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Researchers Use Whole Genome Sequencing to Make Surprising Discovery about Hospital-Acquired C. Diff Infections

By analyzing strains of the bacterium from a hospital ICU, the scientists learned that most infections were triggered within patients, not from cross-transmission

Tracking the source of Hospital-acquired infections (HAI) has long been centered around the assumption that most HAIs originate from cross-transmission within the hospital or healthcare setting. And prevention measures are costly for hospitals and medical laboratories. However, new research puts a surprising new angle on a different source for some proportion of these infections.

The study suggests that most infections caused by Clostridioides difficile (C. Diff), the bacterium most responsible for HAIs, arise not from cross-transmission in the hospital, but within patients who already carry the bacterium.

The research team, led by immunologist Evan Snitkin, PhD, and microbiologist Vincent Young, MD, PhD, both from the University of Michigan (UM), and epidemiologist Mary Hayden, MD, of Rush University Medical Center in Chicago, analyzed fecal samples from more than 1,100 patients in Rush Medical Center’s intensive care unit over a nine-month period.

A researcher performed whole genome sequencing on 425 strains of the bacterium isolated from the samples and found “very little evidence that the strains of C. diff from one patient to the next were the same, which would imply in-hospital acquisition,” according to a UM news story.

“In fact, there were only six genomically supported transmissions over the study period. Instead, people who were already colonized were at greater risk of transitioning to infection,” UM stated.

Arianna Miles-Jay, PhD, a postdoctoral fellow in The Snitkin Lab at the University of Michigan and Manager of the Genomic Analysis Unit at the Michigan Department of Health and Human Services, performed the genomic sequencing. “By systematically culturing every patient, we thought we could understand how transmission was happening. The surprise was that, based on the genomics, there was very little transmission,” she said in the UM news story.

The researchers published their findings in the journal Nature Medicine titled, “Longitudinal Genomic Surveillance of Carriage and Transmission of Clostridioides Difficile in an Intensive Care Unit.”

Evan Snitkin, PhD

“Something happened to these patients that we still don’t understand to trigger the transition from C. diff hanging out in the gut to the organism causing diarrhea and the other complications resulting from infection,” said Evan Snitkin, PhD (above), Associate Professor of Microbiology and Immunology, and Associate Professor of Internal Medicine, Division of Infectious Diseases at University of Michigan, in a UM news story. Medical laboratories involved in hospital-acquired infection prevention understand the importance of this research and its effect on patient safety. (Photo copyright: University of Michigan.)

Only a Fraction of HAIs Are Through Cross-Transmission

In the study abstract, the researchers wrote that “despite enhanced infection prevention efforts, Clostridioides difficile remains the leading cause of healthcare-associated infections in the United States.”

Citing data from the US Centers for Disease Control and Prevention (CDC), HealthDay reported that “nearly half a million C. diff infections occur in the United States each year. Between 13,000 and 16,000 people die from the bacterium, which causes watery diarrhea and inflammation of the colon. Many of these infections and deaths have been blamed on transmission between hospitalized patients.”

The new study, however, notes that 9.3% of the patients admitted to the ICU carried toxigenic (produces toxins) C. diff, but only 1% acquired it via cross-transmission. The carriers, the study authors wrote, “posed minimal risk to others,” but were 24 times more likely to develop a C. diff infection than non-carriers.

“Our findings suggest that measures in place in the ICU at the time of the study—high rates of compliance with hand hygiene among healthcare personnel, routine environmental disinfection with an agent active against C. diff, and single patient rooms —were effective in preventing C. diff transmission,” Snitkin told HealthDay. “This indicates that to make further progress in protecting patients from developing C. diff infections will require improving our understanding of the triggers that lead patients asymptomatically carrying C. diff to transition to having infections.”

Recognizing Risk Factors

Despite the finding that infections were largely triggered within the patients, the researchers still emphasized the importance of taking measures to prevent hospital-acquired infections.

“In fact, the measures in place in the Rush ICU at the time of the study—high rates of compliance with hand hygiene among healthcare personnel, routine environmental disinfection with an agent active against C. diff, and single patient rooms—were likely responsible for the low transmission rate,” the UM news story noted.

One expert not involved with the study suggested that hospitals’ use of antibiotics may be a factor in causing C. diff carriers to develop infections.

“These findings suggest that while we should continue our current infection prevention strategies, attention should also be given to identifying the individuals who are asymptomatic carriers and finding ways to reduce their risk of developing an infection, like carefully optimizing antibiotic usage and recognizing other risk factors,” Hannah Newman, Senior Director of Infection Prevention at Lenox Hill Hospital in New York City, told HealthDay.

Snitkin, however, told HealthDay that other factors are likely at play. “There is support for antibiotic disruption of the microbiota being one type of trigger event, but there is certainly more to it than that, as not every patient who carries C. diff and receives antibiotics will develop an infection.”

