L1 ≥ 1% (both P < .0001).

In patients with PD-L1 ≥ 50%, median overall survival was 16.9 months in those given pembrolizumab and 8.2 months with docetaxel. Among those with PD-L1 ≥ 1%, median overall survival was 11.8 months with pembrolizumab versus 8.4 months with docetaxel.

Overall survival on Kaplan-Meier analysis was 34.5% with pembrolizumab and 12.7% with docetaxel in the PD-L1 ≥ 50% group, and 22.9% versus 11.0% in the PD-L1 ≥ 1% group.

PFS significantly improved with pembrolizumab versus docetaxel, at a hazard ratio of 0.57 (P < .00001) among patients with PD-L1 ≥ 50% and 0.83 (P < .005) in those with PD-L1 ≥ 1%.

In terms of safety, 17.7% of patients who completed 2 years of pembrolizumab had grade 3-5 treatment-related adverse events, compared with 16.6% among all pembrolizumab-treated patients and 36.6% of those given docetaxel.

The team reports that 79 patients completed 35 cycles of pembrolizumab, with a median follow-up of 43.4 months.

Compared with the overall patient group, these patients were less likely to be aged ≥ 65 years and to have received two or more prior treatment lines, although they were more likely to be current or former smokers and to have squamous tumor histology.

Patients who completed 35 cycles had an objective response rate of 94.9%, and 91.0% were still alive at the data cutoff. Overall survival rates were 98.7% at 12 months and 86.3% at 24 months.

Of 71 patients eligible for analysis, 23 experienced progression after completing pembrolizumab, at PFS rates at 12 and 24 months of 72.5% and 57.7%, respectively.

A total of 14 patients were given a second course of pembrolizumab, of whom six had a partial response and five had stable disease. At the data cutoff, five patients had completed 17 additional cycles and 11 were alive.

Pembro Approved at Fixed Dose

One notable aspect of the study is that patients in the pembrolizumab arm were given two different doses of the drug based on body weight, whereas the drug is approved in the United States at a fixed dose of 200 mg.

Herbst told Medscape Medical News he considers the 200-mg dose to be appropriate.

“I didn’t think that the 3-mg versus 10-mg dose per kg that we used in our study made much difference in an average-sized person,” he said, adding that the 200-mg dose “is something a little bit more than 3 mg/kg.”

“So I think that this is clearly the right dos, and I don’t think more would make any difference,” he said.

The study was funded by Merck, the manufacturer of pembrolizumab. Herbst has reported having a consulting or advisory role for many pharmaceutical companies. Other coauthors have also reported relationships with industry, and some of the authors are Merck employees. Peters has reported receiving education grants, providing consultation, attending advisory boards, and/or providing lectures for many pharmaceutical companies.
 

This article first appeared on Medscape.com.

More than a third (35%) of patients with relapsed non–small cell lung cancer (NSCLC) treated with pembrolizumab (Keytruda, Merck) were still alive at 3 years, according to long-term results from a pivotal clinical trial.

The results also showed that, among the 10% of patients who completed all 35 cycles of pembrolizumab, the 3-year overall survival was approximately 99%, with progression-free survival (PFS) at around 70%.

“It is too soon to say that pembrolizumab is a potential cure...and we know that it doesn’t work for all patients, but the agent remains very, very promising,” said lead investigator Roy Herbst, MD, PhD, Department of Medical Oncology, Yale Comprehensive Cancer Center, New Haven, Connecticut.

These new results come from the KEYNOTE-010 trial, conducted in more than 1000 patients with NSCLC who had progressed on chemotherapy, randomized to receive immunotherapy with pembrolizumab or chemotherapy with docetaxel.

The results were published online on February 20 in the Journal of Clinical Oncology and were previously presented at the 2018 annual meeting of the European Society of Medical Oncology.

Overall survival at 3 years was 35% in patients with PD-L1 expression ≥ 50% in the tumor, and 23% in those with PD-L1 ≥ 1%.

This compares with 3-year overall survival of 11-13% with docetaxel.

These results are “really extraordinary,” Herbst commented to Medscape Medical News.

The 3-year overall survival rate of 35% in patients with PD-L1 ≥ 50% “is huge,” he said. “It really shows the durability of the response.”

Herbst commented that the “almost 100%” survival at 3 years among patients who completed 35 cycles of pembrolizumab shows that this treatment period (of about 2 years) is “probably about the right time to treat.”

“Currently, the agent is being used in all potential settings, before any other treatment, after other treatment, and with other treatments,” he said.

“Our hope is to find the very best way to use pembrolizumab to treat individual lung cancer patients, assessing how much PD-L1 a tumor expresses, what stage the patient is in, as well as other variables and biomarkers we are working on. This is the story of tailored therapy,” Herbst said.

Approached for comment, Solange Peters, MD, PhD, Oncology Department, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, said that the results are “very good” and “confirm the paradigms we have been seeing in melanoma,” with good long-term control, which is “very reassuring.”

However, she told Medscape Medical News that the trial raises an important question: «How long do you need to expose your patient with lung cancer to immunotherapy in order to get this long-term control?»

She said the “good news” is that, for the 10% of patients who completed 2 years of treatment per protocol, almost all of them are still alive at 3 years, “which is not observed with chemotherapy.”

The question for Peters is “more about the definition of long-term control,” as it was seen that almost one in three patients nevertheless had some form of progression.

This suggests that you have a group of people “who are nicely controlled, you stop the drug, and 1 year later a third of them have progressed.”

Peters said: “So how long do you need to treat these patients? I would say I still don’t know.”

“If I were one of these patients probably I would still want to continue [on the drug]. Of course, some might have progressed even while remaining on the drug, but the proportion who would have progressed is probably smaller than this one.”
 

Responses on Re-introduction of Therapy

The study also allowed patients who had completed 35 cycles of pembrolizumab to be restarted on the drug if they experienced progression.

The team found that, among 14 patients, 43% had a partial response and 36% had stable disease.

Herbst highlighted this finding and told Medscape Medical News that this «could be very important to physicians because they might want to think about using the drug again» in patients who have progressed on it.

He believes that the progression was not because of any resistance per se but rather a slowing down of the adaptive immune response.

“It’s just that it needs a boost,” he said, while noting that tissue specimens will nevertheless be required to demonstrate the theory.

Peters agreed that these results are “very promising,” but questioned their overall significance, as it is “a very small number of patients” from a subset whose disease was controlled while on treatment and then progressed after stopping.

She also pointed out that, in another study in patients with lung cancer (CheckMate-153), some patients were rechallenged with immunotherapy after having stopped treatment at 1 year “with very poor results.”

Peters said studies in melanoma have shown “rechallenge can be useful in a significant proportion of patients, but still you have not demonstrated that stopping and rechallenging is the same as not stopping.”

Study Details

KEYNOTE-010 involved patients with NSCLC from 202 centers in 24 countries with stage IIIB/IV disease expressing PD-L1 who had experienced disease progression after at least two cycles of platinum-based chemotherapy.

They were randomized 1:1:1 to open-label pembrolizumab 2 mg/kg, pembrolizumab 10 mg/kg, or docetaxel 75 mg/m² every 3 weeks.

Pembrolizumab was continued for 35 treatment cycles over 2 years and docetaxel was continued for the maximum duration allowed by local regulators.

Patients who stopped pembrolizumab after a complete response or completing all 35 cycles, and who subsequently experienced disease progression, could receive up to 17 additional cycles over 1 year if they had not received another anticancer therapy in the meantime.

Among the 1,034 patients originally recruited between August 2013 and February 2015, 691 were assigned to pembrolizumab at 3 mg/kg or 10 mg/kg and 343 to docetaxel.

For the intention-to-treat analysis in 1033 patients, the mean duration of follow-up was 42.6 months, with a median treatment duration of 3.5 months in the pembrolizumab group and 2.0 months in the docetaxel group.

Compared with docetaxel, pembrolizumab was associated with a significant reduction in the risk of death, at a hazard ratio of 0.53 in patients with PD-L1 ≥ 50% and 0.69 in those with PD-L1 ≥ 1% (both P < .0001).

In patients with PD-L1 ≥ 50%, median overall survival was 16.9 months in those given pembrolizumab and 8.2 months with docetaxel. Among those with PD-L1 ≥ 1%, median overall survival was 11.8 months with pembrolizumab versus 8.4 months with docetaxel.

Overall survival on Kaplan-Meier analysis was 34.5% with pembrolizumab and 12.7% with docetaxel in the PD-L1 ≥ 50% group, and 22.9% versus 11.0% in the PD-L1 ≥ 1% group.

PFS significantly improved with pembrolizumab versus docetaxel, at a hazard ratio of 0.57 (P < .00001) among patients with PD-L1 ≥ 50% and 0.83 (P < .005) in those with PD-L1 ≥ 1%.

In terms of safety, 17.7% of patients who completed 2 years of pembrolizumab had grade 3-5 treatment-related adverse events, compared with 16.6% among all pembrolizumab-treated patients and 36.6% of those given docetaxel.

