Journal scan: A review of 10 recent papers of immediate clinical significance, harvested from major international journals

(1). Editorial. A sporting chance: physical activity as part of everyday life. Lancet 2021;398(10298):P365

Ahead of the 2020 Tokyo Olympics and Paralympics, The Lancet launched its third Series on physical activity (previous Series-2012 and 2016) on the importance of regular physical activity and sport to our health and wellbeing.

In the past decade, not enough progress has been made to improve physical activity worldwide, with adolescents and people living with disabilities (PLWD) among the least likely populations to have the support needed to meet WHO’s physical activity guidelines.

Physical inactivity is linked to an increased risk of non-communicable diseases (NCDs) such as heart disease, diabetes, and some cancers. But the health benefits also include improvements in mental health, dementia and cognitive function, sleep, preventing falls, and fall-related injuries.

Increasingly recognized are the co-benefits of physical activity promotion such as improved air quality and climate mitigation.

The COVID-19 pandemic has a reciprocal relationship with physical activity. Lockdowns and restrictions are likely to have decreased physical activity levels, whilst people who are physically active are less likely to experience severe symptoms and hospitalizations from COVID-19.

The authors call for urgent efforts to improve physical activity levels in key populations, and recognize the potential to incorporate population health initiatives into future mass sporting events such as the Olympics.

(2). Chu VT et al. Household transmission of SARS-CoV-2 from children and adolescents. N Engl J Med. 2021;21; NEJMc2031915

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children is often asymptomatic or results in only mild disease. Data on the extent of transmission of SARS-CoV-2 from children and adolescents in the household setting, including transmission to older persons who are at increased risk for severe disease, are limited.

After an outbreak of coronavirus disease 2019 (COVID-19) at an overnight camp, we conducted a retrospective cohort study involving camp attendees and their household contacts to assess secondary transmission and factors associated with household transmission.

We interviewed 224 index patients who were 7 to 19 years of age and for whom there was evidence of SARS-CoV-2 infection on the basis of molecular or antigen laboratory testing. A total of 198 of these campers (88%) were symptomatic; symptoms developed in 141 of these 198 children or adolescents (71%) after they returned home from camp.

Of 526 household contacts of these index patients, 377 (72%) were tested for SARS-CoV-2, and 46 (12%) of those who were tested had positive results. An additional two secondary cases of infection were identified according to clinical and epidemiologic criteria. A total of 38 of the 48 secondary cases (79%) occurred in households where the index patient had become symptomatic after returning home from camp; the median serial interval (i.e., the interval between the onset of symptoms in the index patient and the onset of symptoms in the household contacts infected by that patient) was five days (95% confidence interval [CI], 4.0 to 6.5). Transmission occurred in 35 of 194 households (18%); in these households, the secondary attack rate was 45% (95% CI, 36 to 54) (48 of 107 households). Among the household contacts who became infected and who were at least 18 years of age, 4 of 41 (10%) were hospitalized (length of hospital stay, 5 to 11 days); none of the seven persons with a secondary case of infection who were younger than 18 years were hospitalized.

Of the index patients who responded to our question regarding preventive measures, 146 of 217 (67%) reported that they had maintained physical distancing and 73 of 216 (34%) reported that they had always worn masks around contacts during the infectious period after they returned home. In a univariable logistic-regression model, among the index patients who were 18 years of age or younger, the increasing use of physical distancing and masks was associated with the older age of the patient (with age as a continuous variable, odds ratio for physical distancing, 1.4; 95% CI, 1.2 to 1.5; odds ratio for mask use, 1.4; 95% CI, 1.2 to 1.6). In a multivariable regression model, the risk of a secondary case of infection among household contacts was lower among contacts of index patients who had practiced physical distancing than among contacts of index patients who did not (adjusted odds ratio, 0.4; 95% CI, 0.1 to 0.9). Household members who had close or direct contact with the index patient had a higher risk of infection than those who had minimal to no contact (adjusted odds ratio with close contact, 5.2; 95% CI, 1.2 to 22.5; and adjusted odds ratio with direct contact, 5.8; 95% CI, 1.8 to 18.8). We excluded missing data from the regression models, and confidence intervals were not adjusted for multiplicity.

This retrospective study showed that the efficient transmission of SARS-CoV-2 from school-age children and adolescents to household members led to the hospitalization of adults with secondary cases of COVID-19.

In households in which transmission occurred, half the household contacts were infected. The secondary attack rates in this study were probably underestimates because test results were reported by the patients themselves and testing was voluntary. In addition, a third of the index patients returned home from camp after the onset of symptoms, when they were presumably not as infectious as they were before and during the onset of symptoms, and two thirds adopted physical distancing because of a known exposure at camp; both of these factors probably reduced the transmission of SARS-CoV-2 in the household.

When feasible, children and adolescents with a known exposure to SARS-CoV-2 or a diagnosis of COVID-19 should remain at home and maintain physical distance from household members.

(3). Rapeport G et al. SARS-CoV-2 human challenge studies – establishing the model during an evolving pandemic. 2021.

July 21, 2021, DOI: 10.1056/NEJMp2106970

Human challenge studies (also called controlled human infection models), in which researchers intentionally administer an infectious agent to volunteers, have played major roles in vaccine and treatment development and in elucidation of pathogenesis and immunity. Such studies are not normally undertaken during a pandemic, however, and the potential risks and benefits of such research with SARS-CoV-2 in this setting have triggered widespread debate. While other commentators have made theoretical arguments for and against SARS-CoV-2 challenge studies, a consortium of academics, industry collaborators, and the British government (through the Human Challenge Programme of the UK Vaccines Taskforce) has now proceeded to address the technical and ethical considerations to enable such studies. The consortium’s practical application of ethical principles against a backdrop of rapidly emerging evidence carries lessons for future outbreaks.

