Κυριακή, 9 Αυγούστου 2020

COVID-19 SUPERSPREADERS

While many people with active SARS-CoV-2 infections are unlikely to transmit the virus via aerosols, a new modeling study suggests, so-called superspreaders can put out thousands to millions of virus particles per cubic meter of air.

Using previously reported data on viral load and exhaled microdroplet distributions for people coughing and breathing normally, researchers employed a mathematical model to determine the number of virus particles that might be released by low, typical, and high emitters.

Few SARS-CoV-2 infected individuals are likely to have high enough viral loads to transmit the virus via aerosols, said Michael Riediker, founding director of the Swiss Centre for Occupational and Environmental Health, in Winterthur, who coauthored the new study published in JAMA Network Open.

"But the occasional high-viral-load individuals seem to be relevant for this route," Riediker said in an email. "This would explain the low rate of super-spreading events in indoor situations. Already when such a person breathes, concentrations in a room can quickly go up quite high."

Emissions can be boosted if a high-viral-load individual also engages in high microdroplet emission activities, such as singing, shouting, or even worse, combining those activities with physical exercise, Riediker said. "Finally, the emissions from a coughing patient can result even in well-ventilated rooms in airborne concentrations that bring along a serious risk of infection," he added.

Riediker and his coauthor started out with published data on the number of viral copies present in sputum and swab samples from individuals with COVID-19. They combined this information with data from studies on size distributions and numbers of microdroplets exhaled and coughed by healthy individuals.

Plugging that data into a mathematical model, they calculated how much virus an individual would put into the air of a closed, 50 cubic meter room - about the size of a small office - with every breath. The researchers found low and typical emitters didn't put much virus into the air. But high emitters could put out as many as 1,247.7 virus copies/cubic meter when they were simply breathing normally and as many as 7,442,598 virus copies/cubic meter when coughing every 30 seconds.

In a typical hospital setting, with ventilation that exchanges the air in a room 10 times per hour, the virus concentration plateaus after approximately 30 minutes, the researchers note, while in a typical office with three air exchanges per hour, concentrations continue to increase for more than 1 hour, according to the model.

"It seems advisable to avoid situations where you spend extended time with another person in a room, especially if that room is small and poorly ventilated," Riediker said. "Wearing good quality face coverings such as surgical masks can reduce the emissions to less risky levels if worn correctly, at least as long as the person is not coughing."

"If you are in high-risk situations, for example you're a medical doctor attending patients with respiratory symptoms or an at-risk person needing to spend time in a small room with others, you probably should be wearing a good quality respirator," Riediker cautioned.

The new findings emphasize the importance of staying at home if you have symptoms that have been associated with COVID-19, said Dr. Panagis Galiatsatos, an assistant professor in the division of pulmonary and critical care medicine at the Johns Hopkins School of Medicine, in Baltimore. "People without those symptoms can go about a somewhat normal life with a facemask," Dr. Galiatsatos said.

"It also tells me a cough can be dangerous in addition to other things that can cause a turbulent trajectory, such as singing and yelling loudly," Dr. Galiatsatos said.

The take home message from this study should be the importance of continuing to wear a mask, said Dr. Waleed Javid, an associate professor of medicine at the Icahn School of Medicine at Mount Sinai in New York City and director of infection prevention and control at the Mount Sinai Downtown Network.

"It's a very interesting study," Dr. Javid said. "What you don't know if I am standing in front of you and speaking and I have it is whether I am a high or low emitter. And that's why we should continue to wear our masks. And if I am infected I should wear a mask too, so there will be double coverage."

This issue will become all the more important as businesses reopen in New York City, Dr. Javid said. "It's important for us not to let our guards down," he added. "We are in the pandemic of the century. None of us has seen this before and no one can say they know everything about it."

SOURCE: https://bit.ly/307QsJv JAMA Network Open, online July 27, 2020.

SCHOOLS AND COVID TRANSMISSION

When officials closed US schools in March to limit the spread of COVID-19, they may have prevented more than 1 million cases over a 26-day period, a new estimate published online this week in JAMA suggests.

But school closures also left blind spots in understanding how children and schools affect disease transmission.

"School closures early in pandemic responses thwarted larger-scale investigations of schools as a source of community transmission," researchers note in a separate study published online July 30 in JAMA Pediatrics that examined levels of viral RNA in children and adults with COVID-19.

"Our analyses suggest children younger than 5 years with mild to moderate COVID-19 have high amounts of SARS-CoV-2 viral RNA in their nasopharynx compared with older children and adults," report Taylor Heald-Sargent, MD, PhD, and colleagues. "Thus, young children can potentially be important drivers of SARS-CoV-2 spread in the general population, as has been demonstrated with respiratory syncytial virus, where children with high viral loads are more likely to transmit."

Although the study "was not designed to prove that younger children spread COVID-19 as much as adults," it is a possibility, Heald-Sargent said in a related news release. "We need to take that into account in efforts to reduce transmission as we continue to learn more about this virus." Heald-Sargent is a pediatric infectious diseases specialist at Ann and Robert H. Lurie Children's Hospital and assistant professor of pediatrics at Northwestern University Feinberg School of Medicine in Chicago, Illinois.

The study included 145 patients with mild or moderate illness who were within 1 week of symptom onset. The researchers used reverse transcriptase–polymerase chain reaction (rt-PCR) on nasopharyngeal swabs collected at inpatient, outpatient, emergency department, or drive-through testing sites to measure SARS-CoV-2 levels. The investigators compared PCR amplification cycle threshold (CT) values for children younger than 5 years (n = 46), children aged 5 to 17 years (n = 51), and adults aged 18 to 65 years (n = 48); lower CT values indicate higher amounts of viral nucleic acid.