The team reports that 79 patients completed 35 cycles of pembrolizumab, with a median follow-up of 43.4 months.

Compared with the overall patient group, these patients were less likely to be aged ≥ 65 years and to have received two or more prior treatment lines, although they were more likely to be current or former smokers and to have squamous tumor histology.

Patients who completed 35 cycles had an objective response rate of 94.9%, and 91.0% were still alive at the data cutoff. Overall survival rates were 98.7% at 12 months and 86.3% at 24 months.

Of 71 patients eligible for analysis, 23 experienced progression after completing pembrolizumab, at PFS rates at 12 and 24 months of 72.5% and 57.7%, respectively.

A total of 14 patients were given a second course of pembrolizumab, of whom six had a partial response and five had stable disease. At the data cutoff, five patients had completed 17 additional cycles and 11 were alive.

Pembro Approved at Fixed Dose

One notable aspect of the study is that patients in the pembrolizumab arm were given two different doses of the drug based on body weight, whereas the drug is approved in the United States at a fixed dose of 200 mg.

Herbst told Medscape Medical News he considers the 200-mg dose to be appropriate.

“I didn’t think that the 3-mg versus 10-mg dose per kg that we used in our study made much difference in an average-sized person,” he said, adding that the 200-mg dose “is something a little bit more than 3 mg/kg.”

“So I think that this is clearly the right dos, and I don’t think more would make any difference,” he said.

The study was funded by Merck, the manufacturer of pembrolizumab. Herbst has reported having a consulting or advisory role for many pharmaceutical companies. Other coauthors have also reported relationships with industry, and some of the authors are Merck employees. Peters has reported receiving education grants, providing consultation, attending advisory boards, and/or providing lectures for many pharmaceutical companies.
 

This article first appeared on Medscape.com.

More than a third (35%) of patients with relapsed non–small cell lung cancer (NSCLC) treated with pembrolizumab (Keytruda, Merck) were still alive at 3 years, according to long-term results from a pivotal clinical trial.

The results also showed that, among the 10% of patients who completed all 35 cycles of pembrolizumab, the 3-year overall survival was approximately 99%, with progression-free survival (PFS) at around 70%.

“It is too soon to say that pembrolizumab is a potential cure...and we know that it doesn’t work for all patients, but the agent remains very, very promising,” said lead investigator Roy Herbst, MD, PhD, Department of Medical Oncology, Yale Comprehensive Cancer Center, New Haven, Connecticut.

These new results come from the KEYNOTE-010 trial, conducted in more than 1000 patients with NSCLC who had progressed on chemotherapy, randomized to receive immunotherapy with pembrolizumab or chemotherapy with docetaxel.

The results were published online on February 20 in the Journal of Clinical Oncology and were previously presented at the 2018 annual meeting of the European Society of Medical Oncology.

Overall survival at 3 years was 35% in patients with PD-L1 expression ≥ 50% in the tumor, and 23% in those with PD-L1 ≥ 1%.

This compares with 3-year overall survival of 11-13% with docetaxel.

These results are “really extraordinary,” Herbst commented to Medscape Medical News.

The 3-year overall survival rate of 35% in patients with PD-L1 ≥ 50% “is huge,” he said. “It really shows the durability of the response.”

Herbst commented that the “almost 100%” survival at 3 years among patients who completed 35 cycles of pembrolizumab shows that this treatment period (of about 2 years) is “probably about the right time to treat.”

“Currently, the agent is being used in all potential settings, before any other treatment, after other treatment, and with other treatments,” he said.

“Our hope is to find the very best way to use pembrolizumab to treat individual lung cancer patients, assessing how much PD-L1 a tumor expresses, what stage the patient is in, as well as other variables and biomarkers we are working on. This is the story of tailored therapy,” Herbst said.

Approached for comment, Solange Peters, MD, PhD, Oncology Department, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, said that the results are “very good” and “confirm the paradigms we have been seeing in melanoma,” with good long-term control, which is “very reassuring.”

However, she told Medscape Medical News that the trial raises an important question: «How long do you need to expose your patient with lung cancer to immunotherapy in order to get this long-term control?»

She said the “good news” is that, for the 10% of patients who completed 2 years of treatment per protocol, almost all of them are still alive at 3 years, “which is not observed with chemotherapy.”

The question for Peters is “more about the definition of long-term control,” as it was seen that almost one in three patients nevertheless had some form of progression.

This suggests that you have a group of people “who are nicely controlled, you stop the drug, and 1 year later a third of them have progressed.”

Peters said: “So how long do you need to treat these patients? I would say I still don’t know.”

“If I were one of these patients probably I would still want to continue [on the drug]. Of course, some might have progressed even while remaining on the drug, but the proportion who would have progressed is probably smaller than this one.”
 

Responses on Re-introduction of Therapy

The study also allowed patients who had completed 35 cycles of pembrolizumab to be restarted on the drug if they experienced progression.

The team found that, among 14 patients, 43% had a partial response and 36% had stable disease.

Herbst highlighted this finding and told Medscape Medical News that this «could be very important to physicians because they might want to think about using the drug again» in patients who have progressed on it.

He believes that the progression was not because of any resistance per se but rather a slowing down of the adaptive immune response.

“It’s just that it needs a boost,” he said, while noting that tissue specimens will nevertheless be required to demonstrate the theory.

Peters agreed that these results are “very promising,” but questioned their overall significance, as it is “a very small number of patients” from a subset whose disease was controlled while on treatment and then progressed after stopping.

She also pointed out that, in another study in patients with lung cancer (CheckMate-153), some patients were rechallenged with immunotherapy after having stopped treatment at 1 year “with very poor results.”

Peters said studies in melanoma have shown “rechallenge can be useful in a significant proportion of patients, but still you have not demonstrated that stopping and rechallenging is the same as not stopping.”

Study Details

KEYNOTE-010 involved patients with NSCLC from 202 centers in 24 countries with stage IIIB/IV disease expressing PD-L1 who had experienced disease progression after at least two cycles of platinum-based chemotherapy.

They were randomized 1:1:1 to open-label pembrolizumab 2 mg/kg, pembrolizumab 10 mg/kg, or docetaxel 75 mg/m² every 3 weeks.

Pembrolizumab was continued for 35 treatment cycles over 2 years and docetaxel was continued for the maximum duration allowed by local regulators.

Patients who stopped pembrolizumab after a complete response or completing all 35 cycles, and who subsequently experienced disease progression, could receive up to 17 additional cycles over 1 year if they had not received another anticancer therapy in the meantime.

Among the 1,034 patients originally recruited between August 2013 and February 2015, 691 were assigned to pembrolizumab at 3 mg/kg or 10 mg/kg and 343 to docetaxel.

For the intention-to-treat analysis in 1033 patients, the mean duration of follow-up was 42.6 months, with a median treatment duration of 3.5 months in the pembrolizumab group and 2.0 months in the docetaxel group.

Compared with docetaxel, pembrolizumab was associated with a significant reduction in the risk of death, at a hazard ratio of 0.53 in patients with PD-L1 ≥ 50% and 0.69 in those with PD-L1 ≥ 1% (both P < .0001).

In patients with PD-L1 ≥ 50%, median overall survival was 16.9 months in those given pembrolizumab and 8.2 months with docetaxel. Among those with PD-L1 ≥ 1%, median overall survival was 11.8 months with pembrolizumab versus 8.4 months with docetaxel.

Overall survival on Kaplan-Meier analysis was 34.5% with pembrolizumab and 12.7% with docetaxel in the PD-L1 ≥ 50% group, and 22.9% versus 11.0% in the PD-L1 ≥ 1% group.

PFS significantly improved with pembrolizumab versus docetaxel, at a hazard ratio of 0.57 (P < .00001) among patients with PD-L1 ≥ 50% and 0.83 (P < .005) in those with PD-L1 ≥ 1%.

In terms of safety, 17.7% of patients who completed 2 years of pembrolizumab had grade 3-5 treatment-related adverse events, compared with 16.6% among all pembrolizumab-treated patients and 36.6% of those given docetaxel.

The team reports that 79 patients completed 35 cycles of pembrolizumab, with a median follow-up of 43.4 months.

Compared with the overall patient group, these patients were less likely to be aged ≥ 65 years and to have received two or more prior treatment lines, although they were more likely to be current or former smokers and to have squamous tumor histology.

Patients who completed 35 cycles had an objective response rate of 94.9%, and 91.0% were still alive at the data cutoff. Overall survival rates were 98.7% at 12 months and 86.3% at 24 months.

Of 71 patients eligible for analysis, 23 experienced progression after completing pembrolizumab, at PFS rates at 12 and 24 months of 72.5% and 57.7%, respectively.

A total of 14 patients were given a second course of pembrolizumab, of whom six had a partial response and five had stable disease. At the data cutoff, five patients had completed 17 additional cycles and 11 were alive.

Pembro Approved at Fixed Dose

One notable aspect of the study is that patients in the pembrolizumab arm were given two different doses of the drug based on body weight, whereas the drug is approved in the United States at a fixed dose of 200 mg.