In early 2020, the World Health Organization established working and advisory groups to consider the rationale and ethical criteria for such studies and to issue practical recommendations, although feasibility was initially uncertain. However, accruing clinical data revealed that COVID-19 was mostly mild or asymptomatic and self-limiting in young people (18 to 30 years of age) without preexisting health conditions. This observation supported the decision to advance development of human challenge studies.

After extensive engagement of the public and prospective participants, establishment of a high-containment quarantine facility at the Royal Free London NHS Foundation Trust, manufacture of a challenge virus under Good Manufacturing Practice conditions, and multiple rounds of expert review, a study protocol was submitted for evaluation by the Specialist Ad Hoc Research Ethics Committee convened by the NHS Health Research Authority. This independent review process, undertaken from December 2020 through February 2021 for a study in seronegative participants and immediately afterward for one in previously infected volunteers, scrutinized the ethics of both these individual studies and the entire human challenge program, including issues raised by the evolving pandemic. Two key considerations emerged: the justification for such research and the management and minimization of risks.

Scientific rationale and capabilities for SARS-CoV-2 human challenge studies

Back when neither effective vaccines nor treatments were available for COVID-19, the potential scientific value of human challenge studies was evident. The approval of several highly efficacious vaccines and the emergence of variants of concern (VOCs), however, raised questions about whether such studies were still needed and justifiable. Human challenge studies have features that cannot be replicated in natural infection studies. By eliminating confounders such as different viral strains and infectious doses, uncertain timing of exposure, and patient heterogeneity, investigators can identify protective host factors and immediate responses early during infection. By generating reliably high infection rates and permitting fine control of timing, challenge studies enable rapid direct comparisons of new vaccine candidates, revised regimens, and prophylactic, preemptive, or post symptomatic treatments.

The rollout of first-generation vaccines necessitated reappraisal of what role human challenge studies may still have in the pandemic response. Although speedy phase 3 vaccine efficacy trials were possible initially, dozens of vaccine candidates in earlier stages of clinical development now face uncertainty. With extensive public health measures and increasing vaccination, the feasibility of timely field efficacy trials is now unpredictable, and soon such trials may be impossible. Maintaining an unvaccinated placebo group is ethically questionable, and noninferiority trial designs require even more participants.

With uneven vaccine access, however, approvals of new vaccines and antivirals still need to be prioritized – and some as-yet-unlicensed vaccines (including inhaled and needle-free approaches) may offer major advantages. For new vaccines and antivirals, licensure based on immunogenicity or viral kinetics alone may be impossible, but human challenge studies could contribute efficacy data to complement larger-scale safety trials. This argument will become even stronger when challenge agents based on antigenically diverse VOCs are manufactured, allowing testing of cross-strain protection. Discussions are therefore ongoing with medicine regulators to establish the acceptability of this approach.

For human challenge studies to be acceptable, research risks must be appropriately managed and minimized. Development of SARS-CoV-2 challenge studies could not rely on extrapolation from existing respiratory virus challenge models. Instead, protocol-design decisions were based on emerging evidence; where data were incomplete, the most conservative approaches were taken. The critical component in determining study feasibility was estimating potential individual risk and identifying a sufficiently low-risk participant group. Data from early outbreaks in China indicated that asymptomatic and mild infection were common in young people, but the most relevant estimates of risk in our target population came from real-time access to UK data on clinical outcomes in previously healthy young adults infected in the community. These data suggested that careful volunteer selection, based primarily on younger age and absence of underlying health conditions, could render the model safe.

As an extra precaution, we used the QCOVID algorithm to estimate individual absolute risk for hospitalization or death, taking into account all relevant underlying factors. We could thus set a cautious inclusion threshold (equivalent to that for a 30-year-old with no risk factors, calculated as a 1:250,000 risk of death or 1:4902 risk of hospitalization) and provide individualized risk assessments for participants as part of informed consent. Since QCOVID is based on population data, the risk of exposure cannot be disaggregated from the risk of severe outcomes, but we believe that the resulting potential for overestimating risk in certain groups is appropriately cautious for early model development, when the challenge infection’s features are unknown. Using this risk score as an entry criterion may limit participant diversity, however, so once the model has proven safe, the score should be used only for participant information.

Although data on the relationship between inoculum size and disease severity are limited, it was logical to assume that higher doses might increase risk. Given the pathogenicity of SARS-CoV-2, it was ethically essential to start with the lowest possible amounts of inoculum, followed by careful dose escalation. In addition, to minimize the risk of severe COVID-19, virologic readouts rather than disease end points were targeted.

Some commentators argue that the lack of a guaranteed “rescue” treatment makes challenge studies problematic. Since the principal risk mitigation is participant selection, this gap should not be an absolute barrier. Furthermore, existing interventions (such as monoclonal antibodies) can significantly reduce the likelihood of progression of asymptomatic or mild COVID-19 to more severe disease. No drugs have undergone trials in early, presymptomatic SARS-CoV-2 infection, but to further reduce risk, we included safe, well-tolerated antivirals as preemptive therapy to be given early after the confirmation of infection. Though efficacy in this setting was uncertain, caution argued for antiviral use in case evidence-based assumptions about disease severity proved inaccurate. This approach was designed to be responsive to new data, however, and discontinuation of automatic preemptive treatment of infected participants, once the model was shown to be safe and well-tolerated, was embedded in the protocol to avoid confounding by treatment.

Still, some risks remain. The greatest unknowns relate to “long COVID” (i.e., late complications or protracted disease). Although cases have been reported, data from the U.K. Office for National Statistics and the COVID Symptom Study provided reassuring evidence implying that persistent symptoms beyond three months were rare in young adults after mild disease. Nevertheless, careful follow-up, specialist referral, and compensation to cover inability to work are important components of the study design. To ensure that the existence of risks that are less well quantified is understood, the study’s informed consent process balances participant understanding with comprehensive detail, reiterating at multiple points key facts about potential consequences and the right to withdraw from the research even after inoculation.