Median CT values for older children and adults were similar (about 11), whereas the median CT value for young children was significantly lower (6.5). The differences between young children and adults "approximate a 10-fold to 100-fold greater amount of SARS-CoV-2 in the upper respiratory tract of young children," the researchers write.

"Behavioral habits of young children and close quarters in school and day care settings raise concern for SARS-CoV-2 amplification in this population as public health restrictions are eased," they write.

Modeling the Impact of School Closures

In the JAMA study, Katherine A. Auger, MD, of Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, and colleagues examined at the US population level whether closing schools, as all 50 states did in March, was associated with relative decreases in COVID-19 incidence and mortalityTo isolate the effect of school closures, the researchers used an interrupted time series analysis and included other state-level nonpharmaceutical interventions and variables in their regression models.

"Per week, the incidence was estimated to have been 39% of what it would have been had schools remained open," Auger and colleagues write. "Extrapolating the absolute differences of 423.9 cases and 12.6 deaths per 100,000 to 322.2 million residents nationally suggests that school closure may have been associated with approximately 1.37 million fewer cases of COVID-19 over a 26-day period and 40,600 fewer deaths over a 16-day period; however, these figures do not account for uncertainty in the model assumptions and the resulting estimates."

Relative reductions in incidence and mortality were largest in states that closed schools when the incidence of COVID-19 was low, the authors found.

Decisions With High Stakes

In an accompanying editorial, Julie M. Donohue, PhD, and Elizabeth Miller, MD, PhD, both affiliated with the University of Pittsburgh, Pittsburgh, Pennsylvania, emphasize that the results are estimates. "School closures were enacted in close proximity...to other physical distancing measures, such as nonessential business closures and stay-at-home orders, making it difficult to disentangle the potential effect of each intervention," they write.

Although the findings "suggest a role for school closures in virus mitigation, school and health officials must balance this with academic, health, and economic consequences," Donohue and Miller add. "Given the strong connection between education, income, and life expectancy, school closures could have long-term deleterious consequences for child health, likely reaching into adulthood." Schools provide "meals and nutrition, health care including behavioral health supports, physical activity, social interaction, supports for students with special education needs and disabilities, and other vital resources for healthy development," they note.

In a viewpoint article also published in JAMA, authors who are involved in the creation of a National Academies of Sciences, Engineering, and Medicine (NASEM) report on the reopening of schools recommend that districts "make every effort to prioritize reopening with an emphasis on providing in-person instruction for students in kindergarten–grade 5 as well as those students with special needs who might be best served by in-person instruction.

"To reopen safely, school districts are encouraged to ensure ventilation and air filtration, clean surfaces frequently, provide facilities for regular handwashing, and provide space for physical distancing," write Kenne A. Dibner, PhD, of the NASEM in Washington, DC, and coauthors.

Furthermore, districts "need to consider transparent communication of the reality that while measures can be implemented to lower the risk of transmitting COVID-19 when schools reopen, there is no way to eliminate that risk entirely. It is critical to share both the risks and benefits of different scenarios," they write.

The JAMA modeling study received funding from the Agency for Healthcare Research and Quality and the National Institutes of Health. The NASEM report was funded by the Brady Education Foundation and the Spencer Foundation. The authors have disclosed no relevant financial relationships.

JAMA. Published online July 29, 2020. AbstractEditorialViewpoint

JAMA Pediatrics. Published online July 30, 2020. Abstract

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ACE INHIBITORS IN PATIENTS WITH COVID?

Hospitalized COVID-19 patients with high blood pressure who continue on angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) fare better than those who discontinue the drugs, according to a retrospective study.

Several professional societies have released statements recommending that ACE inhibitors/ARBs should be continued in hypertensive patients with COVID-19, and studies have shown that their use is not associated with worse COVID-19 disease severity or mortality.

Dr. Tim Q. Duong and colleagues from Renaissance School of Medicine, Stony Brook University, in New York, investigated the effects of in-hospital continuation or discontinuation of ACE inhibitors/ARBs on the clinical outcomes of 614 hypertensive COVID-19 patients, controlling for newly developed hypotension or acute kidney injury (AKI) during hospitalization.

Among 279 patients who did not take ACE inhibitors/ARBs prior to admission, 55 required intensive-care unit (ICU) admission and 62 died. Forty-five of 171 patients who discontinued their home ACE inhibitors/ARBs in the hospital required ICU care and 48 died. Of the 164 patients who continued taking their home ACE inhibitors/ARBs in the hospital, 20 required ICU care and 10 died.

Mortality did not differ significantly between the ACE inhibitor/ARB groups and the non-ACE inhibitor/ARB group. But among patients who had been taking ACE inhibitors/ARBs at home, the mortality rate was significantly lower in those who continued their medications than in those who discontinued them (6.09% vs. 28.07%, adjusted P=0.001).

Hospital-onset hypotension and AKI rates were significantly higher in the group that discontinued ACE inhibitors/ARBs. There was no significant difference in mortality between continuing or discontinuing ACE inhibitors/ARBs among patients who developed in-hospital hypotension or AKI.

In contrast, among patients who did not develop hypotension or AKI, continued ACE inhibitor/ARB use was associated with significantly lower mortality compared with discontinuation, the researchers report in the Journal of Infectious Diseases.

ICU admission rates did not differ overall between the groups that were or were not receiving ACE inhibitors/ARBs before hospitalization, but the ICU admission rate was twice as high in the group that discontinued their medications (26.3%) as in the group that continued them (12.2%).