Herbst told Medscape Medical News he considers the 200-mg dose to be appropriate.

“I didn’t think that the 3-mg versus 10-mg dose per kg that we used in our study made much difference in an average-sized person,” he said, adding that the 200-mg dose “is something a little bit more than 3 mg/kg.”

“So I think that this is clearly the right dos, and I don’t think more would make any difference,” he said.

The study was funded by Merck, the manufacturer of pembrolizumab. Herbst has reported having a consulting or advisory role for many pharmaceutical companies. Other coauthors have also reported relationships with industry, and some of the authors are Merck employees. Peters has reported receiving education grants, providing consultation, attending advisory boards, and/or providing lectures for many pharmaceutical companies.
 

This article first appeared on Medscape.com.

Oncology will account for a substantial majority of clinical trials to be launched in 2020, as well as accounting for most of those to be completed this year, according to a new analysis.

“A large number of early stage clinical trials within this field are likely to be due to the demand for novel therapeutic approaches addressing unmet medical need,” commented Mohamed Abukar, pharma analyst at GlobalData.

Most oncology studies planned to start in 2020 are phase 1 and 2, and 61.9% are industry sponsored. Eli Lilly and Novartis have announced the most upcoming studies.

Among the new drugs being evaluated in these clinical trials, four of the top seven drugs in phase 1–3 development are monoclonal antibodies, with the most studies being conducted on the experimental agents ZW25 (Zymeworks) and KSI-301 (Kodiak Sciences), the report notes.

As for clinical trials due for completion this year, many are funded by nonindustry sources, with Memorial Sloan Kettering Cancer Center accounting for the most number of trials.

Top Indications Explored in Clinical Trials

Oncology also accounts for eight of the top ten indications for clinical trials planned to start in 2020, with solid tumors, breast cancer, and non–small cell lung cancer accounting for the second, third, and fourth top spots, respectively, regardless of sponsor type.

However, for industry-sponsored clinical trials, the predominant area is solid tumors for new investigations to start this year, followed by breast cancer, then pain.

“This is attributed to the manner in which the burden of cancer worldwide necessitates industry investment to allow for capitalization on the increasing market size,” Abukar said.

This article first appeared on Medscape.com.

Oncology will account for a substantial majority of clinical trials to be launched in 2020, as well as accounting for most of those to be completed this year, according to a new analysis.

“A large number of early stage clinical trials within this field are likely to be due to the demand for novel therapeutic approaches addressing unmet medical need,” commented Mohamed Abukar, pharma analyst at GlobalData.

Most oncology studies planned to start in 2020 are phase 1 and 2, and 61.9% are industry sponsored. Eli Lilly and Novartis have announced the most upcoming studies.

Among the new drugs being evaluated in these clinical trials, four of the top seven drugs in phase 1–3 development are monoclonal antibodies, with the most studies being conducted on the experimental agents ZW25 (Zymeworks) and KSI-301 (Kodiak Sciences), the report notes.

As for clinical trials due for completion this year, many are funded by nonindustry sources, with Memorial Sloan Kettering Cancer Center accounting for the most number of trials.

Top Indications Explored in Clinical Trials

Oncology also accounts for eight of the top ten indications for clinical trials planned to start in 2020, with solid tumors, breast cancer, and non–small cell lung cancer accounting for the second, third, and fourth top spots, respectively, regardless of sponsor type.

However, for industry-sponsored clinical trials, the predominant area is solid tumors for new investigations to start this year, followed by breast cancer, then pain.

“This is attributed to the manner in which the burden of cancer worldwide necessitates industry investment to allow for capitalization on the increasing market size,” Abukar said.

This article first appeared on Medscape.com.

Oncology will account for a substantial majority of clinical trials to be launched in 2020, as well as accounting for most of those to be completed this year, according to a new analysis.

“A large number of early stage clinical trials within this field are likely to be due to the demand for novel therapeutic approaches addressing unmet medical need,” commented Mohamed Abukar, pharma analyst at GlobalData.

Most oncology studies planned to start in 2020 are phase 1 and 2, and 61.9% are industry sponsored. Eli Lilly and Novartis have announced the most upcoming studies.

Among the new drugs being evaluated in these clinical trials, four of the top seven drugs in phase 1–3 development are monoclonal antibodies, with the most studies being conducted on the experimental agents ZW25 (Zymeworks) and KSI-301 (Kodiak Sciences), the report notes.

As for clinical trials due for completion this year, many are funded by nonindustry sources, with Memorial Sloan Kettering Cancer Center accounting for the most number of trials.

Top Indications Explored in Clinical Trials

Oncology also accounts for eight of the top ten indications for clinical trials planned to start in 2020, with solid tumors, breast cancer, and non–small cell lung cancer accounting for the second, third, and fourth top spots, respectively, regardless of sponsor type.

However, for industry-sponsored clinical trials, the predominant area is solid tumors for new investigations to start this year, followed by breast cancer, then pain.

“This is attributed to the manner in which the burden of cancer worldwide necessitates industry investment to allow for capitalization on the increasing market size,” Abukar said.

This article first appeared on Medscape.com.

Smartphone applications (apps) using so-called artificial intelligence (AI) aimed at the general public for use on suspicious skin lesions are unreliable, said U.K. researchers reporting a systematic review.
 

These apps are providing information that could lead to “potentially life-or-death decisions,” commented co-lead author Hywel C. Williams, MD, from the Centre of Evidence Based Dermatology, University of Nottingham (England).

“The one thing you mustn’t do in a situation where early diagnosis can make a difference between life and death is you mustn’t miss the melanoma,” he said in an interview.

“These apps were missing melanomas, and that’s very worrisome,” he commented.

The review included nine studies of skin cancer smartphone apps, including two apps, SkinScan and SkinVision, that have been given Conformit Europenne (CE) marks, allowing them to be marketed across Europe. These apps are also available in Australia and New Zealand, but not in the United States.

The review found that SkinScan was not able to identify any melanomas in the one study that assessed this app, while SkinVision had a relatively low sensitivity and specificity, with 12% of cancerous or precancerous lesions missed and 21% of benign lesions wrongly identified as cancerous.

This means that among 1,000 people with a melanoma prevalence of 3%, 4 of 30 melanomas would be missed, and 200 people would be incorrectly told that a mole was of high concern, the authors estimated.

The research was published by The BMJ on Feb. 10.

“Although I was broad minded on the potential benefit of apps for diagnosing skin cancer, I am now worried given the results of our study and the overall poor quality of studies used to test these apps,” Dr. Williams commented in a statement.

Coauthor Jac Dinnes, PhD, from the Institute of Applied Health Research at the University of Birmingham (England), added it is “really disappointing that there is not better quality evidence available to judge the efficacy of these apps.”

“It is vital that health care professionals are aware of the current limitations both in the technologies and in their evaluations,” she added.

The results also highlight the limitations of the regulatory system governing smartphone apps in that they are currently not subject to assessment by bodies such as the U.K.’s Medicines and Healthcare Products Regulatory Agency (MHRA), the authors commented.

“Regulators need to become alert to the potential harm that poorly performing algorithm-based diagnostic or risk monitoring apps create,” said co-lead author Jonathan J. Deeks, PhD, also at the Institute of Applied Health Research.

“We rely on the CE mark as a sign of quality, but the current CE mark assessment processes are not fit for protecting the public against the risks that these apps present.”

Speaking in an interview, Williams lamented the poor quality of the research that had been conducted. “These studies were not good enough,” he said, adding that “there’s no excuse for really poor study design and poor reporting.”

He would like to see the regulations tightened around AI apps purporting to inform decision making for the general public and suggests that these devices should be assessed by the MHRA. “I really do think a CE mark is not enough,” he said.

The team noted that the skin cancer apps “all include disclaimers that the results should only be used as a guide and cannot replace health care advice,” through which the manufacturers “attempt to evade any responsibility for negative outcomes experienced by users.”

Nevertheless, the “poor and variable performance” of the apps revealed by their review indicates that they “have not yet shown sufficient promise to recommend their use,” they concluded.

The “official approval” implied by a CE mark “will give consumers the impression that the apps have been assessed as effective and safe,” wrote Ben Goldacre, DataLab director, Nuffield Department of Primary Care, University of Oxford (England), and colleagues in an accompanying editorial.

“The implicit assumption is that apps are similarly low-risk technology” to devices such as sticking plasters and reading glasses, they comment.

“But shortcomings in diagnostic apps can have serious implications,” they warn. The “risks include psychological harm from health anxiety or ‘cyberchondria,’ and physical harm from misdiagnosis or overdiagnosis; for clinicians there is a risk of increased workload, and changes to ethical or legal responsibilities around triage, referral, diagnosis, and treatment.” There is also potential for “inappropriate resource use, and even loss of credibility for digital technology in general.”

Details of the review

For their review, the authors searched the Cochrane Central Register on Controlled Trials, the MEDLNE, Embase, Cumulative Index to Nursing and Allied Health Literature, Conference Proceedings Citation index, Zetoc, and Science Citation Index databases, and online trial registers for studies published between August 2016 and April 2019.

