Jared Kaltwasser

A new report is bolstering the case for the use of an algorithm-based early warning system designed to help healthcare providers more quickly detect patients experiencing sepsis.

 shows the algorithm led to faster administration of antibiotics among septic patients and ultimately shortened the number of days those patients were hospitalized.

The product at the center of the study is Epic Systems Corp.’s sepsis prediction model, which is built directly into patient health records. It uses insights from Epic’s data sets to monitor patient metrics and identify those patients who may be at risk of sepsis. Patients at high risk are flagged, giving human healthcare providers the nudge to investigate and, if warranted, intervene.

Principal investigator Yasir Tarabichi, MD, MSCR, the director of clinical informatics for research support at Cleveland-based MetroHealth, told 

 that sepsis is a good candidate for this type of early warning system.

“The reason why it potentially lends itself to this solution is because it's complicated and hard to identify,” he said. “And on the therapeutic side, identifying it early could 

, primarily through the administration of antibiotics and timely fashion.”

Still, Tarabichi said while the potential benefits were compelling, he and his colleagues wanted to see what benefits the system could produce in a real-world setting. To find out, they constructed a prospective randomized quality improvement study, in which patients who sought emergency care at a single healthcare facility were randomized into a standard care group or a group whose providers had access to Epic’s early warnings.

Of the 598 patients included in the final analysis, 285 patients were in the early warning system cohort. Those patients’ providers received alerts when the system predicted possible sepsis. Alerts for the 313 patients in the standard care group were silenced, though a timestamp of alerts was recorded. The trial ran from August to December of 2019.

The trial had two main endpoints: time to antibiotic administration, and days spent outside of the hospital over the following 28 days. In both categories, the sepsis early warning system outperformed standard care. Time to antibiotic treatment in the early warning group was a median of 2.3 hours (interquartile range, 1.4–4.7 hours) following emergency department arrival, while the standard group received antibiotics a median of 3.0 hours after arrival (interquartile range, 1.6–5.5 hours). The early warning group had a median of 24.1 days alive outside the hospital in the four weeks following presentation; the standard care group had a median of 22.5 days.

Tarabichi said while most patients in the study were getting antibiotics relatively quickly, data show that the sooner a patient with sepsis receives antibiotics, the greater the likelihood of survival.

“So the fact that you can increase [the speed of antibiotic administration] by a little under an hour, that's still important,” he said. “That’s moving the needle.”

Tarabichi said the group that most appreciated the early warning system was the health system’s pharmacists, who reported feeling more connected to the providers and the decision-making process when they had access to the early warning system.

In probing the sepsis model, Tarabichi and colleagues waded into an ongoing conversation about the benefits of artificial intelligence in general, and of the Epic sepsis model in particular. A study

 published earlier this year by the University of Michigan

, which retrospectively examined sepsis cases at the university’s health system, found Epic’s system would have missed a significant number of patients while generating a high number of alerts and creating a risk of alert fatigue.

Tarabichi, however, said his study differs from the Michigan validation study because it does not rely on a retrospective analysis, but instead looked at how the system worked prospectively in the real world.

“The study that the validation study asks is, ‘How does the model do?,’ not, ‘How can a physician do with the model? Can a physician do better with the presence of a model?’,” he said.

Tarabichi said he hopes his study shows the importance of holding models like the sepsis product to high standards, which he said involves undertaking rigorous study to see how they perform in real-world settings.

“And you can't just do that with a validation study, you have to do that with a prospective study... and look at it in the real-world complex environment,” he said. “And ideally, if you can afford it, a randomized control study.”

MetroHealth continues to use the sepsis model in its emergency department, Tarabichi said.

Articles

The model found patients whose physicians received artificial intelligence-based alerts also spend fewer days in the hospital.

Prospective Real-World Study Finds Epic Sepsis Model Speeds Antibiotics 

COVID-19 convalescent plasma does not appear to prevent disease progression in high-risk outpatients who were administered the treatment within a week of symptom onset, according to a new study.

The report is the latest evidence in the ongoing effort to pin down the best strategies for treating patients with COVID-19, though the report does not claim that there might not be other instances in which the treatment is beneficial. The study was 

The use of plasma from patients who recently recovered a particular illness has long been used to deal with emerging infections. COVID-19 has been no different, though corresponding author Clifton W. Callaway, MD, PhD, of the University of Pittsburgh, and colleagues, said few randomized controlled trials have been undertaken to evaluate the therapy’s 

use in patients who have contracted the SARS-CoV-2 virus

Callaway and colleagues with the Strategies to Innovate Emergency Care Clinical Trials Network (SIREN) wanted to know whether the strategy might prove beneficial for high-risk patients who sought care within the first week of COVID-19 symptoms.

