Brian P. Dunleavy

The original article, “Swiss Researchers Propose New Method for Assessing COVID-19 Mortality,” was published on ContagionLive.

As politicians debate the accuracy of coronavirus disease 2019 (COVID-19) case and death totals, researchers with less of an agenda—and likely more expertise—offer a solution.

Epidemiologists from the University of Bern in Switzerland proposed using the symptomatic case fatality ratio (sCFR) and infection fatality ratio (IFR), arguing that they are more accurate, at least when used correctly, than the more commonly used case fatality ratio (CFR), according to an 

. CFR measures the observed deaths over observed cases.

“The crude case fatality ratio… is a meaningless indicator that should not be used for comparison across space and time, as it suffers from two major biases that go in opposite directions,” study coauthor Julien Riou, PhD, MD, a postdoctoral research fellow in the University of Bern’s Institute of Social and Preventive Medicine, told 

®. “On one hand, observed deaths… underestimate the total number of deaths that will occur… because of the delay between infection and death. On the other hand, the number of observed cases underestimates the total number of infections by a factor that is very difficult to determine and is very influential on the CFR.”

In their study, Dr. Riou and his colleagues developed a computational model of the dynamics of transmission of SARS-CoV-2 along with COVID-19 mortality. The model accounted for the delay between infection and death, the increased diagnosis of disease in people with severe symptoms, and stratified data by age, according to the researchers.

The team then applied the model to Hubei province in China, where the pandemic originated, as well as regions in Austria, Germany, Italy, Spain, and Switzerland. In Hubei, the calculated IFR was 2.9% while the CFR was 2.4%, they found.

Conversely, in the European regions included in the analysis, estimates of the IFR ranged from 0.5% to 1.4%, compared to CFRs ranging from 3.9% to 17.8%, the researchers said. Overall, estimates of sCFR and IFR were consistent and varied less geographically than the CFR, they noted. For example, in Austria sCFR and IFR were 1.3% and 1.1%, respectively, while CFR was 2.4%. Similarly, in Switzerland, sCFR and IFR were 0.6% and 0.5%, respectively, while CFR was 3.9%.

Most notably, in Spain, CFR was 10.9%, while sCFR and IFR were 1.3% and 1.0%, respectively.

These more accurate statistics are vital to understanding the COVID-19 epidemic and developing public health interventions to contain it, Riou and his colleagues argue.

“[Some] people had a personal interest in downplaying the danger of SARS-CoV-2, maybe because it gave them fame and exposure to go against the consensus, or because they feared for the political or economic repercussions of control measures,” Riou said. “This controversy was very unfortunate because it hindered or delayed the preparation efforts in many countries. Even so lockdowns and other measures have been very efficient in controlling the spread of SARS-CoV-2 in most of Europe, [but] this early hesitation may have costed many deaths.

“I think it is now clear that the infection fatality ratio of SARS-CoV-2 is around 1%”—or about 10 times that of seasonal influenza, he added. “This clarity comes first from seroprevalence studies that have been repeated in several places. [Our] paper proposes an approach to estimate this IFR when serosurveys are not available.”

In other words, added clarity in a time of uncertainty.

Articles

Swiss researchers propose a new method to assess COVID-19 mortality.

Assessing COVID-19 Mortality

When it comes to addressing health care-associated infections, 

 is the most common nosocomial infection in the United States, with 

 suggests there may be a—relatively&mdash;simple and cost-effective solution: by identifying patients at risk for poor outcomes caused by 

 infection using serum eosinophil count information collected at hospital admission.

“There’s a frequently obtained, but often underutilized, marker that can predict not only mortality but adverse outcomes in disease,” study co-author David B. Stewart, MD, FACS, FASCRS, associate professor and section chief, colorectal surgery, University of Arizona, told 

®. “Eosinophil count is a marker we often ignore because, in general, it’s relatively unimportant for the bacterial infections we deal with. However, what our research shows that undetectable levels of eosinophils at the time of admission can be an accurate predictor of disease severity.”