"These findings not only confirm that ACE inhibitor/ARB use does not worsen clinical outcomes in COVID-19 patients with a history of hypertension, but also suggest that COVID-19 patients who are on ACE inhibitors/ARBs should continue these medications in the hospital as they may have beneficial effects, as long as these patients do not develop hypotension or acute kidney injury," the authors conclude.

Dr. Andrew M. South of Brenner Children's Hospital, Wake Forest School of Medicine, in Winston Salem, North Carolina, has addressed ACE inhibitor/ARB use during the pandemic in several papers. He told Reuters Health by email, "Though limited, the study's findings do support the current recommendation for patients to continue to take their angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker medication if they test positive for SARS-CoV-2 or develop COVID-19, unless there is a clear and previously established indication for stopping the medication, such as low blood pressure."

"It will be very interesting to see the results of ongoing observational studies and clinical trials that will further address these important questions," said Dr. South, who was not involved in the new research.

Dr. Matthias Barton of the University of Zurich, Switzerland, who recently wrote about the potential harmful effects of discontinuing ACE inhibitors and ARBs in COVID-19 patients, told Reuters Health by email, "One has to be careful about interpreting/over-interpreting the data and about drawing conclusions based on the findings reported. At this point we do not know whether any protective effects are (equally) present for ACEI and ARBs, or whether one has advantages over the other."

"ACE inhibitors block ACE-1 (which is identical to kininase-2 which inactivates bradykinin) but not ACE-2, the receptor of SARS-CoV-2, and we still know very little about the potential mechanisms that may provide protection in COVID-19 patients," he said. "Since SARS-CoV-2 is not simply a respiratory disease but rather a systemic illness, vascular effects of RAAS inhibitors, particularly on endothelial cells and on coagulation, may contribute to their protective effects."

"But we do not have the corresponding evidence yet," cautioned Dr. Barton, who also was not involved in the new study. "Again, robust prospective clinical trials are needed to answer such questions."

Dr. Duong did not respond to a request for comments.

SOURCE: https://bit.ly/311F69h Journal of Infectious Diseases, online July 23, 2020.

COVID IN BLOOD DONORS?

Because of high rates of 2019 novel coronavirus disease in Wuhan, China, Wuhan Blood Center began screening for severe acute respiratory syndrome coronavirus 2 RNA on January 25, 2020. We screened donations in real-time and retrospectively and found plasma samples positive for viral RNA from 4 asymptomatic donors.

Because of the rapid increase of cases of 2019 novel coronavirus disease (COVID-19;[1]) and detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA in plasma,[2,3] the safety of China's blood supply became a major concern.[4] Most blood centers and blood banks in China began taking measures to ensure blood safety;[5] on January 25, 2020, we began screening all donations collected at the Wuhan Blood Center.

We performed real-time reverse transcription PCR (RT-PCR) for SARS-CoV-2 RNA by using MultiScreen Pro RT-PCR assay (SYM-BIO LifeScience, https://www.sym-bio.com.cn). We performed pool testing by mixing plasma from 6–8 samples or individual testing by using 1.6 mL of plasma. We eluted 100 μL of nucleic acid template and added 40 μL of it to the RT-PCR mix.

By March 4, we had screened 2,430 donations in real-time, including 1,656 platelet and 774 whole blood donations. We identified the first positive donor in our center in a positive pool with a weak amplification of the open reading frame 1ab gene. The donor gave 2 units of platelets on January 28, which were included in the pool. However, the donor's prior donations collected on December 12 and 26 and January 13 were negative for viral RNA. Hubei Province Center for Disease Control and Prevention performed follow-up tests on plasma on February 2, which showed a weak positive result near the limit of detection; a throat swab specimen collected from the donor on February 10 also was positive, indicating an extremely low viral load in plasma. The donor reported no symptoms and was quarantined in a cabin hospital in Wuhan until 2 consecutive negative throat swab results on February 23 and February 25 (Figure).

Figure.

Timeline of donations and symptom onset of 2019 novel coronavirus disease from 4 blood donors, China. Gray indicates a negative result for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA; yellow indicates a positive result. Green indicates the donor was asymptomatic or their temperature returned to normal; orange indicates fever; red triangle indicates the donor's fever subsided after taking self-prescribed antipyretic medications. PLT, platelet; TS, throat swab; WB, whole blood.

We also performed retrospective testing of 4,995 donations collected during December 21, 2019–January 22, 2020, by using retained nucleic acid template after routine pool testing. On February 10, we found a positive result in a nucleic acid template derived from donations collected on January 19. We individually tested samples that were in storage at 2°C–8°C for 23 days because no plasma samples stored at −20°C were available. We identified another positive donor of whole blood. We tested plasma products from his donation twice and noted similar results, which suggests that viral RNA is relatively stable in plasma (Appendix Table https://wwwnc.cdc.gov/EID/article/26/7/20-0839-App1.pdf). We immediately traced all blood products produced from donor 2's whole blood, and they had not been used. Telephone follow-ups on February 15 and 25 showed donor 2 remained asymptomatic and quarantined at home.

In telephone follow-ups with donors who gave blood during January and February, we identified 33 donors who developed a fever after donation; all of their donations were removed from circulation. We performed retrospective individual screening on frozen plasma products from 17 donors and tested the retained nucleic acid templates after routine pool testing of the other 16 donors. We found 2 more positive donors who donated whole blood on January 20. Both had weak positive results, and donors reported fever onset on January 21 (Figure; Appendix Table). Donor 3 treated patients infected with SARS-CoV-2 in a Wuhan hospital. His temperature returned to normal 8 days after donation. Donor 4's temperature also returned to normal 7 days after taking self-prescribed antipyretic medications.