From 80 studies identified, 9 met the eligibility criteria.

Of those, six studies, evaluating a total of 725 skin lesions, determined the accuracy of smartphone apps in risk stratifying suspicious skin lesions by comparing them against a histopathological reference standard diagnosis or expert follow-up.

Five of these studies aimed to detect only melanoma, while one sought to differentiate between malignant or premalignant lesions (including melanoma, basal cell carcinoma, and squamous cell carcinoma) and benign lesions.

The three remaining studies, which evaluated 407 lesions in all, compared smartphone app recommendations against a reference standard of expert recommendations for further investigation or intervention.

The researchers found the studies had a string of potential biases and limitations.

For example, only four studies recruited a consecutive sample of study participants and lesions, and only two included lesions selected by study participants, whereas five studies used lesions that had been selected by a clinician.

Three studies reported that it took 5-10 attempts to obtain an adequate image. In seven studies, it was the researchers and not the patients who used the app to photograph the lesions, and two studies used images obtained from dermatology databases.

This “raised concerns that the results of the studies were unlikely to be representative of real life use,” the authors comment.

In addition, the exclusion of unevaluable images “might have systematically inflated the diagnostic performance of the tested apps,” they add.

The independent research was supported by the National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre at the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham and is an update of one of a collection of reviews funded by the NIHR through its Cochrane Systematic Review Programme Grant.
 

This article first appeared on Medscape.com.

Smartphone applications (apps) using so-called artificial intelligence (AI) aimed at the general public for use on suspicious skin lesions are unreliable, said U.K. researchers reporting a systematic review.
 

These apps are providing information that could lead to “potentially life-or-death decisions,” commented co-lead author Hywel C. Williams, MD, from the Centre of Evidence Based Dermatology, University of Nottingham (England).

“The one thing you mustn’t do in a situation where early diagnosis can make a difference between life and death is you mustn’t miss the melanoma,” he said in an interview.

“These apps were missing melanomas, and that’s very worrisome,” he commented.

The review included nine studies of skin cancer smartphone apps, including two apps, SkinScan and SkinVision, that have been given Conformit Europenne (CE) marks, allowing them to be marketed across Europe. These apps are also available in Australia and New Zealand, but not in the United States.

The review found that SkinScan was not able to identify any melanomas in the one study that assessed this app, while SkinVision had a relatively low sensitivity and specificity, with 12% of cancerous or precancerous lesions missed and 21% of benign lesions wrongly identified as cancerous.

This means that among 1,000 people with a melanoma prevalence of 3%, 4 of 30 melanomas would be missed, and 200 people would be incorrectly told that a mole was of high concern, the authors estimated.

The research was published by The BMJ on Feb. 10.

“Although I was broad minded on the potential benefit of apps for diagnosing skin cancer, I am now worried given the results of our study and the overall poor quality of studies used to test these apps,” Dr. Williams commented in a statement.

Coauthor Jac Dinnes, PhD, from the Institute of Applied Health Research at the University of Birmingham (England), added it is “really disappointing that there is not better quality evidence available to judge the efficacy of these apps.”

“It is vital that health care professionals are aware of the current limitations both in the technologies and in their evaluations,” she added.

The results also highlight the limitations of the regulatory system governing smartphone apps in that they are currently not subject to assessment by bodies such as the U.K.’s Medicines and Healthcare Products Regulatory Agency (MHRA), the authors commented.

“Regulators need to become alert to the potential harm that poorly performing algorithm-based diagnostic or risk monitoring apps create,” said co-lead author Jonathan J. Deeks, PhD, also at the Institute of Applied Health Research.

“We rely on the CE mark as a sign of quality, but the current CE mark assessment processes are not fit for protecting the public against the risks that these apps present.”

Speaking in an interview, Williams lamented the poor quality of the research that had been conducted. “These studies were not good enough,” he said, adding that “there’s no excuse for really poor study design and poor reporting.”

He would like to see the regulations tightened around AI apps purporting to inform decision making for the general public and suggests that these devices should be assessed by the MHRA. “I really do think a CE mark is not enough,” he said.

The team noted that the skin cancer apps “all include disclaimers that the results should only be used as a guide and cannot replace health care advice,” through which the manufacturers “attempt to evade any responsibility for negative outcomes experienced by users.”

Nevertheless, the “poor and variable performance” of the apps revealed by their review indicates that they “have not yet shown sufficient promise to recommend their use,” they concluded.

The “official approval” implied by a CE mark “will give consumers the impression that the apps have been assessed as effective and safe,” wrote Ben Goldacre, DataLab director, Nuffield Department of Primary Care, University of Oxford (England), and colleagues in an accompanying editorial.

“The implicit assumption is that apps are similarly low-risk technology” to devices such as sticking plasters and reading glasses, they comment.

“But shortcomings in diagnostic apps can have serious implications,” they warn. The “risks include psychological harm from health anxiety or ‘cyberchondria,’ and physical harm from misdiagnosis or overdiagnosis; for clinicians there is a risk of increased workload, and changes to ethical or legal responsibilities around triage, referral, diagnosis, and treatment.” There is also potential for “inappropriate resource use, and even loss of credibility for digital technology in general.”

Details of the review

For their review, the authors searched the Cochrane Central Register on Controlled Trials, the MEDLNE, Embase, Cumulative Index to Nursing and Allied Health Literature, Conference Proceedings Citation index, Zetoc, and Science Citation Index databases, and online trial registers for studies published between August 2016 and April 2019.

From 80 studies identified, 9 met the eligibility criteria.

Of those, six studies, evaluating a total of 725 skin lesions, determined the accuracy of smartphone apps in risk stratifying suspicious skin lesions by comparing them against a histopathological reference standard diagnosis or expert follow-up.

Five of these studies aimed to detect only melanoma, while one sought to differentiate between malignant or premalignant lesions (including melanoma, basal cell carcinoma, and squamous cell carcinoma) and benign lesions.

The three remaining studies, which evaluated 407 lesions in all, compared smartphone app recommendations against a reference standard of expert recommendations for further investigation or intervention.

The researchers found the studies had a string of potential biases and limitations.

For example, only four studies recruited a consecutive sample of study participants and lesions, and only two included lesions selected by study participants, whereas five studies used lesions that had been selected by a clinician.

Three studies reported that it took 5-10 attempts to obtain an adequate image. In seven studies, it was the researchers and not the patients who used the app to photograph the lesions, and two studies used images obtained from dermatology databases.

This “raised concerns that the results of the studies were unlikely to be representative of real life use,” the authors comment.

In addition, the exclusion of unevaluable images “might have systematically inflated the diagnostic performance of the tested apps,” they add.

The independent research was supported by the National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre at the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham and is an update of one of a collection of reviews funded by the NIHR through its Cochrane Systematic Review Programme Grant.
 

This article first appeared on Medscape.com.

Smartphone applications (apps) using so-called artificial intelligence (AI) aimed at the general public for use on suspicious skin lesions are unreliable, said U.K. researchers reporting a systematic review.
 

These apps are providing information that could lead to “potentially life-or-death decisions,” commented co-lead author Hywel C. Williams, MD, from the Centre of Evidence Based Dermatology, University of Nottingham (England).

“The one thing you mustn’t do in a situation where early diagnosis can make a difference between life and death is you mustn’t miss the melanoma,” he said in an interview.

“These apps were missing melanomas, and that’s very worrisome,” he commented.

The review included nine studies of skin cancer smartphone apps, including two apps, SkinScan and SkinVision, that have been given Conformit Europenne (CE) marks, allowing them to be marketed across Europe. These apps are also available in Australia and New Zealand, but not in the United States.

The review found that SkinScan was not able to identify any melanomas in the one study that assessed this app, while SkinVision had a relatively low sensitivity and specificity, with 12% of cancerous or precancerous lesions missed and 21% of benign lesions wrongly identified as cancerous.

This means that among 1,000 people with a melanoma prevalence of 3%, 4 of 30 melanomas would be missed, and 200 people would be incorrectly told that a mole was of high concern, the authors estimated.

The research was published by The BMJ on Feb. 10.

“Although I was broad minded on the potential benefit of apps for diagnosing skin cancer, I am now worried given the results of our study and the overall poor quality of studies used to test these apps,” Dr. Williams commented in a statement.

Coauthor Jac Dinnes, PhD, from the Institute of Applied Health Research at the University of Birmingham (England), added it is “really disappointing that there is not better quality evidence available to judge the efficacy of these apps.”

“It is vital that health care professionals are aware of the current limitations both in the technologies and in their evaluations,” she added.

The results also highlight the limitations of the regulatory system governing smartphone apps in that they are currently not subject to assessment by bodies such as the U.K.’s Medicines and Healthcare Products Regulatory Agency (MHRA), the authors commented.

“Regulators need to become alert to the potential harm that poorly performing algorithm-based diagnostic or risk monitoring apps create,” said co-lead author Jonathan J. Deeks, PhD, also at the Institute of Applied Health Research.