They constructed a randomized, multicenter, single-blind study in which high-risk patients who sought emergency care were assigned to receive either one unit of convalescent plasma with a high titer of antibodies against SARS-CoV-2 or placebo.

Patients were characterized as high-risk if they were at least 50 years old or had at least one risk factor for disease progression. Those included in the study had visited the emergency department within a week of symptom onset and were considered stable enough for outpatient management. The primary outcome was disease progression after 15 days, and the secondary outcomes were disease severity, hospital-free days within 30 days, all-cause mortality.

A total of 511 patients were included in the trial, with 257 given the plasma treatment and 254 given placebo. The outcomes between the two groups were similar. Seventy-seven patients (30%) in the treatment group experienced disease progression, compared with 81 patients (31.9%) in the placebo group. Five patients in the treatment group and one patient in the placebo group died.

Thus, concluded the investigators, the therapy failed to prevent disease progression better than placebo.

 the therapy remains available under an emergency FDA 

, and thus is not available in an outpatient setting, except in trials like this one. He noted an 

 sponsored by Michael J. Joyner MD, of the Mayo Clinic, has reported about 50,000 uses of the therapy in its publications.

While the current study suggests convalescent plasma is not beneficial among high-risk outpatients, Callaway said there may still be other groups of patients for whom this type of passive immunization may prove beneficial.

“For example, emerging data indicate that immunosuppressed persons, such as those with solid organ transplants, may not reliably develop immunity after COVID-19 vaccination,” he said.

It is possible, Callaway said, that such patients might benefit from plasma infusion. It is also possible that that plasma could prevent the development of symptomatic COVID-19 among patients exposed to the virus. However, he said his present study did not include sufficient numbers to test such niche groups.

Callaway added that he and his colleagues are probing whether the immunological status of a patient may determine whether they will benefit from convalescent plasma.

“We collected blood from our patients in this trial, and part of our ongoing work now is to analyze whether the baseline levels of anti-SARS-CoV-2 antibodies in the patients predicted any treatment effect,” he said.

Callaway said results from that analysis will hopefully be made public within the next few months.

In a head-to-head randomized controlled trial, 30% of outpatients who received convalescent plasma had disease progression, compared to 31.9% of patients who received placebo.

Convalescent Plasma Fails to Stop Progression in High-Risk COVID-19 Outpatients

As the COVID-19 pandemic emerged, scientists and public health officials struggled to gather the evidence necessary to craft meaningful mitigation guidelines.

In a new research letter based on a review of national and international guidelines, corresponding author Gabriel Birgand, PhD, discussed the ways in which those guidelines have varied, changed, and conflicted over time. Birgand is affiliated with Imperial College London, in the United Kingdom, and Nantes University Hospital, in France. The review was 

Birgand and colleagues said it is not surprising that there would be variation in the 

 given the scientific uncertainty about how the SARS-CoV-2 virus spreads, particularly with regard to airborne transmission. However, he and his co-authors said the stakes are high when it comes to getting guidelines right.

“Variability among guidelines may generate confusion, anxiety, and mistrust among health care professionals (HCPs) regarding the ability of respiratory protection to prevent SARS-CoV-2 transmission,” they wrote.

The investigators looked for guidelines from public health agencies in 4 countries and from 2 international organizations, the World Health Organizations (WHO) and the European Center for Disease Prevention and Control. After exclusions due to study criteria, the investigators were left with a list of 59 guidelines published between January 1 and December 31 of last year. Those guidelines tell a story of shifting strategies.

For instance, at the start of the year, all guidelines recommended that health care providers wear respirators when in direct contact with a person with confirmed or suspected COVID-19. The next month, both the European CDC, followed by the American CDC, modified the recommendation to support the use of medical face masks when treating COVID-19 patients if respirators were not available. However, respirators were still the recommendation when providers were conducting 

. Other agencies, including the WHO, soon updated their guidelines similarly. However, insofar as those guidelines included recommendations specific to aerosol-generating procedures, Birgand and colleagues noted that the list of what constituted an “aerosol-generating procedure” varied, with lists ranging from 3 to 14 procedures. The most commonly included procedures were bronchoscopy and intubation.

“These discrepancies may reflect controversies related to SARS-CoV-2 transmission routes,” the authors said. “The most recent assessment of the clinical evidence for the risk of transmission of acute respiratory infections to HCPs caring for patients undergoing AGPs dates back to a 2012 systematic review of a limited volume of studies.”