By March 4, we identified 4 blood donors in Wuhan whose plasma samples tested positive for SARS-CoV-2 RNA (Figure; Appendix Table). Samples from these donors were further tested for specific IgG and IgM against SARS-CoV-2 by ELISA; results were negative, indicating the possibility of infection in the early stage and the need to follow-up with these donors.

We found SARS-CoV-2 RNA in plasma during routine screening of blood donors, considered a healthy population. We tested the 4 donors multiple times, using different sample sources, including sample tubes, retained nucleic acid templates, or blood products, indicating the accuracy and validity of our results (Appendix Table). One limitation of our study is that we did not have more detailed information on donors 2, 3, and 4. Although we could not confirm virions in blood or whether the virus could be transmitted in blood products, the potential risk should not be neglected. However, detectable RNA might not signify infectivity. Further studies, such as virus culture, should be done to explore the possibility of viremia and follow-up of donors also is essential.

Of note, the donors all donated in late January, and we did not detect SARS-CoV-2 in plasma samples after then, indicating the strict containment measures taken by the government of China were effective. In China, donors are screened for related symptoms and asked if they feel healthy when they donate blood. Having donors call the blood donation center if they have any symptoms after donating is essential to avoid the risk of donation during the COVID-19 incubation period. Moreover, as more asymptomatic cases occur, screening donors for viral RNA with high-sensitivity assays, as we are doing in Hubei Province, will be critical to ensure blood safety.

OFATUMUMAB FOR MS TREATMENT

Two phase 3 clinical trials showing impressive results with the new subcutaneously-delivered, B-cell depleting multiple sclerosis anti-CD20 mononclonal antibody ofatumumab (Arzerra) have now been published in The New England Journal of Medicine.

The ASCLEPIOS I and II clinical trials were first presented, and reported by Medscape Medical News, at last year's European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) meeting.

Ofatumumab is currently available for the treatment of chronic lymphocytic leukemia. Approval applications for its use in MS are under review by the US Food and Drug Administration, the company notes, "with an action expected by September 2020."

The drug will provide competition for ocrelizumab (Ocrevus), the first B-cell depleting anti-CD20 drug approved for MS, which became available in 2017.

The main difference between the two products is the route of administration. Ocrelizumab is given as an IV infusion every 6 months, which requires medical supervision; by contrast, ofatumumab is administered by monthly subcutaneous injection, which can be done by the patient at home.

The ASCLEPIOS I and II trials were led by Stephen Hauser, MD, University of California San Francisco, and Ludwig Kappos, MD, University Hospital, Basel, Switzerland.

In the two double-blind, double-dummy, randomized ASCLEPIOS trials, a total of 946 patients were assigned to receive ofatumumab (20 mg every 4 weeks after 20-mg loading doses at days 1, 7, and 14) and 936 to receive oral teriflunomide(14 mg daily) for up to 30 months.

After a median follow-up of 1.6 years, the primary outcome (annualized relapse rates) were 0.11 in the ofatumumab group vs 0.22 in the teriflunomide group in trial 1 (P < .001) and 0.10 vs 0.25 in trial 2 (P < .001).

In the pooled trials, the percentage of patients with disability worsening confirmed at 3 months was 10.9% with ofatumumab and 15% with teriflunomide (hazard ratio [HR], 0.66; P = .002). Disability worsening confirmed at 6 months occurred in 8.1% of ofatumumab patients vs 12% of those on teriflunomide (HR, 0.68; P = .01), and disability improvement confirmed at 6 months was seen in 11% of the ofatumumab group vs 8.1% of the teriflunomide group (HR, 1.35; P = .09).

In ASCLEPIOS I, the mean number of gadolinium-enhancing lesions per T1-weighted MRI scan was 0.01 with ofatumumab and 0.45 with teriflunomide (97% lower number of lesions with ofatumumab, P < .001); in ASCLEPIOS II, the corresponding numbers were 0.03 and 0.51, respectively (94% lower with ofatumumab, P < .001).

The mean number of new or enlarging lesions per year on T2-weighted MRI was 0.72 with ofatumumab and 4.00 with teriflunomide in the first trial (82% lower number of lesions with ofatumumab, < .001); corresponding values in ASCLEPIOS II were 0.64 and 4.15, respectively (85% lower with ofatumumab, P< .001).

Serum neurofilament light chain concentration was lower in the ofatumumab group than in the teriflunomide group by 7% at month 3, by 27% at month 12, and by 23% at month 24 in ASCLEPIOS I. Corresponding differences in ASCLEPIOS II were 11%, 26%, and 24%.

However, despite greater reductions in neurofilament light chain concentrations with ofatumumab, change in brain volume did not differ significantly between the two treatments. "This discrepancy between two markers of tissue damage needs further analysis," the authors say.

Adverse events were reported by similar numbers of patients in the two groups. Injection-related reactions occurred in 20.2% in the ofatumumab group and in 15% in the teriflunomide group (placebo injections). Serious adverse events were reported in 9.1% of the patients treated with ofatumumab and 7.9% of those treated with teriflunomide. Serious infections occurred in 2.5% and 1.8% of patients respectively.

Appendicitis was reported in 8 patients who received ofatumumab and in 2 who received teriflunomide.

"The reason for the observed imbalance in appendicitis as an adverse event with ofatumumab is unknown, and no signal for appendicitis has been observed with ofatumumab treatment in phase 2 studies in multiple sclerosis and other autoimmune indications or with other anti-CD20 therapies in multiple sclerosis," the researchers comment.