“We rely on the CE mark as a sign of quality, but the current CE mark assessment processes are not fit for protecting the public against the risks that these apps present.”

Speaking in an interview, Williams lamented the poor quality of the research that had been conducted. “These studies were not good enough,” he said, adding that “there’s no excuse for really poor study design and poor reporting.”

He would like to see the regulations tightened around AI apps purporting to inform decision making for the general public and suggests that these devices should be assessed by the MHRA. “I really do think a CE mark is not enough,” he said.

The team noted that the skin cancer apps “all include disclaimers that the results should only be used as a guide and cannot replace health care advice,” through which the manufacturers “attempt to evade any responsibility for negative outcomes experienced by users.”

Nevertheless, the “poor and variable performance” of the apps revealed by their review indicates that they “have not yet shown sufficient promise to recommend their use,” they concluded.

The “official approval” implied by a CE mark “will give consumers the impression that the apps have been assessed as effective and safe,” wrote Ben Goldacre, DataLab director, Nuffield Department of Primary Care, University of Oxford (England), and colleagues in an accompanying editorial.

“The implicit assumption is that apps are similarly low-risk technology” to devices such as sticking plasters and reading glasses, they comment.

“But shortcomings in diagnostic apps can have serious implications,” they warn. The “risks include psychological harm from health anxiety or ‘cyberchondria,’ and physical harm from misdiagnosis or overdiagnosis; for clinicians there is a risk of increased workload, and changes to ethical or legal responsibilities around triage, referral, diagnosis, and treatment.” There is also potential for “inappropriate resource use, and even loss of credibility for digital technology in general.”

Details of the review

For their review, the authors searched the Cochrane Central Register on Controlled Trials, the MEDLNE, Embase, Cumulative Index to Nursing and Allied Health Literature, Conference Proceedings Citation index, Zetoc, and Science Citation Index databases, and online trial registers for studies published between August 2016 and April 2019.

From 80 studies identified, 9 met the eligibility criteria.

Of those, six studies, evaluating a total of 725 skin lesions, determined the accuracy of smartphone apps in risk stratifying suspicious skin lesions by comparing them against a histopathological reference standard diagnosis or expert follow-up.

Five of these studies aimed to detect only melanoma, while one sought to differentiate between malignant or premalignant lesions (including melanoma, basal cell carcinoma, and squamous cell carcinoma) and benign lesions.

The three remaining studies, which evaluated 407 lesions in all, compared smartphone app recommendations against a reference standard of expert recommendations for further investigation or intervention.

The researchers found the studies had a string of potential biases and limitations.

For example, only four studies recruited a consecutive sample of study participants and lesions, and only two included lesions selected by study participants, whereas five studies used lesions that had been selected by a clinician.

Three studies reported that it took 5-10 attempts to obtain an adequate image. In seven studies, it was the researchers and not the patients who used the app to photograph the lesions, and two studies used images obtained from dermatology databases.

This “raised concerns that the results of the studies were unlikely to be representative of real life use,” the authors comment.

In addition, the exclusion of unevaluable images “might have systematically inflated the diagnostic performance of the tested apps,” they add.

The independent research was supported by the National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre at the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham and is an update of one of a collection of reviews funded by the NIHR through its Cochrane Systematic Review Programme Grant.
 

This article first appeared on Medscape.com.

New research results reinforce the benefits of quitting smoking.
 

Not only does it stop further damage to the lungs, it appears that it also allows new, healthy cells to actively replenish the lining of the airways. This shift in the proportion of healthy cells to damaged cells could reduce the risk for lung cancer, say researchers.

The findings were published online in Nature (2020 Jan 29. doi: 10.1038/s41586-020-1961-1).

The team performed whole-genome sequencing on healthy airway cells collected (during a bronchoscopy for clinical indications) from current smokers and ex-smokers, as well as from adult never-smokers and children.

The investigators found, as expected, that the cells from current and ex-smokers had a far higher mutational burden than those of never-smokers and children, including an increased number of “driver” mutations, which increase the potential of cells to become cancerous.

However, they also found that in ex-smokers – but not in current smokers – up to 40% of the cells were near normal, with far less genetic damage and a low risk of developing cancer.

“People who have smoked heavily for 30, 40 or more years often say to me that it’s too late to stop smoking – the damage is already done,” commented senior author Peter J. Campbell, PhD, Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, England.

“What is so exciting about our study is that it shows that it’s never too late to quit. Some of the people in our study had smoked more than 15,000 packs of cigarettes over their life, but within a few years of quitting, many of the cells lining their airways showed no evidence of damage from tobacco,” he said. The comments appear in a press release issued by Cancer Research UK, which partly funded the study.

This study has “broadened our understanding of the effects of tobacco smoke on normal epithelial cells in the human lung,” Gerd P. Pfeifer, PhD, at the Center for Epigenetics, Van Andel Institute, Grand Rapids, Michigan, writes in an accompanying comment.

“It has shed light on how the protective effect of smoking cessation plays out at the molecular level in human lung tissue and raises many interesting questions worthy of future investigation,” he added.
 

‘Important public health message’

Joint senior author Sam M. Janes, PhD, Lungs for Living Research Center, UCL Respiratory, University College London, added that the study has “an important public health message.

“Stopping smoking at any age does not just slow the accumulation of further damage but could reawaken cells unharmed by past lifestyle choices,” he said.

“Further research into this process could help to understand how these cells protect against cancer and could potentially lead to new avenues of research into anticancer therapeutics,” Dr. James added.

In an interview, Dr. Campbell said that the team would next like to try “to find where this reservoir of normal cells hides out while the patient is smoking. We have some ideas from mouse models and we think, by adapting the methods we used in this study, we will be able to test that hypothesis directly.”

He continued: “If we can find this stem cell niche, then we can study the biology of the cells living in there and what makes them expand when a patient stops smoking.

“Once we understand that biology, we can think about therapies to target that population of cells in beneficial ways.”

Dr. Campbell concluded that they are “a long way away yet, but the toolkit exists for getting there.”
 

Tobacco and mutagenesis

In their article, the team notes that the model explaining how tobacco exposure causes lung cancer centers on the notion that the 60-plus carcinogens in cigarette smoke directly cause mutagenesis, which combines with the indirect effects of inflammation, immune suppression, and infection to lead to cancer.

However, this does not explain why individuals who stop smoking in middle age or earlier “avoid most of the risk of tobacco-associated lung cancer.”

They questioned the relationship between tobacco and mutagenesis. For two people who smoke the same number of cigarettes over their lifetime, the observation that the person with longer duration of cessation has a lower risk for lung cancer is difficult to explain if carcinogenesis is induced exclusively by an increase in the mutational burden, they noted.

To investigate further, the team set out to examine the “landscape” of somatic mutations in normal bronchial epithelium. They recruited 16 individuals: three children, four never-smokers, six ex-smokers, and three current smokers.

All the participants underwent bronchoscopy for clinical indications. Samples of airway epithelium were obtained from biopsies or brushings of main or secondary bronchi.

The researchers performed whole-genome sequencing of 632 colonies derived from single bronchial epithelial cells. In addition, cells from squamous cell carcinoma or carcinoma in situ from three of the patients were sequenced.
 

Cells show different mutational burdens

The results showed there was “considerable heterogeneity” in mutational burden both between patients and in individual patients.

Moreover, single-base substitutions increased significantly with age, at an estimated rate of 22 per cell per year (P = 10^–8). In addition, previous and current smoking substantially increased the substitution burden by an estimated 2,330 per cell in ex-smokers and 5,300 per cell in current smokers.

The team was surprised to find that smoking also increased the variability of the mutational burden from cell to cell, “even within the same individual.”

They calculated that, even between cells from a small biopsy sample of normal airway, the standard deviation in mutational burden was 2,350 per cell in ex-smokers and 2,100 per cell in current smokers, but only 140 per cell in children and 290 per cell in adult never-smokers (P less than 10^–16 for within-subject heterogeneity).

Between individuals, the mean substitution burden was 1,200 per cell in ex-smokers, 1,260 per cell in current smokers, and 90 per cell for nonsmokers (P = 10^–8 for heterogeneity).

Driver mutations were also more common in individuals who had a history of smoking. In those persons, they were seen in at least 25% of cells vs. 4%-14% of cells from adult never-smokers and none of the cells from children.

It was calculated that current smokers had a 2.1-fold increase in the number of driver mutations per cell in comparison with never-smokers (P = .04).

In addition, the number of driver mutations per cell increased 1.5-fold with every decade of life (P = .004) and twofold for every 5,000 extra somatic mutations per cell (P = .0003).

However, the team also found that some patients among the ex-smokers and current smokers had cells with a near-normal mutational burden, similar to that seen for never-smokers of the equivalent age.

Although these cells were rare in current smokers, their relative frequency was, the team reports, an average fourfold higher in ex-smokers and accounted for between 20% and 40% of all cells studied.

Further analysis showed that these near-normal cells had less damage from tobacco-specific mutational processes than other cells and that they had longer telomeres.

“Two points remain unclear: how these cells have avoided the high rates of mutations that are exhibited by neighbouring cells, and why this particular population of cells expands after smoking cessation,” the team writes.