Although the scientific justifications for such research remain unchanged despite pandemic surges, limitations in clinical capacity can affect the conduct of challenge studies, which requires access to specialist support in the rare event that a participant needs higher-level care. Investigators should consider this possibility in advance to avoid allowing the study’s operational needs to negatively affect another patients’ treatment. Collaboration with government and the NHS has assisted in prioritizing limited resources and determining optimal timing. Implementing challenge studies during a pandemic wave might also affect public health messaging when social distancing and lockdown measures are being emphasized. This potential conflict highlights the importance of ongoing public engagement.

Our experience thus far indicates that a SARS-CoV-2 human challenge research program can be developed as part of the pandemic response. Its establishment has relied on broad collaboration (established before the pandemic through the Human Infection Challenge Network for Vaccine Development) that provided the varied expertise, broad consensus, and funding required. This approach accelerated both challenge-virus manufacture and the ethics review process, ensuring that study design was informed by real-time scientific data. With SARS-CoV-2 continuing to cause major outbreaks globally and improved vaccination and treatment still necessary, the ethical arguments for human challenge studies remain compelling, despite the changing nature of the pandemic.

(4). Thompson MG et al. Prevention and attenuation of COVID-19 with the BNT162b2 and mRNA-1273 vaccines in health care personnel. N Engl J Med. 2021; 385:320-329.

Background

Information is limited regarding the effectiveness of the two-dose messenger RNA (mRNA) vaccines BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) in preventing infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and in attenuating coronavirus disease 2019 (COVID-19) when administered in real-world conditions.

Methods

We conducted a prospective cohort study involving 3975 health care personnel, first responders, and other essential and frontline workers. From December 14, 2020, to April 10, 2021, the participants completed weekly SARS-CoV-2 testing by providing mid-turbinate nasal swabs for qualitative and quantitative reverse-transcriptase-polymerase-chain-reaction (RT-PCR) analysis. The formula for calculating vaccine effectiveness was 100% × (1−hazard ratio for SARS-CoV-2 infection in vaccinated vs unvaccinated participants), with adjustments for the propensity to be vaccinated, study site, occupation, and local viral circulation.

Results

SARS-CoV-2 was detected in 204 participants (5%), of whom five were fully vaccinated (≥ 14 days after dose 2), 11 partially vaccinated (≥ 14 days after dose 1 and < 14 days after dose 2), and 156 unvaccinated; the 32 participants with indeterminate vaccination status (< 14 days after dose 1) were excluded. Adjusted vaccine effectiveness was 91% (95% confidence interval [CI], 76 to 97) with full vaccination and 81% (95% CI, 64 to 90) with partial vaccination. Among participants with SARS-CoV-2 infection, the mean viral RNA load was 40% lower (95% CI, 16 to 57) in partially or fully vaccinated participants than in unvaccinated participants. In addition, the risk of febrile symptoms was 58% lower (relative risk, 0.42; 95% CI, 0.18 to 0.98) and the duration of illness was shorter, with 2.3 fewer days spent sick in bed (95% CI, 0.8 to 3.7).

Conclusions

Authorized mRNA vaccines were highly effective among working-age adults in preventing SARS-CoV-2 infection when administered in real-world conditions, and the vaccines attenuated the viral RNA load, risk of febrile symptoms, and duration of illness among those who had breakthrough infection despite vaccination.

(5). Mahase E. COVID-19: Longer interval between Pfizer doses results in higher antibody levels, research finds. BMJ 2021;374: n1875

An interval of at least six weeks between the two doses of the Pfizer-BioNTech COVID-19 vaccine increased concentrations of neutralising antibodies, research funded by the Department of Health and Social Care for England has found.

The preprint, released on 23 July, looked at immune responses in 503 healthcare workers who had received the Pfizer vaccine. It found that, after the second vaccine dose, neutralising antibody concentrations were higher after an interval of 6-14 weeks than after the 3-4-week regimen that was initially recommended.

When looking at the delta variant, researchers also noted that, though there were good levels of antibodies after the shorter dosing interval, levels were 2.3-fold higher with the longer dosing interval.

The researchers said the findings “indicate that extension of the dosing interval is an effective, immunogenic protocol.”

The UK extended the dosing interval for COVID-19 vaccines as part of its decision to accelerate population coverage with a single dose. At the time, evidence indicated that the Oxford-AstraZeneca vaccine was more effective with a longer dosing interval but the effect was less clear with the Pfizer vaccine.

Speaking at a Science Media Centre briefing, study joint chief investigator Susanna Duanchie, from the University of Oxford, said that an eight-week interval was the “sweet spot.” But she added that the Pfizer vaccine was “very good at inducing immune responses no matter what regimen you get. So both the short and the long dosing regimen give a good response of both antibodies and T cells.”

The Protective Immunity from T cells to COVID-19 in Health workers (PITCH) study, which is being carried out across five UK universities and NHS trusts, in collaboration with Public Health England, also found that four weeks after the first dose of vaccine there was a “marked decline in SARS-CoV-2 neutralizing antibody levels, but, in contrast, a sustained T cell response to spike protein.”

Duanchie said, “After the first dose, if you’re on the long dosing interval, you’re neutralising antibodies do wane over the 10 weeks while you’re waiting for the second dose, particularly to the delta virus, but the T cell response is well maintained.

“Comparing the long and the short dosing interval, we saw that neutralising antibodies were about twofold higher after the second vaccine-the longer dosing interval gave slightly lower T cells when we look at those effector killer cells compared with the short regimen. But when we look in more depth at the character of the T cells, we find that the long dosing interval gives rise to T cells which are more typical of helper T cells and long-term memory T cells that promote memory and generation of antibodies.”

(6). Ken Wu. Clinical decisions: elective surgery during the COVID-19 pandemic. N Engl J Med. 2020; 383:1787-1790

A Committee Deciding Policy on Elective Surgery during the COVID-19 Pandemic

Clinical scenario

You are a physician leader on a senior committee that is responsible for your hospital’s COVID-19 response. For the past week, the hospital census has been over 90% of capacity, and almost all usual intensive care unit (ICU) beds have been occupied, more than half with patients who have COVID-19. You are using 10% of the ICU surge capacity created by your hospital to accommodate patients with COVID-19. The hospital has limited personal protective equipment (PPE) available, although supplies are adequate for current use. The 7-day average for daily new cases of COVID-19 in your region is 30 cases per 100,000 people; the rate is rising but has fluctuated for the past week. Hospitals in neighboring regions have similar capacities and limited availability to accept transfers of patients with COVID-19 from other hospitals. The local government has mandated that people wear face masks in public, but there is no stay-at-home order.