"Larger and longer trials are required," the authors conclude, "to determine the long-term effect and risks of ofatumumab as compared with other disease-modifying treatments, including other anti-CD20 monoclonal antibodies."

The ASCLEPIOS trials were funded by Novartis. Hauser reports receiving travel reimbursement and writing assistance from Roche and Novartis for CD20-related meetings and presentations. Kappos reports grants from Novartis to his institution, during the conduct of the trial. Some other coauthors are employees of Novartis.

N Eng J Med.  Published online August 6, 2020. Abstract 

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DO NOT OVERSCREEN OLDER ADULTS FOR CANCER

Older adults are being "overscreened" for cancer, say researchers who discovered that many report undergoing screening for cancer even though they were older than the upper age limit recommended.

The US Preventive Services Task Force (USPTF) recommends an upper age limit on cancer screening that varies by cancer type — 75 years old for colorectal cancer, 74 for breast cancer, and 65 for cervical cancer.

The study found that 59.3% of men and 56.2% of women being screening for colorectal cancer were above that cut-off age, as were 45.8% of women being screened for cervical cancer and 74.1% of women being screened for breast cancer.    

Overscreening was particularly high for women living in metropolitan areas.

The finding is of concern, say the researchers, because "continuing to screen patients who are older and/or who have limited life expectancy may cause more harms than benefits."

"The development of success interventions to address this problem are thus essential," they write.

The study was published online July 27 in JAMA Network Open.

Clinicians, patients, and healthcare systems can be changed — and should be changed — to minimize overscreening," said lead author Jennifer L. Moss, PhD, assistant professor of family and community medicine and public health sciences at Penn State College of Medicine, Hershey, Pennsylvania.

"It will probably take many changes to meaningfully decrease overscreening," she told Medscape Medical News.

One change that would help is if health insurance companies stopped reimbursing providers for screening after the recommended upper age limit, she continued. "Another change is if providers had evidence-based tools to guide conversations about stopping screening, given an individual patient's demographics, health status, and risks and benefits of the screening test."

Approached for comment on the study, Nancy Schoenborn, MD, MHS, an associate professor of medicine in the Division of Geriatric Medicine and Gerontology at Johns Hopkins University School of Medicine, Baltimore, Maryland, noted that the finding of high overscreening is not surprising and is consistent with prior works that found similar results.

"One value of this paper is that the timing of the study is more recent and confirms that the issue of overscreening is one that is still ongoing," she told Medscape Medical News. Schoenborn was not associated with the study.

As for what physicians should do about the findings in this study, Schoenborn suggested the first step is to simply recognize that overscreening is likely a problem and "to reflect if there are instances in one's own practice where overscreening may occur."

In her own work, Schoenborn continued, "I was recently surprised that a substantial minority of clinicians actually do not believe overscreening to be a problem in older adults, and they have a number of concerns about how overscreening is defined and about unintended consequences that can occur from efforts to reduce overscreening.The first step would be the clinician recognizing and agreeing that this is a problem that needs to be addressed. Dr Nancy Schoenborn

She added that there are a number of reasons why overscreening occurs. These include guideline inconsistencies, inertia, patient request, clinician knowledge gaps, and discomfort with discussing stopping. "A lot of work is ongoing to address each of these issues, but I think the first step would be the clinician recognizing and agreeing that this is a problem that needs to be addressed," she said.

Unnecessary Screening

The authors note that the prevalence estimates for overscreening have not been reported on a national level, and it is also unclear how overscreening may vary among subgroups.

"The reason I focused on colorectal, cervical, and breast cancers is because USPSTF has very clear, age-based recommendations for these cancers in terms of who should and should not get screened routinely," explained Moss. "This was important because it allowed me and my coauthors to clearly say, based on age alone, this person probably was screened unnecessarily, and this person was not."

She noted that that the age-based recommendations for routine screening are based on very large clinical trials to examine the effectiveness of the screening tool. "The recommendations for lung and prostate cancer screening are not so clear cut, and we would not be able to tell, based only on the available survey data, if someone was overscreened," she said.

For their study, the team used data from the 2018 Behavioral Risk Factor Surveillance System (BRFSS), administered by the US Centers for Disease Control and Prevention.

Overscreening was assessed in a cohort of 20,937 men and 34,244 women for colorectal cancer, 82,811 women for cervical cancer, and 38,356 women for breast cancer. Most the participants lived in a metropolitan area (about 80%) and were White (about 80%).

Being overscreened was also more common in metropolitan vs nonmetropolitan areas for colorectal cancer in women (adjusted odds ratio [aOR], 1.23), cervical cancer (aOR, 1.20) and breast cancer (aOR, 1.36).

Overscreening for cervical and breast cancers was also associated with having a usual source of care, good/very good/excellent self-reported health, education beyond a high school diploma, and being married or living as married.

The study was carried out in 2018, and the situation is likely to have changed over recent months during the COVID-19 pandemic.

"We have already seen dramatic reductions in routine cancer screening among age-eligible adults, so part of this problem of overscreening among older adults will likely diminish," said Moss. "State and national cancer surveillance systems will continue to monitor trends in cancer screening, including overscreening, cancer incidence, and cancer mortality."

Johns Hopkins' Schoenborn said one finding of particular interest was that colorectal cancer overscreening rate was higher in those older than 80 and in those with higher mortality risk. "It makes me wonder if this is due to the increasing use of non-invasive colorectal cancer screening modalities, such as the fecal immunochemical test FIT or Cologuard," Schoenborn commented. "It would be important for clinicians to consider downstream effects even when the initial test is low risk, such as if the stool test screens positive, would the patient still need a colonoscopy and is that something the patient can undergo and wants to undergo?"