Meanwhile, Germany in late March became the first country to recommend that all people entering a hospital wear a face mask, and it was soon followed by other countries. The authors said the relatively slow speed at which universal masking was adopted could be related to early confusion around asymptomatic transmission. New, stronger research is needed in order to better understand which procedures should be considered aerosol-generating, and how individual procedures might affect risk levels to HCPs treating patients with respiratory illnesses.

Finally, the investigators said, guidelines also appear to have been crafted in part to deal with resource limitations, which sometimes differed from country to country. The authors said better research and better collaboration could help eliminate such problems in the future.

“Inconsistencies in respiratory protection guidelines between neighboring countries created confusion over optimal measures,” they said. “Strong collaborations between national and international organizations are critical in such circumstances.”

Public health guidance differed between countries in part because of a lack of relevant scientific evidence, resource limitations, and differing strategies, according to a new report.

How Public Health Guidelines Shifted, Conflicted as Pandemic Unfolded

The Centers for Disease Control and Prevention (CDC) is standing behind the safety of 2 prominent coronavirus disease 2019 (COVID-19) vaccines, calling incidences of major adverse events “rare.”

 following the July 22 meeting of the agency’s Advisory Committee on Immunization Practices (ACIP).

“The estimated benefits (prevention of COVID-19 disease and associated hospitalizations, ICU admissions, and deaths) outweighed the risks... in all persons aged ≥18 years included in this analysis,” wrote corresponding author Hannah Rosenblum, MD, and colleagues. Rosenblum is a member of the CDC’s COVID-19 Response Team and its Epidemic Intelligence Service.

The Food and Drug Administration (FDA) granted emergency authorization to the 2-dose Pfizer/BioNTech and Moderna vaccines back in December; Johnson & Johnson’s single-dose vaccine gained the same status in February of this year. As of the July ACIP meeting, some 187 million Americans had received at least one vaccine dose.

Though the vaccines have been credited with helping to slow the spread of the SARS-CoV-2 virus and curb hospitalizations and deaths, there have been isolated reports of significant adverse events.

The new report focuses on 3 types of adverse events: 

 following the Pfizer/BioNTech vaccine (particularly after the second dose), and thrombosis with thrombocytopenia (TTS) and 

 following the Johnson & Johnson vaccine.

ACIP used reports submitted through the CDC’s Vaccine Adverse Event Reporting System (VAERS) to re-weigh the costs and benefits associated with the vaccines in light of those reports and the ongoing pandemic. Their calculations looked at the risk of each adverse event per million doses in adults 18 and older, as well as the benefits, assuming a 95% vaccine effectiveness rate for the Pfizer/BioNTech vaccine and a 90% vaccine effectiveness rate for the Johnson & Johnson vaccine.

Between February and June, 100 cases of GBS following the Johnson & Johnson vaccine were reported through VAERS. The median age was 57 years for patients, 61 patients were male, the median time from vaccination to symptom onset was 13 days (though it took 75 days in one patient), and 95% of patients ended up in the hospital. Ten patients were admitted to the ICU. As of the report, one patient had died. ACIP calculated that the unadjusted rate of GBS cases following vaccination was approximately 20.2 per million doses.

As of July 8, 38 cases of TTS had been reported within 15 days of vaccination with the Johnson & Johnson (Janssen) dose. Those cases were each reviewed and confirmed by physicians at the FDA and CDC. As of the report, 4 patients had died. Females ages 30-49 were the most likely to experience TTS following vaccination, and ACIP calculated a TTS report rate of 3.0 per million doses.

For myocarditis, 497 patients reported the condition following their second shot, resulting in a reporting rate of 3.5 cases per mission second doses. Males between the ages of 18 and 29 were most likely to experience myocarditis following vaccination. There have been no reports of deaths associated with post-vaccine myocarditis.

Based on those data, as well as the ongoing risk of COVID-19 transmission, ACIP said the benefits of vaccination outweigh the risks, though they said continued vigilant monitoring is “critical,” as is transparency with the public and patients about the risks.

“ACIP emphasized the importance of informing vaccination providers, and all persons receiving COVID-19 vaccines about the benefits and risks, including the risks after Janssen COVID-19 vaccination for GBS, particularly in males aged 50–64 years, and for TTS among females aged 30–49; and the risk for myocarditis after mRNA COVID-19 vaccination, particularly in males aged 18–29 years,” Rosenblum and colleagues said.

Given the rapid spread of the Delta variant, the CDC said, vaccination “is more urgent than ever.”

The CDC said both it and the FDA have updated their guidance and approval documents in order to ensure patients are fully informed.

The most common adverse event was myocarditis, which was reported in nearly 500 patients. None of those patients had died as of the new analysis, and the rate per million cases was 3.5 cases.