They argue that the presence of longer telomeres suggests they are “recent descendants of quiescent stem cells,” which have been found in mice but “remain elusive” in human lungs.

“The apparent expansion of the near-normal cells could represent the expected physiology of a two-compartment model in which relatively short-lived proliferative progenitors are slowly replenished from a pool of quiescent stem cells, but the progenitors are more exposed to tobacco carcinogens,” they suggest.

“Only in ex-smokers would the difference in mutagenic environment be sufficient to distinguish newly produced progenitors from long-term occupants of the bronchial epithelial surface,” they add.

However, in his commentary, Dr. Pfeifer highlights that a “potential caveat” of the study is the small number of individuals (n = 16) from whom cells were taken.

In addition, Dr. Pfeifer notes that the “lack of knowledge” about the suggested “long-lived stem cells and information about the longevity of the different cell types in the human lung make it difficult to explain what occurred in the ex-smokers’ cells with few mutations.”

The study was supported by a Cancer Research UK Grand Challenge Award and the Wellcome Trust. Dr. Campbell and Dr. Janes are Wellcome Trust senior clinical fellows. The authors have disclosed no relevant financial relationships.
 

This article first appeared on Medscape.com.

New research results reinforce the benefits of quitting smoking.
 

Not only does it stop further damage to the lungs, it appears that it also allows new, healthy cells to actively replenish the lining of the airways. This shift in the proportion of healthy cells to damaged cells could reduce the risk for lung cancer, say researchers.

The findings were published online in Nature (2020 Jan 29. doi: 10.1038/s41586-020-1961-1).

The team performed whole-genome sequencing on healthy airway cells collected (during a bronchoscopy for clinical indications) from current smokers and ex-smokers, as well as from adult never-smokers and children.

The investigators found, as expected, that the cells from current and ex-smokers had a far higher mutational burden than those of never-smokers and children, including an increased number of “driver” mutations, which increase the potential of cells to become cancerous.

However, they also found that in ex-smokers – but not in current smokers – up to 40% of the cells were near normal, with far less genetic damage and a low risk of developing cancer.

“People who have smoked heavily for 30, 40 or more years often say to me that it’s too late to stop smoking – the damage is already done,” commented senior author Peter J. Campbell, PhD, Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, England.

“What is so exciting about our study is that it shows that it’s never too late to quit. Some of the people in our study had smoked more than 15,000 packs of cigarettes over their life, but within a few years of quitting, many of the cells lining their airways showed no evidence of damage from tobacco,” he said. The comments appear in a press release issued by Cancer Research UK, which partly funded the study.

This study has “broadened our understanding of the effects of tobacco smoke on normal epithelial cells in the human lung,” Gerd P. Pfeifer, PhD, at the Center for Epigenetics, Van Andel Institute, Grand Rapids, Michigan, writes in an accompanying comment.

“It has shed light on how the protective effect of smoking cessation plays out at the molecular level in human lung tissue and raises many interesting questions worthy of future investigation,” he added.
 

‘Important public health message’

Joint senior author Sam M. Janes, PhD, Lungs for Living Research Center, UCL Respiratory, University College London, added that the study has “an important public health message.

“Stopping smoking at any age does not just slow the accumulation of further damage but could reawaken cells unharmed by past lifestyle choices,” he said.

“Further research into this process could help to understand how these cells protect against cancer and could potentially lead to new avenues of research into anticancer therapeutics,” Dr. James added.

In an interview, Dr. Campbell said that the team would next like to try “to find where this reservoir of normal cells hides out while the patient is smoking. We have some ideas from mouse models and we think, by adapting the methods we used in this study, we will be able to test that hypothesis directly.”

He continued: “If we can find this stem cell niche, then we can study the biology of the cells living in there and what makes them expand when a patient stops smoking.

“Once we understand that biology, we can think about therapies to target that population of cells in beneficial ways.”

Dr. Campbell concluded that they are “a long way away yet, but the toolkit exists for getting there.”
 

Tobacco and mutagenesis

In their article, the team notes that the model explaining how tobacco exposure causes lung cancer centers on the notion that the 60-plus carcinogens in cigarette smoke directly cause mutagenesis, which combines with the indirect effects of inflammation, immune suppression, and infection to lead to cancer.

However, this does not explain why individuals who stop smoking in middle age or earlier “avoid most of the risk of tobacco-associated lung cancer.”

They questioned the relationship between tobacco and mutagenesis. For two people who smoke the same number of cigarettes over their lifetime, the observation that the person with longer duration of cessation has a lower risk for lung cancer is difficult to explain if carcinogenesis is induced exclusively by an increase in the mutational burden, they noted.

To investigate further, the team set out to examine the “landscape” of somatic mutations in normal bronchial epithelium. They recruited 16 individuals: three children, four never-smokers, six ex-smokers, and three current smokers.

All the participants underwent bronchoscopy for clinical indications. Samples of airway epithelium were obtained from biopsies or brushings of main or secondary bronchi.

The researchers performed whole-genome sequencing of 632 colonies derived from single bronchial epithelial cells. In addition, cells from squamous cell carcinoma or carcinoma in situ from three of the patients were sequenced.
 

Cells show different mutational burdens

The results showed there was “considerable heterogeneity” in mutational burden both between patients and in individual patients.

Moreover, single-base substitutions increased significantly with age, at an estimated rate of 22 per cell per year (P = 10^–8). In addition, previous and current smoking substantially increased the substitution burden by an estimated 2,330 per cell in ex-smokers and 5,300 per cell in current smokers.

The team was surprised to find that smoking also increased the variability of the mutational burden from cell to cell, “even within the same individual.”

They calculated that, even between cells from a small biopsy sample of normal airway, the standard deviation in mutational burden was 2,350 per cell in ex-smokers and 2,100 per cell in current smokers, but only 140 per cell in children and 290 per cell in adult never-smokers (P less than 10^–16 for within-subject heterogeneity).

Between individuals, the mean substitution burden was 1,200 per cell in ex-smokers, 1,260 per cell in current smokers, and 90 per cell for nonsmokers (P = 10^–8 for heterogeneity).

Driver mutations were also more common in individuals who had a history of smoking. In those persons, they were seen in at least 25% of cells vs. 4%-14% of cells from adult never-smokers and none of the cells from children.

It was calculated that current smokers had a 2.1-fold increase in the number of driver mutations per cell in comparison with never-smokers (P = .04).

In addition, the number of driver mutations per cell increased 1.5-fold with every decade of life (P = .004) and twofold for every 5,000 extra somatic mutations per cell (P = .0003).

However, the team also found that some patients among the ex-smokers and current smokers had cells with a near-normal mutational burden, similar to that seen for never-smokers of the equivalent age.

Although these cells were rare in current smokers, their relative frequency was, the team reports, an average fourfold higher in ex-smokers and accounted for between 20% and 40% of all cells studied.

Further analysis showed that these near-normal cells had less damage from tobacco-specific mutational processes than other cells and that they had longer telomeres.

“Two points remain unclear: how these cells have avoided the high rates of mutations that are exhibited by neighbouring cells, and why this particular population of cells expands after smoking cessation,” the team writes.

They argue that the presence of longer telomeres suggests they are “recent descendants of quiescent stem cells,” which have been found in mice but “remain elusive” in human lungs.

“The apparent expansion of the near-normal cells could represent the expected physiology of a two-compartment model in which relatively short-lived proliferative progenitors are slowly replenished from a pool of quiescent stem cells, but the progenitors are more exposed to tobacco carcinogens,” they suggest.

“Only in ex-smokers would the difference in mutagenic environment be sufficient to distinguish newly produced progenitors from long-term occupants of the bronchial epithelial surface,” they add.

However, in his commentary, Dr. Pfeifer highlights that a “potential caveat” of the study is the small number of individuals (n = 16) from whom cells were taken.

In addition, Dr. Pfeifer notes that the “lack of knowledge” about the suggested “long-lived stem cells and information about the longevity of the different cell types in the human lung make it difficult to explain what occurred in the ex-smokers’ cells with few mutations.”

The study was supported by a Cancer Research UK Grand Challenge Award and the Wellcome Trust. Dr. Campbell and Dr. Janes are Wellcome Trust senior clinical fellows. The authors have disclosed no relevant financial relationships.
 

This article first appeared on Medscape.com.

New research results reinforce the benefits of quitting smoking.
 

Not only does it stop further damage to the lungs, it appears that it also allows new, healthy cells to actively replenish the lining of the airways. This shift in the proportion of healthy cells to damaged cells could reduce the risk for lung cancer, say researchers.

The findings were published online in Nature (2020 Jan 29. doi: 10.1038/s41586-020-1961-1).

The team performed whole-genome sequencing on healthy airway cells collected (during a bronchoscopy for clinical indications) from current smokers and ex-smokers, as well as from adult never-smokers and children.

The investigators found, as expected, that the cells from current and ex-smokers had a far higher mutational burden than those of never-smokers and children, including an increased number of “driver” mutations, which increase the potential of cells to become cancerous.