Your committee must decide whether elective surgical procedures should be deferred. In determining your recommendation to the committee, you will have to consider the effect that deferring these procedures will have on hospital revenue, as well as the potential negative health consequences to patients whose surgery will be delayed; however, you must also consider the effect that proceeding with these surgeries will have on bed capacity, staffing (since physicians and nurses may need to be redeployed if COVID-19 cases continue to rise), the limited supplies of PPE, and patients’ risk of contracting or transmitting COVID-19 while they are in the hospital for the elective procedure.

Treatment Options

Which one of the following approaches would you take? Base your choice on the published literature, your own experience, published guidelines, and other information sources.

To aid in your decision making, each of these approaches is defended in a short essay by an expert in the field. Given your knowledge of the issue and the points made by the experts, which approach would you choose?

Option 1: Continue to schedule elective surgical procedures

Smith CR. From the Department of Surgery, Columbia University Irving Medical Center, New York.

In the scenario described in the vignette, it is perfectly reasonable to continue scheduling elective surgical procedures. The vignette states that the rate of new COVID-19 cases is 30 cases per day per 100,000 people, expressed as a 7-day average. This describes the situation in many regions in the United States, except New York City at its peak in April 2020, when the rate was more than twice as high. The description of the 7-day average for daily new cases as “fluctuating” for the past week implies a slowing of the rate of increase in new cases, even if the number of cases is still rising. The effect of these new cases on hospital resources depends on the population the hospital serves and on regional factors, such as population density and the macroenvironment, which in this scenario is not locked down. A high rate of new cases is also less worrisome for a hospital that is large for its regional population, as might be the case for a tertiary referral center. The hospital in this scenario has been dealing with the COVID-19 pandemic long enough to have built substantial surge capacity, which suggests that the rate of new cases is several weeks mature and close to a manageable plateau. As a point of reference, New York-Presbyterian Hospital required almost 3 weeks to create substantial surge capacity. The vignette specifies that the burden of the pandemic to date has filled only half the hospital’s existing ICU beds with patients who are positive for COVID-19, and 90% of the surge capacity remains unused. Supplies of PPE are said to be limited, but that is a universal truth, and they have been declared adequate for current use in this scenario. In addition, bed capacity and supply of PPE are easily monitored. For persons with nonacute elective cases, such as those defined as low-acuity by the Elective Surgery Acuity Scale (ESAS) used by the American College of Surgeons, the risk of nosocomial coronavirus infection is important to consider. Columbia University Irving Medical Center of the New York-Presbyterian Hospital studied the incidence of nosocomial COVID-19 infection from March 1 through April 27, 2020, in two patient-care units restricted to COVID-19-negative patients (a cardiothoracic ICU and a regular floor unit). Health care-associated transmission and infection with SARS-CoV-2 occurred in 0 to 2% of 311 patients. The units studied were surrounded by units – adjacent, above, and below – filled with COVID-19-positive patients. The study period also encompassed the worst of the COVID-19 surge and plateau in New York City, and mitigation of infection was seriously compromised, at least in March, by shortages of PPE. Despite these factors, the risk of nosocomial infection was found to be notably low. Finally, continuing or resuming the scheduling of elective surgical procedures in this scenario is reasonable because canceling them later, if necessary, poses little difficulty. Whereas cancellation of emergency surgery may cause patients harm, an abrupt change of course causing cancellation of elective procedures imposes inconvenience but no serious risk to patients. Most patients undergoing elective surgical procedures do not need ICU beds and intensive nursing support, and the rapid turnover of elective surgery cases also minimizes the extra pressure on resources. Nevertheless, daily monitoring of all relevant factors is essential if any type of surgery is allowed to continue. In addition to new case rates and the associated burden on the hospital and ICU, hospital staffing is another weak link. We can’t assume that staff can be driven through elective schedules the way they drove themselves through an extraordinary crisis.

Option 2: Defer all elective surgical procedures

Lembcke BT. From Baylor St. Luke’s Medical Center, Houston, and Catholic Health Initiatives Texas Division

Throughout the COVID-19 pandemic, professional societies and national organizations in the United States have offered guidance related to elective procedures, initially calling for their cancellation and later issuing guidance for their resumption. In addition, the Centers for Disease Control and Prevention (CDC) has offered guidance on optimizing the use of personal protective equipment (PPE) on the basis of anticipated inventory and demand. The CDC also offers strong guidance to the public about ways to protect against COVID-19 and to health care providers about ways to safely care for patients who do not have COVID-19 and prevent the further spread of the disease. When applied to this case scenario, these guidelines support the decision to defer elective surgeries.

First, let’s define elective procedures. The American College of Surgeons (ACS) supports the use of the ESAS, which defines low- and intermediate-acuity procedures as those that can be safely delayed without substantial risk to the patient. High-acuity cases should not be postponed. If we assume that the elective procedures in this case scenario are of low or intermediate acuity according to the ESAS, guidance provided by the ACS supports deferring them as long as the assessment is in alignment with clinical judgment.

Next, we should recognize that elective procedures involve the use of a substantial amount of PPE, as well as hospital resources such as beds and staff, and increase the risk of exposure for other patients and staff. In the vignette, PPE is described as limited and cases in the community are rising. The hospital is nearing total capacity, especially in the ICU, and surge capacity is already being utilized. The guidelines mentioned above, when applied to factors such as PPE, case counts, hospital and staff capacity, and patient and staff exposures, help inform the decision to defer elective surgeries.