Another expert not involved with the study told HealthDay that “many patients are already colonized,” especially older ones or those who have been previously hospitalized.

“A lot of their normal flora in their GI tract can be altered either through surgery or antibiotics or some other mechanism, and then symptoms occur, and that’s when they are treated with antibiotics,” said Donna Armellino, RN, Senior VP of Infection Prevention at Northwell Health in Manhasset, New York.

Whatever is taking place, hospital-acquired infections kill thousands of people every years. It’s on the federal Centers for Medicare and Medicaid Services’ (CMS) “never event” list of hospital-acquired conditions (HOC) that should never happen to hospital patients. This affects reimbursement to hospitals for treatment of infections under Medicare’s Hospital-Acquired Condition Reduction Program

This research also demonstrates the value of faster, cheaper, more accurate gene sequencing for researching life-threatening conditions. Microbiologists, Clinical laboratory scientists, and pathologists will want monitor further developments involving these findings as researchers from University of Michigan and Rush University Medical Center continue to learn more about the source of C. diff infections.

—Stephen Beale

Related Information:

The Surprising Origin of a Deadly Hospital Infection

Patient-to-Patient Transmission Not to Blame for Most C. Difficile Infections in Hospitals

Longitudinal Genomic Surveillance of Carriage and Transmission of Clostridioides difficile in an Intensive Care Unit

Millions of COVID-19 At-Home Tests Set to Flood Market as HHS Asks 12 Test Manufacturers to Produce 200 Million Tests

Free at home clinical-laboratory testing for COVID-19 has been provided in the past, but this time the federal government wants to manufacture as many tests as possible in the US

Pathologists and clinical laboratory managers may be interested to learn that the US market is about to be flooded with millions of at-home COVID-19 rapid tests. The federal government has contracted with 12 US-based test manufacturers to produce 200 million at-home self-tests aimed at detecting “currently circulating COVID-19 variants” through the end of this year, according to a US Department of Health and Human Services (HHS) news release.

Through the Administration for Strategic Preparedness and Response (ASPR), HHS is investing $600 million to fund the self-tests, which are available for delivery through a reopening of the COVID.Gov/Test website.

Federal officials want to head off “supply chain issues” that developed in the past with reliance on tests made overseas, and to address a possible COVID-19 surge during the fall and winter, the Associated Press (AP) reported.

In fact, 500 million tests have already been distributed through US government channels to long-term care facilities, schools, and low-income senior housing.

Dawn O’Connell, JD

“Manufacturing COVID-19 tests in the United States strengthens our preparedness for the upcoming fall and winter seasons, reduces our reliance on other countries, and provides good jobs to hardworking Americans,” said Assistant Secretary for Preparedness and Response Dawn O’Connell, JD (above), in an HHS news release. “ASPR’s investments in these domestic manufacturers will increase availability of tests in the future.” With the federal government preparing for what it expects to be a surge in demand for COVID-19 testing, clinical laboratories may want to track the CDC’s weekly reports on the number of positive COVID-19 cases as this year’s influenza season progresses. (Photo copyright: Administration for Strategic Preparedness and Response.)

In Vitro Diagnostics Test Makers Get Government Gigs

This is not the first time federal officials sent out free COVID-19 tests to consumers. According to the AP, more than 755 million tests went out to US households in previous efforts to fight the spread of infections. But unlike those tests, these tests will be manufactured entirely within the US.

The government’s latest wave of free tests is meant to “complement ASPR’s ongoing distribution of free COVID-19 tests to long-term care facilities, low-income senior housing, uninsured individuals, and underserved communities, with 500 million tests provided to date through these channels,” the HHS news release noted.  

Both large and lesser-known in vitro diagnostics (IVD) manufacturers were selected by the federal government to receive funding. They include:

HHS advises people to take the test at the first sign of symptoms (fever, sore throat, runny nose, others), after coming into contact someone who has COVID-19, or prior to gathering with a group, as a preventative to spread of the coronavirus.

Tracking New BA.2.86 COVID Variant

Currently, the federal Centers for Disease Control and Prevention (CDC) is tracking BA.2.86 (aka, Pirola), a new SARS-CoV-2 variant.

According to CDC’s latest Respiratory Viruses Update:

  • Reporting laboratories say existing antibodies work against the BA.2.86 variant.
  • The variant does not appear to be linked in the US with increasing infections or hospitalizations.
  • It is “unclear how easily BA.2.86 spreads” relative to other variants.
  • BA.2.86 has been detected in nine states: Colorado, Delaware, Michigan, Ohio, Pennsylvania, Virginia, Washington, and in wastewater in New York and Ohio, as well as in other countries. 

