Post-op complications increase < 8 weeks after COVID-19 diagnosis

 - Jennifer Middleton, MD, MPH

Health care systems across the world have paused elective surgeries at various points during the COVID-19 pandemic. Numerous asymptomatic patients have also been surprised by a positive pre-op COVID-19 test and had to reschedule their planned surgery. In the health system where I work, once those patients have finished their quarantine, they are free to reschedule their procedures. A new database study suggests that a longer waiting period might reduce post-operative complications; the study reviewed the records of over 5000 persons who had a positive COVID-19 PCR test and had surgery, either in the 4 week period before their positive test or in the weeks after their COVID-19 diagnosis; the study found an increased risk of post-operative complications for patients who had elective surgery within 8 weeks of documented COVID-19 infection.

The study authors used the COVID-19 Research Database, which "includes de-identified and limited datasets from medical and pharmacy claims data, EHR data, mortality data, and consumer data" from across the United States. Over 316 million unique individuals are captured in this database, which the researchers searched to identify persons with positive COVID-19 tests who had undergone elective surgeries in the weeks prior to or following their positive test. The study authors included a wide range of major, but not urgent or emergent, surgeries including mastectomies, colorectal resections, joint replacements, spinal fusions, and coronary artery bypass grafting (CABG). They identified 5479 patients who met study criteria, about half of whom had their surgeries before their COVID-19 diagnosis and about half of whom had their surgeries after their COVID-19 diagnosis. They divided patients into 4 categories: "pre-COVID-19" (control group), "peri-COVID-19" (0-4 weeks after diagnosis), "early-post-COVID-19" (4-8 weeks after diagnosis), and "late-COVID-19" (more than 8 weeks after diagnosis). Less than 2% of included patients had COVID-19 disease considered severe or critical. The researchers found that:

After adjustment for patient characteristics and type of surgery, peri-Covid-19 patients had a significantly higher risk of developing postoperative pneumonia [adjusted odds ratio (aOR), 6.46; 95% confidence interval (CI), 4.06–10.27], respiratory failure (aOR, 3.36; 95% CI, 2.22–5.10), PE (aOR, 2.73; 95% CI, 1.35–5.53) and sepsis (aOR, 3.67; 95% CI, 2.18–6.16) when compared to pre-Covid-19 patients. For most complications, early post-Covid-19 patients did not have a higher risk when compared to pre-Covid-19 patients; however, early post-Covid-19 patients did have a higher risk of developing postoperative pneumonia (aOR, 2.44; 95% CI: 1.20–4.96). 

The study authors appropriately note that "the balance between the risk of postoperative complications and the risk of worse overall survival associated with delayed surgical treatment should be carefully discussed;" for some patients, especially those with cancer, postponing surgery may not be the best balance of benefit and harms. When appropriate, though, discussing this apparent benefit of postponing surgery with our patients - and our surgical colleagues - may help decrease patients' risk of post-operative pneumonia, respiratory failure, and sepsis.

You can find AFP content with the keyword "perioperative care" here, including this article on "Preoperative Testing Before Noncardiac Surgery: Guidelines and Recommendations." The AFP By Topic page on COVID-19 also continues to be regularly updated if you'd like to read more. 

Neurocognitive symptoms in patients with celiac disease and non-celiac gluten sensitivity

- Lilian White, MD

Celiac disease is an autoimmune disorder that results from antibodies to components of gluten. Globally, about 0.7-1.4% of the population has celiac disease. When people with celiac disease eat gluten, their bodies respond by forming antibodies to components of the gluten protein. These antibodies also bind to the villi of intestinal cells, resulting in a variety of signs and symptoms. Classic celiac disease typically presents with localized gastrointestinal (GI) symptoms, including diarrhea, constipation, malabsorption, abdominal pain, bloating, and weight loss. Patients with non-classic celiac disease (which, interestingly, is more common than classic celiac disease) develop symptoms that do not significantly involve the GI tract. These signs and symptoms can include fatigue, joint pain, dermatitis herpetiformis, iron deficiency anemia, migraines, depression, attention deficit disorder, epilepsy, infertility, and low bone density. Some experts prefer to use the terms “intestinal” and “extraintestinal” in place of classic and non-classic celiac disease.

Non-celiac gluten sensitivity is characterized by signs or symptoms associated with gluten ingestion without laboratory findings associated with celiac disease or wheat allergy. Estimates of its prevalence range widely from 0.49% to 14.9%. Symptoms vary and may present in a wide variety of ways, like the intestinal and extraintestinal manifestations of celiac disease.