However, they also found that in ex-smokers – but not in current smokers – up to 40% of the cells were near normal, with far less genetic damage and a low risk of developing cancer.

“People who have smoked heavily for 30, 40 or more years often say to me that it’s too late to stop smoking – the damage is already done,” commented senior author Peter J. Campbell, PhD, Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, England.

“What is so exciting about our study is that it shows that it’s never too late to quit. Some of the people in our study had smoked more than 15,000 packs of cigarettes over their life, but within a few years of quitting, many of the cells lining their airways showed no evidence of damage from tobacco,” he said. The comments appear in a press release issued by Cancer Research UK, which partly funded the study.

This study has “broadened our understanding of the effects of tobacco smoke on normal epithelial cells in the human lung,” Gerd P. Pfeifer, PhD, at the Center for Epigenetics, Van Andel Institute, Grand Rapids, Michigan, writes in an accompanying comment.

“It has shed light on how the protective effect of smoking cessation plays out at the molecular level in human lung tissue and raises many interesting questions worthy of future investigation,” he added.
 

‘Important public health message’

Joint senior author Sam M. Janes, PhD, Lungs for Living Research Center, UCL Respiratory, University College London, added that the study has “an important public health message.

“Stopping smoking at any age does not just slow the accumulation of further damage but could reawaken cells unharmed by past lifestyle choices,” he said.

“Further research into this process could help to understand how these cells protect against cancer and could potentially lead to new avenues of research into anticancer therapeutics,” Dr. James added.

In an interview, Dr. Campbell said that the team would next like to try “to find where this reservoir of normal cells hides out while the patient is smoking. We have some ideas from mouse models and we think, by adapting the methods we used in this study, we will be able to test that hypothesis directly.”

He continued: “If we can find this stem cell niche, then we can study the biology of the cells living in there and what makes them expand when a patient stops smoking.

“Once we understand that biology, we can think about therapies to target that population of cells in beneficial ways.”

Dr. Campbell concluded that they are “a long way away yet, but the toolkit exists for getting there.”
 

Tobacco and mutagenesis

In their article, the team notes that the model explaining how tobacco exposure causes lung cancer centers on the notion that the 60-plus carcinogens in cigarette smoke directly cause mutagenesis, which combines with the indirect effects of inflammation, immune suppression, and infection to lead to cancer.

However, this does not explain why individuals who stop smoking in middle age or earlier “avoid most of the risk of tobacco-associated lung cancer.”

They questioned the relationship between tobacco and mutagenesis. For two people who smoke the same number of cigarettes over their lifetime, the observation that the person with longer duration of cessation has a lower risk for lung cancer is difficult to explain if carcinogenesis is induced exclusively by an increase in the mutational burden, they noted.

To investigate further, the team set out to examine the “landscape” of somatic mutations in normal bronchial epithelium. They recruited 16 individuals: three children, four never-smokers, six ex-smokers, and three current smokers.

All the participants underwent bronchoscopy for clinical indications. Samples of airway epithelium were obtained from biopsies or brushings of main or secondary bronchi.

The researchers performed whole-genome sequencing of 632 colonies derived from single bronchial epithelial cells. In addition, cells from squamous cell carcinoma or carcinoma in situ from three of the patients were sequenced.
 

Cells show different mutational burdens

The results showed there was “considerable heterogeneity” in mutational burden both between patients and in individual patients.

Moreover, single-base substitutions increased significantly with age, at an estimated rate of 22 per cell per year (P = 10^–8). In addition, previous and current smoking substantially increased the substitution burden by an estimated 2,330 per cell in ex-smokers and 5,300 per cell in current smokers.

The team was surprised to find that smoking also increased the variability of the mutational burden from cell to cell, “even within the same individual.”

They calculated that, even between cells from a small biopsy sample of normal airway, the standard deviation in mutational burden was 2,350 per cell in ex-smokers and 2,100 per cell in current smokers, but only 140 per cell in children and 290 per cell in adult never-smokers (P less than 10^–16 for within-subject heterogeneity).

Between individuals, the mean substitution burden was 1,200 per cell in ex-smokers, 1,260 per cell in current smokers, and 90 per cell for nonsmokers (P = 10^–8 for heterogeneity).

Driver mutations were also more common in individuals who had a history of smoking. In those persons, they were seen in at least 25% of cells vs. 4%-14% of cells from adult never-smokers and none of the cells from children.

It was calculated that current smokers had a 2.1-fold increase in the number of driver mutations per cell in comparison with never-smokers (P = .04).

In addition, the number of driver mutations per cell increased 1.5-fold with every decade of life (P = .004) and twofold for every 5,000 extra somatic mutations per cell (P = .0003).

However, the team also found that some patients among the ex-smokers and current smokers had cells with a near-normal mutational burden, similar to that seen for never-smokers of the equivalent age.

Although these cells were rare in current smokers, their relative frequency was, the team reports, an average fourfold higher in ex-smokers and accounted for between 20% and 40% of all cells studied.

Further analysis showed that these near-normal cells had less damage from tobacco-specific mutational processes than other cells and that they had longer telomeres.

“Two points remain unclear: how these cells have avoided the high rates of mutations that are exhibited by neighbouring cells, and why this particular population of cells expands after smoking cessation,” the team writes.

They argue that the presence of longer telomeres suggests they are “recent descendants of quiescent stem cells,” which have been found in mice but “remain elusive” in human lungs.

“The apparent expansion of the near-normal cells could represent the expected physiology of a two-compartment model in which relatively short-lived proliferative progenitors are slowly replenished from a pool of quiescent stem cells, but the progenitors are more exposed to tobacco carcinogens,” they suggest.

“Only in ex-smokers would the difference in mutagenic environment be sufficient to distinguish newly produced progenitors from long-term occupants of the bronchial epithelial surface,” they add.

However, in his commentary, Dr. Pfeifer highlights that a “potential caveat” of the study is the small number of individuals (n = 16) from whom cells were taken.

In addition, Dr. Pfeifer notes that the “lack of knowledge” about the suggested “long-lived stem cells and information about the longevity of the different cell types in the human lung make it difficult to explain what occurred in the ex-smokers’ cells with few mutations.”

The study was supported by a Cancer Research UK Grand Challenge Award and the Wellcome Trust. Dr. Campbell and Dr. Janes are Wellcome Trust senior clinical fellows. The authors have disclosed no relevant financial relationships.
 

This article first appeared on Medscape.com.

A study of lung cancer in younger adults (less than 50 years) has found a recent trend of higher lung cancer rates in women, compared with men. The increase is driven by cases of adenocarcinoma of the lung.

The “emerging pattern of higher lung cancer incidence in young females” is not confined to geographic areas and income levels and “is not fully explained by sex-differences in smoking prevalence,” the authors comment.

Miranda M. Fidler-Benaoudia, PhD, Cancer Control Alberta, Alberta Health Services, Calgary, and colleagues examined lung cancer cases in 40 countries from 1993 to 2012.

They found that the female-to-male incidence rate ratio (IRR) had significantly crossed over from men to women in six countries, including the United States and Canada, and had nonsignificantly crossed over in a further 23 countries.

The research was published online Feb. 5 in the International Journal of Cancer.

These findings “forewarn of a higher lung cancer burden in women than men at older ages in the decades to follow, especially in higher-income settings,” write the authors. They highlight “the need for etiologic studies.”

Historically, lung cancer higher in men

Historically, lung cancer rates have been higher among men than women, owing to the fact that men start smoking in large numbers earlier and smoke at higher rates, the researchers comment.

However, there has been a convergence in lung cancer incidence between men and women. A recent study suggests that, in the United States, the incidence in young women is higher than that in their male counterparts.

To determine the degree to which this phenomenon is occurring globally, the team used national or subnational registry data from Cancer Incidence in Five Continents, volumes VIII–XI.

These included lung and bronchial cancer cases in 40 countries from 1993 to 2012, divided into 5-year periods. Individuals were categorized into 5-year age bands.

In addition, the team used the Global Health Data Exchange to extract data from the Global Burden of Disease Study 2015 and derive country- and sex-specific daily smoking prevalence rates.

The researchers found that among young men and women, there were three patterns in the occurrence of lung cancer between the periods 1993-1997 and 2008-2012:

• A significant crossover from male to female dominance, seen in six countries.
• An insignificant crossover from male to female dominance, found in 23 countries.
• A continued male dominance, observed in 11 countries.

Higher incidence in women in six countries

The six countries with significant crossover from male to female dominance were Canada, Denmark, Germany, New Zealand, the Netherlands, and the United States.

Further analysis showed that, in general, age-specific lung cancer incidence rates decreased in successive male birth cohorts in these six countries. There was more variation across female birth cohorts.

Calculating female-to-male incidence rate ratios, the team found, for example, the IRR increased in New Zealand from 1.0 in the 1953 birth cohort to 1.6 in the 1968 birth cohort for people aged 40-44 years.

In addition, among adults aged 45-49 years in the Netherlands, the IRR rose from 0.7 in those born in the circa 1948 cohort to 1.4 in those from the circa 1958 cohort.