For week ending Sept. 23, the CDC reported the following statistics compared to the prior week:

  • 19,079 COVID-19 hospitalizations, down 3.1%.
  • Total hospitalizations: 6.3 million.
  • 2.7% of total deaths were due to COVID-19, up 8%.
  • COVID-19 test positivity rate was 11.6%, down 1.1%.
  • 1.8% of emergency department visits were diagnosed with COVID-19, down 11.7%.

According to Verywell Health, BA.2.86 carries more than 30 mutations.  

“Even with a lot of mutations, there are a lot of spots in the virus that can be recognized by our immune system, and there are many shared mutations as well. There will be some protection from new vaccine booster as well as prior infections,” Rajendram Rajnarayanan, PhD, Assistant Dean of Research and Associate Professor, Basic Sciences, Arkansas State University, told Verywell Health.

During an online media briefing conducted by the World Health Organization (WHO), Maria Van Kerkhove, PhD, COVID-19 Technical Lead at WHO, said that the variant could be classified by WHO as a “variant of concern” in the event of widespread circulation. 

COVID-19, an Endemic Disease?

It’s worth noting that the common cold, influenza, SARS, and SARS-CoV-2 are all in the coronavirus family, and thus closely related with similar symptoms. It would not be a surprise that SARS-CoV-2 joins those other viruses as an endemic virus with a similar yearly cycle of infection rates.

If that happens, and no surge in infections appears that would motivate orders for the new COVID-19 at-home tests, the government may find itself with a lot of unused tests at the end of the year. The US Food and Drug Administration (FDA) is aware of this possibility and provides a website where people can check to see if their test has an extended expiration date.

Plus, folks who are tired of the pandemic may not respond at all to the government’s insistence to prepare for possible surges in infection rates.

“Whether or not people are done with it, we know the virus is there, we know that it’s circulating. We know, if past is prologue, it’ll circulate to a higher degree and spread, and cases will go up in the fall and winter seasons,” said Assistant Secretary for Preparedness and Response Dawn O’Connell, JD, in the HHS new release. “Anticipating that that would be true again, or something similar, we want to make sure the American people have these tools.”

Clinical laboratories may want to prepare as well. Many people are not comfortable with at-home self-testing and prefer to have their local medical labs perform the tests.

—Donna Marie Pocius

Related Information:

Biden-Harris Administration Awards $600 Million to Bolster US Manufacturing of COVID-19 Tests and Announces the Re-Opening of COVIDTests.gov

Biden Administration Announces $600 Million to Produce COVID-19 Tests and Will Reopen Website to Order Them

Free COVID Testing Will Fade with US Health Emergency in May

CDC’s COVID-19 Variant Update

CDC’s COVID-19 Data Tracker

Why B.2.86 Stands Out from Other COVID-19 Variants

US Works with Clinical Laboratories to Launch Several Large-Scale COVID-19 Serological Surveys to Track Undetected COVID-19 in the Nation’s Population

Though some experts claim widespread antibody testing is key to effective public health safety, the WHO warns positive serological tests may not indicate immunity from reinfection or transmission of SARS-CoV-2

It may be the largest program of clinical laboratory testing ever conducted in the United States. Health officials are preparing to undertake large-scale serological surveys (serosurveys) to detect and track previously undetected cases of SARS-CoV-2, the novel coronavirus, that causes the COVID-19 illness.

Microbiologists, epidemiologists, and medical laboratory leaders will be interested in these studies, which are aimed at determining how many adults in the US with no confirmed history of SARS-CoV-2 infection actually possess antibodies to the coronavirus.

Serological screening testing may also enable employers to identify employees who can safely return to their job. And researchers may be able to identify communities and populations that have been most affected by the virus.

Serological Study of COVID-19 Taking Place in Five States

In an interview with Science, Michael Busch, MD, PhD, Senior Vice President, Research and Scientific Affairs of Vitalant (formerly Blood Systems), one of the nation’s oldest and largest nonprofit community blood service providers, and Director of the Vitalant Research Institute, discussed several serological studies in which he is involved. The first study, which he said is being funded by the National Institutes of Health (NIH), is taking place in six metropolitan regions in the US: Seattle, New York City, San Francisco, Los Angeles, Boston, and Minneapolis.

The interesting twist in these studies is that they will test blood samples from people donating blood. In March, participating blood centers in each region started saving 1,000 donor samples per month. Six thousand samples will be assessed monthly for a six-month period using an antibody testing algorithm that enables researchers to monitor how people develop SARS-CoV-2 antibodies over time.

Busch told Science this regional study will evolve into three “national, fully representative serosurveys of the US population using blood donors.” This particular national serosurvey will study 50,000 donations in September and December of 2020 and in November 2021.