Neurocognitive symptoms are commonly described by patients with celiac disease; however, there has been little formal study of these symptoms. Neurologic effects of celiac disease have generally been limited to descriptions of neuropathy, epilepsy, and ataxia. A recent survey study of 1396 patients with celiac disease and non-celiac gluten sensitivity was conducted to better understand neurocognitive effects (referred to more informally as “brain fog”) in patients following gluten ingestion. Participants were recruited from the e-mail contact database and social media platforms of the patient advocacy organization Beyond Celiac. 9 in 10 participants reported acute neurocognitive symptoms after gluten ingestion, including forgetfulness, difficulty concentrating, and grogginess. Both groups also noted similar onset and peak of symptoms at 1-2 days, with many continuing to have symptoms 3-5 days later.

While limited by the self-selected population, this study suggests that both patients with celiac disease and non-celiac gluten sensitivity have neurocognitive symptoms following gluten ingestion. The duration of symptoms observed demonstrates the potential to significantly affect patients’ work and/or school performance. It may be helpful for family physicians to ask patients with celiac disease and non-celiac gluten sensitivity if they experience neurocognitive symptoms to better understand how these may be affecting their cognitive functioning and performance.

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Dr. White, a second-year resident at the Cleveland Clinic Family Medicine Residency Program, is a 2022 AFP Resident Representative.

"Long COVID" symptoms in COVID-19 ICU survivors

 - Jennifer Middleton, MD, MPH

Our understanding of Post-Acute Sequelae of SARS-CoV-2 (PASC), also known as "post-COVID conditions," and/or "long COVID," continues to grow as we pass the 2-year mark of the onset of the COVID pandemic in the United States (US). In the spring of 2021, Dr. Lin reviewed data suggesting that approximately 10% of persons who are infected with COVID experience symptoms for greater than 4 weeks; since then, estimates of PASC have ranged as high as 50% in COVID survivors. A new study sought to identify the prevalence of PASC in persons with COVID-19 infection who required care in the intensive care unit (ICU) and found even higher rates of persistent symptoms, but it's unclear what degree of those symptoms were specifically due to COVID-19.

The symptoms associated with PASC are numerous and include physical, mental, and cognitive concerns, including "cough, breathlessness, fatigue, fever, sore throat, nonspecific chest pains (lung burn), cognitive blunting (brain fog), anxiety, depression, skin rashes, and diarrhea." This study of ICU COVID-19 survivors followed the outcomes of 246 persons in the Netherlands who had been admitted at least one year prior. The researchers sent surveys to these survivors that included several validated symptom scores for physical, mood, and cognitive symptoms following hospitalization. They found that:

At 1 year after ICU treatment for COVID-19, physical symptoms were reported by 182 of 245 patients (74.3% [95% CI, 68.3% to 79.6%]), mental symptoms were reported by 64 of 244 patients (26.2% [95% CI, 20.8% to 32.2%]), and cognitive symptoms were reported by 39 of 241 patients (16.2% [95% CI, 11.8% to 21.5%]).

The study authors appropriately note that these outcomes are quite similar to those published in patients without COVID-19 surviving ICU care. It's difficult to disentangle, at this point, how much of this symptom burden is directly attributable to COVID-19 infection versus just the expected sequelae of illness serious enough to require ICU care - not to mention that the stress of ICU care itself can cause post-traumatic stress disorder (PTSD) (with a prevalence of approximately 10%). It certainly seems plausible, though, that patients with severe COVID-19 infection would also have at least a similar, if not higher, risk of PASC as those patients with COVID-19 who didn't need ICU care. 

Regardless of the exact numbers and/or the degree of contribution of COVID-19 itself, primary care clinicians are likely to provide much of the care to COVID-19 survivors with persistent symptoms. These high prevalence rates should encourage us to ask proactively about PASC/"long COVID" symptoms in our COVID-19 survivors and to validate our patients' frustration and suffering. Though we still have much to learn about PASC, informal guidelines are emerging regarding best treatment practices; this AFP editorial on "Long COVID: A Primer for Clinicians" contains a helpful overview, and look soon for review article on long COVID in an upcoming issue of AFP. The US Centers for Disease Control and Prevention (CDC) also has interim guidance on Post-COVID conditions on its website, and this AFP article on "Post-ICU Care in the Outpatient Setting" provides excellent guidance as well for caring for ICU survivors in general.