The study was funded by the National Cancer Institute and American Cancer SocietyMoss, study coauthors, and Schoenborn have disclosed no relevant financial relationships.

JAMA Netw Open. Published online July 27, 2020. Full text

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NO CHEMO AT HOME

The American Society of Clinical Oncology (ASCO) "does not generally support" the administration of anticancer therapy in patients' homes because of safety concerns, the organization says in a new policy statement issued July 31.

At the same time, it supports exceptions: namely, when individual physicians and patients, having jointly discussed risks and benefits, agree to have treatments administered in the home.

The new policy is limited to intravenous infusion of anticancer agents such as chemotherapy, monoclonal antibodies, and other drugs — administered by health care personnel. It does not refer to injections.

The policy was prompted by regulatory flexibilities from the Centers for Medicare & Medicaid Services (CMS) made in response to the accelerating COVID-19 pandemic. "Among these flexibilities were new provisions that enabled providers to deliver care in a setting most appropriate — and safest — for individual patient circumstances," which has "opened the path for potential increases in use of home infusion for anticancer therapy," says ASCO.

"We're not ready to endorse [chemo at home] as a general policy until we have evidence that it's safe. At the same time, the policy gives physicians and patients autonomy to respond to whatever situation they find themselves in," said Stephen Grubbs, MD, ASCO's senior director of clinical affairs, in an interview with Medscape Medical News

"Antineoplastic drugs are effective at treating cancer but can be extremely toxic to normal human cells," reads the statement, which was written by a group of about 25 professionals, including Grubbs and other ASCO staff as well as independent advisors.

"There is a paucity of evidence directly comparing the safety of chemotherapy infusions in the home and outpatient settings," the ASCO policy explains.

ASCO's policy acknowledges that there are data "from other countries demonstrating that...home infusion can be safe, well-tolerated, and may be preferred by some patients." But such data are limited and only apply "to certain circumstances and for specific agents," it adds.

One US cancer center (in Philadelphia) already has an established chemo-at-home program and has seen an increase in its use during the pandemic, as reported by Medscape Medical News. Approached for comment, Justin Bekelman, MD, director of the Penn Center for Cancer Care Innovation in Philadelphia, interpreted the new ASCO policy in a positive light.

"Physicians at the Abramson Cancer Center of the University of Pennsylvania and ASCO agree — home-based cancer therapy with oncologist oversight and well-designed safety protocols can be a safe option for patients with cancer," he said in a statement. 

Safety Is Major Concern

ASCO says its existing safety standards "may be difficult to satisfy in the home infusion context," including for safely resolving life-threatening emergenciesGrubbs said that in the worst-case scenario, such as anaphylactoid reaction, "you can die from [it] if you don't manage it quickly and properly."

"When I was practicing, we always had a physician present right next to the infusion area because these are severe reactions that happen very quickly," he said, adding that "several a year" occurred when he practiced full-time.

Also, chemotherapy spills are a "big deal" in the home, as clean-up may be complex and difficult, added Grubbs.

Data from ASCO's PracticeNET program show that in the first months (March and April) of the COVID-19 pandemic, chemotherapy visits to infusion suites were not reduced in a dataset of 16 US practices, he noted. However, there are exceptions and variance based on location, Grubbs said, such as "hot spots" including New York City in April.

While the pandemic has no end in sight, ASCO issued a set of six recommendations for use of anticancer therapies infused in the home. First, they call for independent, publicly funded research to evaluate the safety and effectiveness of home infusion of anticancer therapy.

Next in importance, ASCO wants the current temporary regulation change from CMS due to the pandemic to end.

"CMS should not extend the temporary flexibility related to home infusion for Part B cancer drugs that was approved as part of their response to the public health emergency," they state.

Even before the pandemic, changes were afoot. Under the 21st Century Cures Act, which was passed in 2019 and will be implemented in 2021, CMS instituted a permanent home infusion therapy services benefit, which includes anticancer therapies. It "remains to be seen what, if any, shift away from outpatient infusion facilities will occur," observes ASCO in its policy statement.

Nick Mulcahy is an award-winning senior journalist for Medscape. He previously freelanced for HealthDay and MedPageToday, and had bylines in the WashingtonPost.com, MSNBC, and Yahoo. Reach him by email and follow him on Twitter.

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NO GOOD NEWS FOR STROMA TARGETING AT PANCREATIC CANCER

Adding pegvorhyaluronidase alfa (PEGPH20) to treatment with nab-paclitaxel and gemcitabine (AG) did not improve survival in adults with previously untreated metastatic pancreatic ductal adenocarcinoma in a phase 3 trial.

The median overall survival was 11.2 months with PEGPH20 plus AG and 11.5 months with placebo plus AG. The median progression-free survival was 7.1 months in both treatment arms.

Eric Van Cutsem, MD, PhD, of University Hospitals Gasthuisberg Leuven and KU Leuven in Belgium, and colleagues reported these findings in the Journal of Clinical Oncology.

The authors explained that, in pancreatic ductal adenocarcinoma, "a dense fibrotic stroma (i.e., desmoplasia) surrounds the growing tumor mass, which can compress tumor vasculature within the microenvironment and increase interstitial pressure, impeding perfusion and delivery of systemic agents."

PEGPH20 is an enzyme that degrades hyaluronan, a major component of the stroma. The researchers' hypothesis was that PEGPH20 would weaken the stromal barrier and facilitate greater penetration of the AG combination into the tumor.

However, PEGPH20 failed to improve upon results with AG in this trial, which led Halozyme Therapeutics to halt further development of PEGPH20.