Deferring elective procedures will ensure that our frontline providers have adequate PPE, since supplies are limited. We anticipate shortages of this equipment as cases of COVID-19 continue to rise. To conserve PPE, we should follow the CDC contingency capacity guidelines, which call for the cancellation of elective cases. The American College of Surgeons, American Society of Anesthesiologists, Association of periOperative Registered Nurses, and American Hospital Association call for a sustained reduction in cases for 14 days before resumption of elective surgeries. In the vignette, the community case counts are described as still rising. The hospital is near capacity and anticipates further demands. Ensuring adequate bed capacity is another reason that CDC guidelines call for deferral of elective procedures. With the prevalence of COVID-19 rising, we should minimize the risk of exposure for patients and staff. We need to emphasize safe behaviors, which include adhering to disciplined social distancing and minimizing the need for in-person services. Deferring elective procedures protects both patients and staff from unnecessary exposure to COVID-19 and risk of illness.

We must be able to care for the urgent needs of our community and provide adequate resources to our health care providers before scheduling procedures that can be safely delayed. This means ensuring adequate PPE, adequate staffing, and adequate beds. It also means minimizing unnecessary risks of exposure. Deferring elective surgeries will increase the likelihood that we can meet those demands while keeping our patients, staff, and communities safe.

Option 3: Proceed with Scheduled Elective Surgical Procedures but Defer New Cases

Ferreira TBD. From the Division of Pulmonary, Critical Care Medicine, and Sleep Medicine, Department of Medicine, University of Miami Miller School of Medicine, Miami

In March 2020, the American College of Surgeons recommended the cancellation of elective surgical procedures to ensure the availability of beds for patients with COVID-19, conserve PPE, and allow staff reallocation. Since then, the adverse outcomes in patients whose care was deferred and the financial implications for hospitals have become evident. As many institutions prepared to resume elective procedures in May 2020, a second COVID-19 surge occurred in the United States, affecting various regions differently. Institutions now face the burden of deciding how to proceed with surgical procedures in the absence of a unified national public health policy to mandate mask use and social distancing and with a poorly designed contact-tracing program.

The vignette describes a hospital at 90% capacity, with high occupancy in the ICU, in a community with 30 new COVID-19 cases per 100,000 people per day. As of August 27, cumulative data from the CDC show that there were 1769 cases of COVID-19 per 100,000 people, with a hospitalization rate of 156.8 per 100,000 people, which implies that 8.9% of cases result in hospitalization. Although these are national data, institutions can use their regional COVID-19 data as a basic model for the expected effect on their hospitals. Calculations that use data from the CDC show that for the hospital in the vignette, 2.61 cases per day will result in hospitalization. Guidelines from the European Society of Intensive Care Medicine recommend planning for 20% of hospitalized adult patients with COVID-19 to be admitted to the ICU, with an average stay of seven days. Therefore, assuming that 0.52 patients per day will need ICU care for seven days, this hospital will typically need 3.64 (0.52 new patients per day times seven days) ICU beds each day for patients with COVID-19 per 100,000 population. Data from 2009 show that there were 34.7 ICU beds per 100,000 U.S. population, albeit with considerable regional variability.

Postponing elective surgeries that have already been scheduled could result in considerably worse outcomes for the community. Hospitals have a duty to their communities, trainees, and employees in addition to their responsibility to the patients. Establishing a new normal that is clinically appropriate and fiscally responsible also allows hospitals to maintain financial viability. This “two-in-one” health system – one for COVID-19 and one for non-COVID-19 – that was developed during the surge should remain for the duration of the pandemic. New elective surgeries should be considered only when the rates of new cases of COVID-19 flatten and decline.

For elective procedures that have already been scheduled, priority should be given to cases for which a short length of stay is anticipated, cases that have same-day discharges, or time-sensitive surgeries in which patients are likely to have adverse outcomes from further delays. Scheduling surgeries at atypical times (e.g., on weekends) and expediting throughput and efficiency (e.g., using a dedicated discharge team) are critical to maintaining adequate operating room and ICU capacity. Since the number of admissions may fluctuate, models that can predict the number of admissions for COVID-19 and non-COVID-19 illness and can anticipate use of PPE are essential to the strategy.

At my institution in Miami, we test all patients with a reverse-transcriptase-polymerase-chain-reaction assay for COVID-19 on admission and separate patients into COVID-19 and non-COVID-19 floors. All wards are capable of generating negative room pressure, as recommended by the CDC in their guidelines for health care personnel on COVID-19 infection prevention and control. This ensures flexibility between medical-surgical and ICU use for each unit. The surgical schedule is modified according to models that predict the number of new patients with COVID-19 who require admission. The COVID-19 surge described in the vignette is more favorable than the situation we faced in Miami in June and July 2020.

Continuing scheduled elective surgeries but deferring new cases achieves the core goal of health care institutions – providing high quality, safe care to all patients regardless of their COVID-19 status. Achieving this goal requires a well-designed, comprehensive surge plan and a reliable model to predict demand and supply.

Poll: Which option would you choose?

Continue to schedule elective surgical procedures.33%

Defer all elective surgical procedures.25%

Proceed with scheduled elective surgical procedures but defer new cases.41

(7). Kadire SR et al. Doctor, how long should I isolate? N Engl J Med. 2021;384: e47

Case Vignette

A Woman with COVID-19

A 24-year-old woman with no relevant medical history presented to the emergency department with a 1-week history of cough and shortness of breath. She stated that she had not had any contact with people who were sick but had recently attended a small event. She reported no fever, diarrhea, or loss of taste or smell. On physical examination, she was found to have hypoxemia, with an oxygen saturation of 88%, and crackles were heard on lung auscultation. A chest radiograph showed bilateral interstitial opacities, and a polymerase-chain-reaction (PCR) assay was positive for SARS-CoV-2. She was given supplemental oxygen, delivered by nasal cannula at 2 L per min, and was placed in an isolation observation unit overnight for monitoring.