For their research, Dr. Stewart and his colleagues performed a cohort study 2065 adult patients admitted for 

 infection through the emergency departments of 2 tertiary referral centers over a 10-year period. The study population was then stratified based on eosinophil count (0.0 cells/μL or >0.0 cells/μL) at the time of admission, and divided into a training and validation cohort. The authors used multivariable logistic regression to construct a predictive model for inpatient mortality as well as other disease-related outcomes.

What they found is that of the 2065 patients in the study (52.9% of whom were women; participants had a mean age of 63.4 years), those with an undetectable eosinophil count at admission had increased in-hospital mortality in both the training and validation cohorts. In addition, undetectable eosinophil counts were associated with indicators of severe sepsis “such as admission to monitored care settings, the need for vasopressors, and emergency total colectomy,” according to the authors.

 infection mortality at admission included other readily obtainable and easily available markers such as comorbidity burden and lower systolic blood pressures. A subgroup analysis of patients presenting with no initial tachycardia or hypotension revealed that only those with undetectable admission eosinophil counts, but not those with elevated white blood cell counts, “had significantly increased odds of inpatient mortality” due to 

 infection. In fact, the multivariable logistic analysis revealed that undetectable eosinophil levels (eosinopenia) had greater than 90% accuracy among patients with a predicted probability of mortality of more than 20%.

 paper is the first human study to follow up on the work of co-author William A. Petri, MD, PhD, Wade Hampton Frost Professor of Medicine and chief, division of infectious disease, University of Virginia, who had explored the relationship between eosinophil levels and 

. Given that most emergency departments call for complete blood counts and differentials for every new patient that’s admitted, obtaining eosinophil counts for patients shouldn’t be a costly or inefficient step to take; it would merely entail accessing data that has already been collected, in most cases.

“What we demonstrate in our present study is that eosinophil counts at the time admission are strongly predictive of outcomes with relation to 

 infection,” Dr. Stewart explained. “Now, we need to look determine, if we were to change the management of patients based on that information, would that change outcomes? [As such,] we are in the planning stages of a prospective clinical trial to see if we can lower the incidence of adverse events like the need for vasopressors and emergency total colectomy by responding to that information.”

In a related commentary published with the study, authors from the department of surgery at McGovern Medical School at the University of Texas Health Science Center in Houston wrote that “admission eosinopenia may be a novel and inexpensive prognosticator for guiding the management of [

 infections]. Moreover, there are data to suggest that the resolution of eosinopenia may be a marker for a response to antimicrobial therapy in infections. Ultimately, interventions to block the TLR2-dependent pathway or to restore eosinophil cell counts may have therapeutic potential in [

Brian P. Dunleavy is a medical writer and editor based in New York. His work has appeared in numerous health care-related publications. He is the former editor of Infectious Disease Special Edition.

A new study is the first to identify eosinophil counts as a predictor of outcomes in human patients.
 

Research Reveals Potential New Marker for Mortality Due to Clostridium difficile Infection

Helaina Hovitz Regal was in middle school in lower Manhattan when 2 planes crashed into the Twin Towers of the World Trade Center on September 11, 2001. In the ensuing chaos, she and her classmates evacuated under orders to cover their mouths to avoid inhaling the soot and smoke that hung in the air, and to avert their eyes from the area that would come to be known as “Ground Zero,” so as not to witness the death and destruction.

The family apartment was located just blocks from the site of the attack. It left her rattled, and she was eventually diagnosed with post-traumatic stress disorder (PTSD). The diagnosis was not surprising, but the shocking part of her story is that it took several years for her health care team to agree on it. By then, her PTSD had already begun to take a toll mentally and physically, causing migraine headaches and gastrointestinal (GI) issues.