The negative findings in this trial, as well as the failure of other stroma-remodeling agents in pancreatic ductal adenocarcinoma, "collectively indicates the need to reevaluate this treatment strategy," Dr. Van Cutsem and colleagues wrote.

"More preclinical and retrospective analyses are needed to better understand the failures of tumor stroma remodeling and whether and how it should continue to be pursued," the authors added.

Phase 3 Results 

The intent-to-treat analysis included 492 adults with previously untreated metastatic pancreatic ductal adenocarcinoma. All patients expressed high hyaluronan levels, as defined by at least 50% hyaluronan staining in the extracellular matrix from tumor samples.

There were 165 subjects randomized to receive placebo plus AG and 327 randomized to receive PEGPH20 plus AG. Baseline characteristics were similar between the treatment arms.

The overall response rate was 47% with PEGPH20-AG and 36% with placebo-AG. The median duration of response was 6.1 months and 7.4 months, respectively.

The overall survival analysis was performed after 330 deaths. There were no significant differences between the PEGPH20 and placebo arms with regard to median overall survival (11.2 months and 11.5 months, respectively; hazard ratio, 1.00, P = .97) or progression-free survival (7.1 months in both arms; HR, 0.97).

All patients experienced at least one treatment-emergent adverse event (AE). The most common AEs of any grade that were more frequent in the PEGPH20 arm than in the placebo arm (≥ 2%) were peripheral edema (61.8% vs. 33.3%), muscle spasms (51.4% vs. 9.6%), myalgia (28.9% vs. 14.7%), and arthralgia (19.4% vs. 11.5%).Grade 3 or higher AEs that were more common with PEGPH20 (≥ 2%) included fatigue (16.0% vs. 9.6%), muscle spasms (6.5% vs. 0.6%), and hyponatremia(8.0% vs. 3.8%).

"[T]here were no apparent safety signals that affected study treatment exposure or survival," the investigators noted.

Two Failed Trials 

"We now have two failed clinical trials for PEGPH20. Could it be perhaps that our theory of targeting the desmoplastic response is simply not enough?" Nausheen Hakim, DO, of Northwell Health Cancer Institute in New York, and colleagues wrote in a commentary shortly after Halozyme released topline results from the phase 3 trial (Pancreas [Fairfax]. 2019;3[1]:e1-e4. doi: 10.17140/POJ-3-e010).

The second study the editorialists were referring to is a phase 1b/2 trial of PEGPH20 added to fluorouracilleucovorinirinotecan, and oxaliplatin (J Clin Oncol. 2019 May 1;37[13]:1062-9).

In this trial, the median overall survival was worse with PEGPH20 than without it, at 7.7 months and 14.4 months, respectively. The difference was probably due to the increased toxicity with the PEGPH20 regimen, which led to subjects receiving only half the number of chemotherapy cycles as the control group, Dr. Hakim and colleagues wrote.

"Perhaps it is not solely the desmoplastic reaction that is the cause of chemoresistance of pancreatic cells but additional intrinsic factors at play," the editorialists wrote. "It may indeed be a combination of stroma-modifying agents as well as other strategies to overcome chemoresistance to better fight pancreatic cancer. Further studies in molecular biology to better characterize the complex interaction between the microenvironment and cancer cells are warranted."

The phase 3 study was funded by Halozyme Therapeutics. The authors disclosed relationships with Halozyme and many other companies. The editorialists disclosed no conflicts of interest.

SOURCE: Van Cutsem E et al. J Clin Oncol. 2020 Jul 24;JCO2000590. doi: 10.1200/JCO.20.00590.

This article originally appeared on MDedge.com.

HBV SCREENING FOR ALL CANCER PATIENTS

All patients with cancer who are candidates for systemic anticancer therapy should be screened for hepatitis B virus (HBV) infection prior to or at the start of therapy, according to an updated provisional clinical opinion (PCO) from the American Society of Clinical Oncology.

"This is a new approach [that] will actively take system changes...but it will ultimately be safer for patients ― and that is crucial," commented Jessica P. Hwang, MD, MPH, co-chair of the American Society of Clinical Oncology (ASCO) HBV Screening Expert Panel and the first author of the PCO.

Uptake of this universal screening approach would streamline testing protocols and identify more patients at risk for HBV reactivation who should receive prophylactic antiviral therapy, Hwang told Medscape Medical News. 

The PCO calls for antiviral prophylaxis during and for at least 12 months after therapy for those with chronic HBV infection who are receiving any systemic anticancer treatment and for those with have had HBV in the past and are receiving any therapies that pose a risk for HBV reactivation.

"Hepatitis B reactivation can cause really terrible outcomes, like organ failure and even death," Hwang, who is also a professor at the University of Texas MD Anderson Cancer Center, Houston, commented in an interview.

"This whole [issue of] reactivation and adverse outcomes with anticancer therapies is completely preventable with good planning, good communication, co-management with specialists, and antiviral therapy and monitoring," she added.

The updated opinion was published online July 27 in The Journal of Clinical Oncology.

It was developed in response to new data that call into question the previously recommended risk-adaptive approach to HBV screening of cancer patients, say the authors.

ASCO PCOs are developed "to provide timely clinical guidance" on the basis of emerging practice-changing information. This is the second update to follow the initial HBV screening PCO, published in 2010. In the absence of clear consensus because of limited data, the original PCO called for a risk-based approach to screening. A 2015 update extended the recommendation for screening to patients starting anti-CD20 therapy or who are to undergo stem cell transplant and to those with risk factors for HBV exposure.