“We’re going to be estimating overall antibody prevalence to SARS-CoV-2 within each state, but also map it down within the states to regions and metropolitan urban areas, and look at the differences,” Busch told Science, which called the serosurvey “unprecedented.”

“It’s certainly the largest serosurvey I’ve ever been involved with,” Busch said.

Serological versus PCR Testing for COVID-19

Unlike polymerase-chain-reaction (PCR)-based COVID-19 diagnostic testing, which uses nasopharyngeal swabs to detect the presence of viral RNA, serological testing such as LabCorp’s 164055 IgG test looks for the presence of SARS-CoV-2 antibodies in blood samples. A positive test indicates a previous infection.

In the third NIH serosurvey, according to Busch, NIH blood-donor serosurveys will be compared with results from population serosurveys taking place through the University of Washington and University of California San Francisco, which involve neighborhood door knocking and sampling from hematology labs.

“An antibody test is looking back into the immune system’s history with a rearview mirror,” said Matthew J. Memoli, MD (above,) an infection disease specialist with the NIH and Director of the National Institute of Allergy and Infectious Diseases (NIAID), in a news release. “By analyzing an individual’s blood, we can determine if that person has encountered SARS-CoV-2 previously.” (Photo copyright: National Institutes of Health.)

Some of the SARS-CoV-2 serological surveys underway include:

  • The National Institutes of Health serosurvey involving as many as 10,000 adults in the US who have no confirmed history of infection with SARS-CoV-2, which will analyze blood samples for two types of antibodies—anti-SARS-CoV-2 protein IgG and IgM. Researchers also may perform additional tests to evaluate volunteers’ immune responses to the virus.
  • A World Health Organization (WHO) coordinated follow-up study to its Solidarity Trial named Solidarity 2, which will “pool data from research groups in different countries to compare rates of infection,” which WHO officials say is ‘critical’ to understanding the true extent of the pandemic and to inform policy, Research Professionals News reported.
  • In Germany, the Robert Koch Institute, the country’s disease control and prevention agency, is tackling Europe’s first large-scale COVID-19 antibody testing. Its three-phase study will include serological testing on blood from donation centers, followed by testing on blood samples from coronavirus regional hotspots and then the country’s broader population.

But Can Serological Testing Prove Immunity to COVID-19?

Dark Daily previously reported on the critical role serology testing played in Singapore to help officials use contact tracing to identify people involved in COVID-19 outbreaks. (See, “Asian Cities, Countries Stand Out in the World’s Fight Against COVID-19, US Clinical Laboratory Testing in the Spotlight,” March 30, 2020.)

However, whether having COVID-19 antibodies will make people immune to reinfection or unable to spread the disease is not yet known.

“We don’t have nearly the immunological or biological data at this point to say that if someone has a strong enough immune response that they are protected from symptoms, … that they cannot be transmitters,” Michael Mina, MD, PhD, Assistant Professor of Epidemiology at Harvard’s T.H. Chan School of Public Health and Associate Medical Director in Clinical Microbiology (molecular diagnostics) in the Department of Pathology at Brigham and Women’s Hospital, told STAT.

The Times of Sweden reported the WHO warned in mid-April that there is no proof recovering from COVID-19 provides immunity.

“There are a lot of countries that are suggesting using rapid diagnostic serological tests to be able to capture what they think will be a measure of immunity,” said Maria Van Kerkhove, PhD, the WHO’s Technical Lead for COVID-19, at a news conference in Geneva, Switzerland, the Times of Sweden reported.

“Right now, we have no evidence that the use of a serological test can show that an individual has immunity or is protected from reinfection,” she said, adding, “These antibody tests will be able to measure that level of seroprevalence—that level of antibodies—but that does not mean that somebody with antibodies [is] immune.”

In addition, the reliability and quality of some serological tests produced in China, as well as some being manufactured in the US, have come into question, the Financial Times reported.

Nevertheless, as serological testing for COVID-19 becomes more widespread, clinical laboratories should plan to play an ever-increasing role in the battle to stop a second wave of the epidemic in this country.

—Andrea Downing Peck

Related Information:

Unprecedented Nationwide Blood Studies Seek to Track U.S. Coronavirus Spread

WHO Marshalls Global Study of Coronavirus Infection

Population-based Age-stratified Seroepidemiological Investigation Protocol for COVID-19 Virus Investigation

How Many People Are Immune to the New Corona Virus? Robert Koch Institute Starts Nationwide Antibody Studies

Everything We Know About Coronavirus Immunity and Antibodies–and Plenty We Still Don’t

The WHO Warns ‘No Evidence’ of Immunity to Corona Virus for Recovered Patients

Quest for Accurate Antibody Tests in Fight Against COVID-19

Asian Cities, Countries Stand Out in the World’s Fight Against COVID-19, US Clinical Laboratory Testing in the Spotlight

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