“In my research, I found that 1 in 2 children in America will have a traumatic experience at some point in their lives,” said Hovitz Regal, a freelance journalist who has since written about her experiences in several articles and in a memoir titled 

After 9/11: One Girl’s Journey through Darkness to a New Beginning

. “Not all of them will experience something like 9/11, of course, but it’s still trauma. And from my own experience, I can tell you that trauma has an effect on your brain and your body.”

In the 17 years since the attacks, medicine has only recently come to understand their health implications. A recent 

Circulation: Cardiovascular Quality and Outcomes

, a publication of the American Heart Association, highlights that those diagnosed with PTSD, as a result, may be at increased risk for future cardiovascular disease, including myocardial infarction (MI) and stroke.

“There [is] evidence from studies on veterans that PTSD could cause cardiovascular disease,” said Alfredo Morabia, MD, PhD, professor, clinical epidemiology, Mailman School of Public Health, Columbia University, in an interview with 

. “Since PTSD was so prevalent [in our study], we decided to test the hypothesis in this population. What makes this study unique is that we have a 15-year follow-up of people who were all exposed to the same highly traumatic event at the same time.”

The so-called “World Trade Center-Heart” study focuses on a cohort of more than 6400 first responders (nonfirefighter workers and untrained volunteers, 82.8% of whom are men; average age: 51 years) enrolled in the 

 (WTCHP) in New York City, which is operated under the auspices of the US Centers for Disease Control and Prevention.

Starting in 2012, epidemiologists and physicians working within the WTCHP and affiliated with the City University of New York (CUNY) and the Mailman School of Public Health at Columbia University began baseline assessments for the cohort, recording blood pressure, weight and height, and blood lipids for each of the participants. Study subjects self-reported any diagnosis of PTSD or depression and a history of smoking and dust exposure during the 2001 cleanup. Investigators followed the cohort for a 4-year period.

In all, among this subset of first responders, the prevalence of PTSD was 19.9% in men and 25.9% in women. To compare, among Americans as a whole, according to 

 available from the US Department of Veterans’ Affairs, 3.6% of men and 9.7% of women will be diagnosed with the condition during their respective lifetimes. Over the course of the 4-year study period, for those diagnosed with PTSD, Morabia and his colleagues calculated adjusted hazard ratios at 2.22 for MI and 2.51 for stroke; for pooled MI and stroke, adjusted hazard ratios were 2.35 in all and 1.88 in men free of depression. Using hospitalization registry data, the authors calculated adjusted hazard ratios of 2.17 for MI and 3.01 for stroke.

Simply put, this means those first responders on September 11th subsequently diagnosed with PTSD are more than twice as likely to suffer from MI or stroke, both of which are significant health concerns. Interestingly, the authors were not able to identify any correlation between World Trade Center dust exposure and future cardiovascular considerations within this population of first responders.

“Hopefully, [as a result of our findings], medical personnel will be looking for PTSD and when it is present, be ultra-careful that their patients refrain from cardiovascular disease risk factors such as smoking, or obesity, or treat aggressively biologic risk factors such as high blood pressure and high cholesterol,” Morabia said. In future work, he and his colleagues hope to obtain a greater understanding of the long-term effects of PTSD on cardiovascular disease risk among the population of first responders. If they have 2.5 times the risk for cardiovascular disease in the short-term, he added, “long-term, when people get into the age categories when cardiovascular disease becomes more common, what will it be?”

Despite the large sample size of the World Trade Center-Heart study, however, Morabia cautions that the findings may not be generalizable to the nearly 90,000 first responders who helped in lower Manhattan following the September 11th attack. And to truly understand the effects of PTSD on cardiovascular health, there must first be an accurate diagnosis of the mental health disorder.

“John,” a pseudonym for a 70-year-old now-retired technician for a telecommunications company who performed repair work in lower Manhattan in the weeks after the World Trade Center attack, has not been diagnosed with PTSD, but has suffered myriad health problems since, including pneumonia and chronic obstructive pulmonary disease (COPD), as well as high blood pressure. Enrolled in the WTCHP, he has been told by his health care team that he is at increased risk for cardiovascular disease, likely as a result of his time in lower Manhattan.