The current update provides "a clinically pragmatic approach to HBV screening and management" that is based on the latest findings, say the authors. These include findings from a multicenter prospective cohort study of more than 3000 patients. In that study, 21% of patients with chronic HBV had no known risk factors for the infection. In another large prospective observational cohort study, led by Hwang, which included more than 2100 patients with cancer, 90% had one or more significant risk factors for HBV infection, making selective screening "inefficient and impractical," she said.

"The results of these two studies suggest that a universal screening approach, its potential harms (eg, patient and clinician anxiety about management, financial burden associated with antiviral therapy) notwithstanding, is the most efficient, clinically pragmatic approach to HBV screening in persons anticipating systemic anticancer treatment," the authors commentThe screening recommended in the PCO requires three tests: hepatitis B surface antigen (HBsAg), core antibody total immunoglobulin or IgG, and antibody to HBsAg tests.

Anticancer therapy should not be delayed pending the results, they write.

Planning for monitoring and long-term prophylaxis for chronic HBV infection should involve a clinician experienced in HBV management, the authors write. Management of those with past infection should be individualized. Alternatively, patients with past infection can be carefully monitored rather than given prophylactic treatment, as long as frequent and consistent follow-up is possible to allow for rapid initiation of antiviral therapy in the event of reactivation, they say.

Hormonal therapy without systemic anticancer therapy is not likely to lead to HBV reactivation in patients with chronic or past infection; antiviral therapy and management of these patients should follow relevant national HBV guidelines, they note.

Challenges in Implementing Universal HBV Screening

The expert panel acknowledges the challenges associated with implementation of universal HBV screening as recommended in their report and notes that electronic health record (EHR)–based approaches that use alerts to prompt screening have demonstrated success. In one study of high-risk primary care patients, an EHR alert system significantly increased testing rates (odds ratio, 2.64 in comparison with a control group without alerts), and another study that used a simple "sticky-note" alert system to promote referral of HBsAg patients to hepatologists increased referrals from 28% to 73%.

In a cancer population, a "comprehensive set of multimodal interventions," including pharmacy staff checks for screening prior to anti-CD20 therapy administration and electronic medication order reviews to assess for appropriate testing and treatment before anti-CD20 therapy, increased testing rates to greater than 90% and antiviral prophylaxis rates to more than 80%.

A study of 965 patients in Taiwan showed that a computer-assisted reminder system that prompted for testing prior to ordering anticancer therapy increased screening from 8% to 86% but was less effective for improving the rates of antiviral prophylaxis for those who tested positive for HBV, particularly among physicians treating patients with nonhematologic malignancies.

"Future studies will be needed to make universal HBV screening and linkage to care efficient and systematic, likely based in EHR systems," the panel says. The authors note that "[o]ngoing studies of HBV tests such as ultrasensitive HBsAg, HBV RNA, and hepatitis B core antigen are being studied and may be useful in predicting risk of HBV reactivation."

The panel also identified a research gap related to HBV reactivation risks "for the growing list of agents that deplete or modulate B cells." It notes a need for additional research on the cost-effectiveness of HBV screening. The results of prior cost analyses have been inconsistent and vary with respect to the population studied. For example, universal screening and antiviral prophylaxis approaches have been shown to be cost-effective for patients with hematologic malignancies and high HBV reactivation risk but are less so for patients with solid tumors and lower reactivation risk, they explain.

Hwang told Medscape Medical News that not one of the more than 2100 patients in her HBV screening cohort study encountered problems with receiving insurance payment for their HBV screening.

"That's a really strong statement that insurance payers are accepting of this kind of preventative service," she said.

Expert panel co-chair Andrew Artz, MD, commented that there is now greater acceptance of the need for HBV screening across medical specialties.

"There's growing consensus among hepatologists, infectious disease specialists, oncologists, and HBV specialists that we need to do a better job of finding patients with hepatitis B [who are] about to receive immunocompromising treatment," Artz told Medscape Medical News. 

Artz is director of the Program for Aging and Blood Cancers and deputy director of the Center for Cancer and Aging at City of Hope Comprehensive Cancer Center, Duarte, CaliforniaHe suggested that the growing acceptance is due in part to the increasing number of anticancer therapies available and the resulting increase in the likelihood of patients receiving therapies that could cause reactivation.

More therapies ― and more lines of therapy ― could mean greater risk, he explained. He said that testing is easy and that universal screening is the simplest approach to determining who needs it.

"There's no question we will have to change practice," Art said in an interview. "But this is easier than the previous approach that essentially wasn't being followed because it was too difficult to follow and patients were being missed."

Most clinicians will appreciate having an approach that's easier to follow, Artz predicted.

If there's a challenge it will be in developing partnerships with HBV specialists, particularly in rural areas. In areas where there is a paucity of subspecialists, oncologists will have to "take some ownership of the issue," as they often do in such settings, he said.

However, with support from pharmacists, administrators, and others in embracing this guidance, implementation can take place at a systems level rather than an individual clinician level, he added.

The recommendations in this updated PCO were all rated as "strong," with the exception of the recommendation on hormonal therapy in the absence of systemic anticancer therapy, which was rated as "moderate." All were based on "informal consensus," with the exception of the key recommendation for universal HBV screening ― use of three specific tests ― which was "evidence-based."

The expert panel agreed that the benefits outweigh the harms for each recommendation in the update.

Hwang received research funding to her institution from Gilead Sciences and Merck Sharp & Dohme. She also has a relationship with the Asian Health Foundation. Artz received research funding from Miltenyi Biotec. All expert panel members' disclosures are available in the PCO update.

J Clin Oncol. Published online July 27, 2020. Full text

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