The next day, she continued to require oxygen and was admitted to a ward bed. Her oxygen requirements increased, and she was given supplemental oxygen at a rate of 15 L per min through a nonrebreather mask and was admitted to the intensive care unit (ICU). Her condition improved over the course of the week, and her need for supplemental oxygen decreased. The remainder of her course was uneventful, and she was transferred back to a ward bed.

It has now been one week since her admission to the hospital, and discharge planning has started. The patient plans to go home to stay with her parents, both of whom are over the age of 65 years, while she recuperates. She is concerned about the risk of transmission of SARS-CoV-2 to her parents. Her father is taking immunosuppressive medication after recent kidney transplantation. She has requested that PCR testing be performed again on a repeat nasopharyngeal swab. The PCR test is performed, and the result is positive.

You must advise the patient about the risk of transmitting the virus to her parents, given the time since the onset of COVID-19 symptoms and the positive repeat PCR test.

Treatment options

Which one of the following approaches would you take? Base your choice on the literature, your own experience, published guidelines, and other information sources.

• Recommend continued isolation.
• Reassure the patient of the low risk of transmission.

To aid in your decision making, each of these approaches is defended in a short essay by an expert in the field. Given your knowledge of the issue and the points made by the experts, which approach would you choose?

1. Recommend continued isolation

Fabre V. Johns Hopkins University School of Medicine, Baltimore

Recommendations on the duration of isolation for patients with COVID-19 continue to evolve with increased understanding of SARS-CoV-2 transmission dynamics. Early in the COVID-19 pandemic, recommendations from the Centers for Disease Control and Prevention (CDC) included discontinuing isolation when there was clinical improvement and a negative molecular SARS-CoV-2 test. This recommendation was replaced by a time-based approach (rather than a test-based one) when it became apparent that shedding of nonviable SARS-CoV-2 RNA in the upper respiratory tract can continue for days to weeks after recovery from illness. Early, albeit small studies showed that SARS-CoV-2 detected by PCR in respiratory specimens beyond day 10 after the onset of symptoms did not grow in cell culture and was probably not transmissible. Large population-based studies conducted by CDC South Korea indicate that the infectious potential of SARS-CoV-2 declines after the first week following symptom onset, irrespective of resolution of symptoms.

However, a few studies have recently challenged this concept. One study showed viable virus by in vitro growth in cell culture in 14% of patients (4 of 29) with persistent positive SARS-CoV-2 PCR tests from upper respiratory specimens obtained after the first week following the initial positive PCR test; one patient was never hospitalized, and one had been hospitalized with mild symptoms. Complete viral genome sequencing indicated that these cases represented the same infection rather than reinfection. Age, immunocompromised status, and severe illness have been associated with prolonged SARS-CoV-2 RNA shedding; however, data are insufficient regarding factors associated with prolonged shedding of viable SARS-CoV-2. One recent study showed that some patients with immunosuppression after treatment for cancer could shed viable SARS-CoV-2 for at least two months. A study of 129 severe cases of COVID-19 showed that the probability of detecting viable virus beyond day 15 after symptom onset was 5% or less. The CDC currently recommends isolation precautions for 10 days after symptom onset (with fever resolution lasting at least 24 hours without the use of fever-reducing medications), with extension to 20 days for immunocompromised patients or those with severe illness. The patient described in the clinical vignette had severe infection according to the World Health Organization severity scale and CDC criteria; thus, continuing isolation for a total of 20 days seems reasonable and in accordance with current evidence. No studies to date have reported person-to-person transmission occurring from the observed late shedding of viable SAR-CoV-2; thus, it may be reasonable to customize decisions regarding duration of isolation on the basis of individual circumstances. In the current case, a household member is a kidney transplant recipient, a condition in which COVID-19 infection is associated with high morbidity and mortality, which further justifies a 20-day isolation period.

Repeat SARS-CoV-2 PCR testing to determine the duration of isolation should not be recommended for this patient because, as noted, a positive PCR test does not mean that she is infectious, and viral tissue culture is not available to assess for viable virus in clinical laboratories. Repeat PCR testing can result in unnecessarily prolonged isolation and anxiety for patients and medical teams. Public awareness of the shortcomings of COVID-19 diagnostic tests and the distinction between shedding of viral RNA and viable virus is essential to ensure that patients and health care workers are comfortable with our current approach to isolation precautions for patients with COVID-19.

2. Reassure the patient of the low risk of transmission

Wenzel RP. Department of Internal Medicine, Virginia Commonwealth University Health, Richmond

The scenario in the vignette focuses on the question of how long after symptom onset a patient with COVID-19 can transmit the virus, SARS-CoV-2. Behind that question are additional questions that highlight current shortcomings in testing. First, is a reverse-transcriptase PCR test result a valid surrogate for the presence of transmissible virus? Second, does in vitro growth of virus from respiratory specimens predict transmissibility to people?

I’ll argue that the answer to the first question is “no” and to the latter “probably,” though we don’t know the infecting dose for transmission.

Fourteen days after the onset of symptoms, a 24-year-old woman with no underlying coexisting conditions is undergoing discharge planning. Though she spent several days in the ICU, her course was moderate, not severe: she was persistently afebrile, was never intubated, and had only moderate changes on chest radiography.

Some reports suggest that patients with COVID-19 who are older, male, or obese, who are immunosuppressed, or who have severe disease have longer-than-average periods of shedding virus. This patient has none of the above characteristics and would not be expected to have prolonged viral shedding.

In a retrospective, cross-sectional study of 90 patients with confirmed COVID-19 (severity not described), the investigators placed respiratory specimens on African green monkey (Vero) cell lines. In vitro infectivity was observed in 29%, and the odds ratio for viral growth decreased by 37% for each additional day after the onset of symptoms. No growth was detected in samples collected more than 8 days after the onset of symptoms.