Hovitz Regal, meanwhile, is not a first responder. But her PTSD diagnosis, which stems from her experiences on 9/11 and the days and weeks that followed, has forced her to pay greater attention to her overall health in the years since. She is not a clinician but recommends that those who experience trauma seek out specialists with expertise in diagnosing and managing PTSD as a first step to ensuring they receive quality care.

“With PTSD, you have high levels of anxiety, and stress hormone levels spiking,” she said. “It affects your sleep and blood pressure, and so many other things. Unfortunately, I’m not surprised at the connection found in [World Trade Center-Heart] study at all. I’m not a doctor, but people I know who had many of the same experiences I had on 9/11 are having similar health problems to what I have had. I think we’ll all have to be vigilant, even as time goes on.”

Preliminary findings from WTC Health Program are the first to make the connection among workers at "Ground Zero."

Post-9/11 PTSD Among First Responders Linked With Increased Risk of Heart Disease, Stroke

The US Food and Drug Administration (FDA) approved the 

 formulation for diphtheria, tetanus, pertussis, and poliomyelitis (DTaP) in 2015 and Sanofi announced that the vaccine is now available on January 31, 2017. This new vaccine has the potential to resolve issues of under-vaccination for these troubling diseases.

In approving Diphtheria and Tetanus Toxoids and Acellular Pertussis Absorbed and Inactivated Poliovirus, or DTaP-IPV (Quadracel, Sanofi Pasteur), the FDA has cleared the way for a novel vaccine for children between 4 and 6 years of age that features a reduced dosing requirement.

The dosing schedule is notable because, according to a 2015 

 from the Centers for Disease Control and Prevention (CDC), there is a adherence issue with the currently available four-plus dose formulations for the DTaP vaccine, with vaccine coverage dropping 11% between the third and fourth doses. In addition, there was reported to be a 12% drop-off from the primary to full series of 

 type b (Hib). Overall, vaccine uptake for DTaP (84.6%) and Hib (82.7%) remains below the CDC’s target threshold of 90%, the report found.

Although the CDC report concluded that “nationally, coverage with vaccines recommended… for children aged 19-35 months remains high and stable,” it highlighted significant disparities in uptake among children in rural areas and those living below the federal poverty level, identifying potential access issues associated with existing vaccines.

“Far too many children remain under-vaccinated against serious diseases like pertussis, polio and 

 type b disease,” David P. Greenberg, MD, Associate Vice President and Regional Medical Head North America, Sanofi Pasteur said in a 

. “We are committed to helping protect more children by making vaccination as easy and convenient as possible for parents and healthcare providers. The availability of [DTaP-IPV] is a step in this direction.”

With its sign-off, the FDA has cleared DTaP-IPV single-dose for use as a fifth dose in the DTaP series, and as a fourth or fifth dose in the inactivated poliovirus vaccination (IPV) series. Importantly, according to the company, DTaP-IPV can be used in children who have already started their immunization series with the four-dose vaccine, DTaP-IPV/Hib (Pentacel, Sanofi Pasteur), which was approved in 2008 for use in children between 6 weeks and 4 years of age, or the Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed (Daptacel, Sanofi Pasteur), which was approved last year for children between 6 weeks and 6 years of age. A Sanofi spokesperson told 

 that the novel formulation is designed to “save an extra shot and may help improve vaccination coverage for children through 6 years of age.”

Currently, to protect infants and children from life-threatening diseases, the CDC 

 children 4 through 6 years of age receive the fifth dose of the DTaP vaccine and the fourth dose of IPV vaccine. The new formulation, DTAP-IPV is designed to provide these two vaccines in a single shot.

The novel formulation carries a small risk for allergic reactions, which typically occur immediately after receiving the vaccine. Side effects include pain, redness, and swelling at the injection site as well as muscle pain, fatigue, and headache.

The FDA approved a pediatric vaccine combo to prevent four illnesses.