Overall, female-to-male IRRs increased notably among the following groups:

• Individuals aged 30-34 years in Canada, Denmark, and Germany.
• Those aged 40-44 years in Germany, the Netherlands, and the United States.
• Those aged 44-50 years in the Netherlands and the United States.
• Those aged 50-54 years in Canada, Denmark, and New Zealand.

Countries with an insignificant crossover from male to female dominance of lung cancer were located across Africa, the Americas, Asia, Europe, and Oceania.

Again, incidence rates were typically characterized by falling rates of lung cancer among men in more recent birth cohorts, and lung cancer incidence trends were more variable in women.

The team writes: “Of note, the six countries demonstrating a significant crossover are among those considered to be more advanced in the tobacco epidemic.

“Many of the countries where the crossover was insignificant or when there was no crossover are considered to be late adopters of the tobacco epidemic, with the effects of the epidemic on the burden of lung cancer and other smoking-related diseases beginning to manifest more recently, or perhaps yet to come.”

They suggest that low- and middle-resource countries may not follow the tobacco epidemic pattern of high-income countries, and so “we may not see higher lung cancer incidence rates in women than men for the foreseeable future in these countries.”

No funding for the study has been disclosed. The authors have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

A study of lung cancer in younger adults (less than 50 years) has found a recent trend of higher lung cancer rates in women, compared with men. The increase is driven by cases of adenocarcinoma of the lung.

The “emerging pattern of higher lung cancer incidence in young females” is not confined to geographic areas and income levels and “is not fully explained by sex-differences in smoking prevalence,” the authors comment.

Miranda M. Fidler-Benaoudia, PhD, Cancer Control Alberta, Alberta Health Services, Calgary, and colleagues examined lung cancer cases in 40 countries from 1993 to 2012.

They found that the female-to-male incidence rate ratio (IRR) had significantly crossed over from men to women in six countries, including the United States and Canada, and had nonsignificantly crossed over in a further 23 countries.

The research was published online Feb. 5 in the International Journal of Cancer.

These findings “forewarn of a higher lung cancer burden in women than men at older ages in the decades to follow, especially in higher-income settings,” write the authors. They highlight “the need for etiologic studies.”

Historically, lung cancer higher in men

Historically, lung cancer rates have been higher among men than women, owing to the fact that men start smoking in large numbers earlier and smoke at higher rates, the researchers comment.

However, there has been a convergence in lung cancer incidence between men and women. A recent study suggests that, in the United States, the incidence in young women is higher than that in their male counterparts.

To determine the degree to which this phenomenon is occurring globally, the team used national or subnational registry data from Cancer Incidence in Five Continents, volumes VIII–XI.

These included lung and bronchial cancer cases in 40 countries from 1993 to 2012, divided into 5-year periods. Individuals were categorized into 5-year age bands.

In addition, the team used the Global Health Data Exchange to extract data from the Global Burden of Disease Study 2015 and derive country- and sex-specific daily smoking prevalence rates.

The researchers found that among young men and women, there were three patterns in the occurrence of lung cancer between the periods 1993-1997 and 2008-2012:

• A significant crossover from male to female dominance, seen in six countries.
• An insignificant crossover from male to female dominance, found in 23 countries.
• A continued male dominance, observed in 11 countries.

Higher incidence in women in six countries

The six countries with significant crossover from male to female dominance were Canada, Denmark, Germany, New Zealand, the Netherlands, and the United States.

Further analysis showed that, in general, age-specific lung cancer incidence rates decreased in successive male birth cohorts in these six countries. There was more variation across female birth cohorts.

Calculating female-to-male incidence rate ratios, the team found, for example, the IRR increased in New Zealand from 1.0 in the 1953 birth cohort to 1.6 in the 1968 birth cohort for people aged 40-44 years.

In addition, among adults aged 45-49 years in the Netherlands, the IRR rose from 0.7 in those born in the circa 1948 cohort to 1.4 in those from the circa 1958 cohort.

Overall, female-to-male IRRs increased notably among the following groups:

• Individuals aged 30-34 years in Canada, Denmark, and Germany.
• Those aged 40-44 years in Germany, the Netherlands, and the United States.
• Those aged 44-50 years in the Netherlands and the United States.
• Those aged 50-54 years in Canada, Denmark, and New Zealand.

Countries with an insignificant crossover from male to female dominance of lung cancer were located across Africa, the Americas, Asia, Europe, and Oceania.

Again, incidence rates were typically characterized by falling rates of lung cancer among men in more recent birth cohorts, and lung cancer incidence trends were more variable in women.

The team writes: “Of note, the six countries demonstrating a significant crossover are among those considered to be more advanced in the tobacco epidemic.

“Many of the countries where the crossover was insignificant or when there was no crossover are considered to be late adopters of the tobacco epidemic, with the effects of the epidemic on the burden of lung cancer and other smoking-related diseases beginning to manifest more recently, or perhaps yet to come.”

They suggest that low- and middle-resource countries may not follow the tobacco epidemic pattern of high-income countries, and so “we may not see higher lung cancer incidence rates in women than men for the foreseeable future in these countries.”

No funding for the study has been disclosed. The authors have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

A study of lung cancer in younger adults (less than 50 years) has found a recent trend of higher lung cancer rates in women, compared with men. The increase is driven by cases of adenocarcinoma of the lung.

The “emerging pattern of higher lung cancer incidence in young females” is not confined to geographic areas and income levels and “is not fully explained by sex-differences in smoking prevalence,” the authors comment.

Miranda M. Fidler-Benaoudia, PhD, Cancer Control Alberta, Alberta Health Services, Calgary, and colleagues examined lung cancer cases in 40 countries from 1993 to 2012.

They found that the female-to-male incidence rate ratio (IRR) had significantly crossed over from men to women in six countries, including the United States and Canada, and had nonsignificantly crossed over in a further 23 countries.

The research was published online Feb. 5 in the International Journal of Cancer.

These findings “forewarn of a higher lung cancer burden in women than men at older ages in the decades to follow, especially in higher-income settings,” write the authors. They highlight “the need for etiologic studies.”

Historically, lung cancer higher in men

Historically, lung cancer rates have been higher among men than women, owing to the fact that men start smoking in large numbers earlier and smoke at higher rates, the researchers comment.

However, there has been a convergence in lung cancer incidence between men and women. A recent study suggests that, in the United States, the incidence in young women is higher than that in their male counterparts.

To determine the degree to which this phenomenon is occurring globally, the team used national or subnational registry data from Cancer Incidence in Five Continents, volumes VIII–XI.

These included lung and bronchial cancer cases in 40 countries from 1993 to 2012, divided into 5-year periods. Individuals were categorized into 5-year age bands.

In addition, the team used the Global Health Data Exchange to extract data from the Global Burden of Disease Study 2015 and derive country- and sex-specific daily smoking prevalence rates.

The researchers found that among young men and women, there were three patterns in the occurrence of lung cancer between the periods 1993-1997 and 2008-2012:

• A significant crossover from male to female dominance, seen in six countries.
• An insignificant crossover from male to female dominance, found in 23 countries.
• A continued male dominance, observed in 11 countries.

Higher incidence in women in six countries

The six countries with significant crossover from male to female dominance were Canada, Denmark, Germany, New Zealand, the Netherlands, and the United States.

Further analysis showed that, in general, age-specific lung cancer incidence rates decreased in successive male birth cohorts in these six countries. There was more variation across female birth cohorts.

Calculating female-to-male incidence rate ratios, the team found, for example, the IRR increased in New Zealand from 1.0 in the 1953 birth cohort to 1.6 in the 1968 birth cohort for people aged 40-44 years.

In addition, among adults aged 45-49 years in the Netherlands, the IRR rose from 0.7 in those born in the circa 1948 cohort to 1.4 in those from the circa 1958 cohort.

Overall, female-to-male IRRs increased notably among the following groups:

• Individuals aged 30-34 years in Canada, Denmark, and Germany.
• Those aged 40-44 years in Germany, the Netherlands, and the United States.
• Those aged 44-50 years in the Netherlands and the United States.
• Those aged 50-54 years in Canada, Denmark, and New Zealand.

Countries with an insignificant crossover from male to female dominance of lung cancer were located across Africa, the Americas, Asia, Europe, and Oceania.

Again, incidence rates were typically characterized by falling rates of lung cancer among men in more recent birth cohorts, and lung cancer incidence trends were more variable in women.

The team writes: “Of note, the six countries demonstrating a significant crossover are among those considered to be more advanced in the tobacco epidemic.

“Many of the countries where the crossover was insignificant or when there was no crossover are considered to be late adopters of the tobacco epidemic, with the effects of the epidemic on the burden of lung cancer and other smoking-related diseases beginning to manifest more recently, or perhaps yet to come.”

They suggest that low- and middle-resource countries may not follow the tobacco epidemic pattern of high-income countries, and so “we may not see higher lung cancer incidence rates in women than men for the foreseeable future in these countries.”

No funding for the study has been disclosed. The authors have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.