A detailed virologic analysis of nine cases of mild COVID-19 in young and middle-aged professionals showed no virus isolation in serial samples of blood, urine, or stool. Viral growth was found from oral-pharyngeal or nasopharyngeal swabs in all the patients from days 1 through 5 after symptom onset. Although viral RNA was detected in 40% of the patients after day 5, and was even detected up to 28 days, viral growth was not detected after day

Cheng and colleagues prospectively enrolled 100 patients with confirmed COVID-19 and 2761 contacts. The attack rate for 1818 contacts who were exposed within five days after symptom onset in the primary pool of patients was 1% (95% confidence interval [CI], 0.6 to 1.6), yet the attack rate among 852 contacts exposed later was 0% (95% CI, 0.0 to 0.4).

A systematic review and meta-analysis of SARS-CoV-2 case series, cohort studies, and randomized trials showed RNA shedding for 17 days after symptom onset (95% CI, 15.5 to 18.6) in upper respiratory samples among a total of 3229 participants in 43 studies and for 14.6 days (95% CI, 14.4 to 20.1) in lower respiratory tract samples among a total of 260 participants in seven studies. Although RNA could be detected up to 83 days and 59 days in upper and lower respiratory samples, respectively, no study detected live virus beyond day 9 of illness.

In February 2021, the CDC, citing their own unpublished data and those from other sources, stated that in patients with mild or moderate COVID-19, replication-competent virus hasn’t been recovered after 10 days following symptom onset. Even in severe illness (the vast of majority of patients admitted to the ICU had been intubated), the probability of virus isolation after 15 days was 5%.

In summary, a 24-year-old woman with moderate COVID-19 infection and no markers for extended viral shedding has positive RNA detection yet probably has no replication-competent virus. She has little probability of transmitting SARS-CoV-2 to an immunosuppressed family member at home.

Poll: Which option would you choose?

Recommend continued isolation.68%

Reassure the patient of the low risk of transmission.

(8). Bergwerk M et al. COVID-19 breakthrough infections in vaccinated health care workers. DOI: 10.1056/NEJMoa21090722021. July 28, 2021

Background

Despite the high efficacy of the BNT162b2 messenger RNA vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), rare breakthrough infections have been reported, including infections among health care workers. Data are needed to characterize these infections and define correlates of breakthrough and infectivity.

Methods

At the largest medical center in Israel, we identified breakthrough infections by performing extensive evaluations of health care workers who were symptomatic (including mild symptoms) or had known infection exposure. These evaluations included epidemiologic investigations, repeat reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assays, antigen-detecting rapid diagnostic testing (Ag-RDT), serologic assays, and genomic sequencing. Correlates of breakthrough infection were assessed in a case-control analysis. We matched patients with breakthrough infection who had antibody titers obtained within a week before SARS-CoV-2 detection (peri-infection period) with four to five uninfected controls and used generalized estimating equations to predict the geometric mean titers among cases and controls and the ratio between the titers in the two groups. We also assessed the correlation between neutralizing antibody titers and N gene cycle threshold (Ct) values with respect to infectivity.

Results

Among 1497 fully vaccinated health care workers for whom RT-PCR data were available, 39 SARS-CoV-2 breakthrough infections were documented. Neutralizing antibody titers in case patients during the peri-infection period were lower than those in matched uninfected controls (case-to-control ratio, 0.361; 95% confidence interval, 0.165 to 0.787). Higher peri-infection neutralizing antibody titers were associated with lower infectivity (higher Ct values). Most breakthrough cases were mild or asymptomatic, although 19% had persistent symptoms (>6 weeks). The B.1.1.7 (alpha) variant was found in 85% of samples tested. A total of 74% of case patients had a high viral load (Ct value, <30) at some point during their infection; however, of these patients, only 17 (59%) had a positive result on concurrent Ag-RDT. No secondary infections were documented.

Conclusions

Among fully vaccinated health care workers, the occurrence of breakthrough infections with SARS-CoV-2 was correlated with neutralizing antibody titers during the peri-infection period. Most breakthrough infections were mild or asymptomatic, although persistent symptoms did occur.

(9). TODAY Study Group. Long-term complications in youth-onset type 2 diabetes. N Engl J Med. 2021; 385:416-426

Background

The prevalence of type 2 diabetes in youth is increasing, but little is known regarding the occurrence of related complications as these youths transition to adulthood.

Methods

We previously conducted a multicenter clinical trial (from 2004 to 2011) to evaluate the effects of one of three treatments (metformin, metformin plus rosiglitazone, or metformin plus an intensive lifestyle intervention) on the time to loss of glycemic control in participants who had onset of type 2 diabetes in youth. After completion of the trial, participants were transitioned to metformin with or without insulin and were enrolled in an observational follow-up study (performed from 2011 to 2020), which was conducted in two phases; the results of this follow-up study are reported here. Assessments for diabetic kidney disease, hypertension, dyslipidemia, and nerve disease were performed annually, and assessments for retinal disease were performed twice. Complications related to diabetes identified outside the study were confirmed and adjudicated.

Results

At the end of the second phase of the follow-up study (January 2020), the mean (±SD) age of the 500 participants who were included in the analyses was 26.4 ± 2.8 years, and the mean time since the diagnosis of diabetes was 13.3 ± 1.8 years. The cumulative incidence of hypertension was 67.5%, the incidence of dyslipidemia was 51.6%, the incidence of diabetic kidney disease was 54.8%, and the incidence of nerve disease was 32.4%. The prevalence of retinal disease, including more advanced stages, was 13.7% in the period from 2010 to 2011 and 51.0% in the period from 2017 to 2018. At least one complication occurred in 60.1% of the participants, and at least two complications occurred in 28.4%. Risk factors for the development of complications included minority race or ethnic group, hyperglycemia, hypertension, and dyslipidemia. No adverse events were recorded during follow-up.

Conclusions

Among participants who had onset of type 2 diabetes in youth, the risk of complications, including microvascular complications, increased steadily over time and affected most participants by the time of young adulthood. Complications were more common among participants of minority race and ethnic group and among those with hyperglycemia, hypertension, and dyslipidemia.

(10). Becker SJ et al. Identifying and tracking SARS-CoV-2 variants – A challenge and an opportunity. N Engl J Med. 2021; 385:389-391.

The emergence of worrisome variants of the SARS-CoV-2 virus has exposed the limited scale of surveillance efforts in the United States. More than 30 other countries conduct more sequencing of viral isolates than the United States does, thereby permitting greater understanding of the potential threat associated with various variants.

To address this challenge, the Biden administration is planning to spend $1.75 billion included in the March 2021 American Rescue Plan on strengthening and expanding activities related to genomic sequencing, analytics, and disease surveillance and the workforce in these areas. This funding provides an opportunity to work toward establishing a more coherent and organized public health response system.

Public health surveillance encompasses the interactive system of public health agencies at various levels (including federal, state, and local) working with health care providers and the public to detect, report, and prevent illness and death. These activities depend on the availability of accurate and timely data that can be analyzed using modern epidemiologic methods. In the United States, public health surveillance and data systems are poorly funded, however, and they exist in silos. To avoid simply supporting the development of new silos for sequencing SARS-CoV-2 isolates, we believe the administration could pursue several approaches to building stronger surveillance infrastructure for the future.

First, to solve the current problem related to COVID-19 surveillance and tracking of variants, the federal government could build on the country’s existing network of 130 state and local public health laboratories to expand capacity in the multiple areas required to support genomic surveillance. These laboratories already use next-generation sequencing to monitor seasonal influenza, identify pathogens associated with foodborne disease outbreaks, and track antimicrobial resistance, among other applications.

In recent years, state and local laboratories have been constrained by budget cuts and personnel attrition. Ensuring that a strong genomic-sequencing effort is maintained over the long term in every public health laboratory would promote a much-needed rebuilding process. Funds are needed not only to build instrument and information-technology infrastructure and enable electronic data acquisition and transfer but also to support academic and professional training programs in expanding the workforce by building a pipeline of students with appropriate laboratory, data analytic, and epidemiologic skills.

Having fully resourced and highly capable state and local laboratories operating in the high-complexity, wet-bench mode and performing low-complexity testing in nontraditional sites using point-of-care devices would result in a more resilient national surveillance system. It would enable the development of skills and resources that could be applied to a range of pathogens beyond SARS-CoV-2. If such a system had been in place in late 2019, some of the testing difficulties that the United States experienced early in the COVID-19 pandemic might have been avoided.

Second, the newly designated funding could be used to build and support a national, publicly accessible database of viral sequences. A substantial amount of COVID-19 laboratory data has remained locked within single institutions or has been submitted to restricted databases. When each institution pursues its own research mission in isolation, the ability to identify larger, important trends is compromised. To counter this phenomenon, the government could require all laboratories – both public and private – that receive federal funding to immediately share sequencing information and associated metadata with a national, publicly accessible database, modeled in part on the system at the National Institutes of Health’s National Center for Biotechnology Information. It will be important to ensure that the database-submission process is simple, efficient, and straightforward. Whenever possible, submissions should be linked to metadata with clinical information about patients, an approach similar to that used by the United Kingdom’s COVID-19 surveillance program.

Data that are stored in this warehouse and stripped of individually identifiable patient information should be accessible to government and academic researchers. The Centers for Disease Control and Prevention (CDC) could create a governance structure to oversee the use of these data – one that considers issues such as patient privacy and intellectual property. Whether the warehouse is established at the CDC or elsewhere in coordination with the CDC and other federal agencies, the database’s initial guiding principle should be to promote broad use to address COVID-19. The information collected in the database will be invaluable for the development of new metagenomic-analysis tools; for research on pathogen properties, including virulence, host range, and the potential for drug resistance; and most important, for the development of new therapeutics.

Third, the new funds could support the establishment of a national public health data network. The United States has too many stand-alone, disconnected surveillance networks that require their own data-collection systems and data-transfer pathways. It makes little sense to have separate workflows and information systems for each pathogen or public health problem.

Genomic-sequencing funds could be tapped to develop a new, flexible infrastructure that could ultimately support broad pathogen surveillance and data modernization for genomic sequencing for many infectious diseases. Eventually, such an effort might require a less-siloed organizational structure at the CDC. The agency could establish a training program to provide education on using these data, with training available at the state and local levels to boost investigational capacity.

Finally, funding for addressing SARS-CoV-2 variants could go toward fostering a new model of collaboration between public health and academic medicine. Public health agencies must monitor and respond to the urgent challenges facing populations; academic researchers excel at making discoveries that advance knowledge and capabilities. Too often, these worlds are isolated, thereby limiting opportunities for implementing research findings that could have practical applications for improving health.

To avoid a similar fate for genomic-sequencing efforts, the Department of Health and Human Services (HHS) could create a funding mechanism that requires state and local public health laboratories and their parent agencies to establish formal partnerships with academic medical centers. The model would align academia’s role in developing new technical methods and data-analysis tools with public health’s role in implementing these tools in the field. In addition to supporting the development of a pipeline for students interested in public health careers, this approach could become a model for further collaboration between academic medicine and public health.

Guiding near-term COVID-19 initiatives using these strategies won’t be easy. The current scattered approach to public health surveillance reflects our health care system’s disorganization, the chronic underfunding of public health, and the inconsistent engagement of academic medicine in these efforts. Fixing these problems will require strong federal leadership, starting with an empowered team at HHS that can set conditions for spending the funds included in the American Rescue Plan to bring about important changes. Success will pay dividends not only during the COVID-19 pandemic but also for other major health threats. It will lead to more effective ways of tracking and controlling seasonal influenza and other respiratory diseases, antibiotic resistance, and the emergence of new pathogens.

COVID-19 has caused hardship and loss for millions of Americans, and the emergence and spread of viral variants raise concerns that our global battle with the pandemic is far from over. Even as these variants expose the weaknesses in our laboratory infrastructure, new investments create the potential for designing a stronger public health system for the future. Funding designated for increasing our understanding of SARS-CoV-2 variants could be used in ways that would help guide the current pandemic response and yield benefits for years to come.