Debating colorectal cancer screening recommendations: too young, too often?

 - Kenny Lin, MD, MPH

Last year, the U.S. Preventive Services Task Force (USPSTF) updated its colorectal cancer screening recommendations, lowering the starting age for average-risk adults from 50 to 45 years; this change was reflected in the Putting Prevention Into Practice case study in American Family Physician's September 2021 issue. However, after reviewing the USPSTF statement and supporting documents, the American Academy of Family Physicians (AAFP) concluded that the evidence was insufficient to recommend a starting age younger than 50. Two editorials in the February issue of AFP outlined the arguments for and against starting routine screening at 45 years of age.

In the first editorial, Dr. Richard Wender argued that "lowering the starting age is a settled issue," noting that several organizations, including the American Cancer Society, the National Comprehensive Cancer Network, and the American College of Gastroenterology have all independently reviewed the data and come to the same conclusion as the USPSTF. He pointed out that "the incidence of colorectal cancer in 45 year-olds today is ... almost identical to the risk in 50-year-olds in 1979 when colorectal cancer screening was first recommended," and that nearly a quarter of deaths from colorectal cancer in the U.S. occur in individuals diagnosed between 45 and 54 years of age. Four microsimulation models have also concluded that starting screening at 45 years of age is the most efficient strategy to maximize life-years gained per colonoscopy regardless of the initial screening test used (including the multitarget stool DNA test discussed in the same issue of AFP).

The second editorial, by Drs. Corey Lyon, Alexis Vosooney, and Melanie Bird, elaborated on the AAFP's position. The authors noted that "many of the trials used in the modeling studies did not include individuals younger than 50 years or did not provide separate data for this younger age group, decreasing confidence in the data inputs." They also expressed concern about costs to patients and the health care system from implementing the USPSTF recommendation as opposed to optimizing screening in patients age 50 years and older: "Expanding screening to up to 80% of eligible patients 50 to 75 years of age would prevent three times as many colon cancer deaths at one-third of the cost [of routinely screening Americans 45 to 49 years of age]." (A previous AFP Community Blog post by Dr. Jennifer Middleton described two modestly successful outreach strategies to patients who were not up to date on colorectal cancer screening.) Finally, they argued that persistent disparities in colorectal cancer incidence and mortality in Black patients would be more appropriately addressed by improving insurance coverage and access to care in this population rather than lowering the age to start screening. 

While colorectal cancer screening tests remain underused by many patients, studies have also documented that screening colonoscopies are performed more often than necessary - for example, being repeated 9 or fewer years after an initial high-quality colonoscopy showed no significant pathology, in contrast to the American Gastroenterological Association's Choosing Wisely recommendation. A recent systematic review of 6 studies that estimated the rate of overuse of screening colonoscopy in U.S. populations found that it ranged from 17% to 25.7%. Overuse occurs when endoscopists recommend that patients have subsequent colonoscopies at intervals shorter than those supported by guidelines, and primary care physicians (PCPs) defer to subspecialists' recommendations. In an editorial, Drs. Archana Radhakrishnan and Craig Pollack explained the obstacles that PCPs face in going against subspecialist advice but argued that they can still "play an important role in preventing overuse of colorectal cancer screening and surveillance colonoscopies" by directing referrals appropriately and communicating with endoscopists about deviations from evidence-based practices.

What are the best medications for panic disorder?

 - Jennifer Middleton, MD, MPH

The COVID-19 pandemic is continuing to worsen mental health around the world; early studies from 2020 were already showing an increased prevalence of depression, anxiety, and panic disorder, and studies from 2021 demonstrate continued increasing rates of these mental health disorders. With several Food and Drug Administration (FDA) approved medications for panic disorder currently available in the United States, choosing an initial medication for patients with a new diagnosis can feel overwhelming. A newly published systematic review and network meta-analysis sought to identify the most effective medications for panic disorder and found that sertraline and escitalopram had the best balance of benefit and adverse events.

The systematic review and network meta-analysis examined the literature through June 2021 regarding pharmaceutical options for panic disorder. The researchers looked for randomized controlled trials (RCTs) that included adults aged 18 years and older and cited outcomes related to either benefit (remission rates) and/or harm (including somnolence, gastrointestinal problems, and cognitive impairment). They identified 87 studies with a total of 12,800 participants and followed appropriate systematic review methodology to extract and synthesize the data. Most of the studies compared medication treatment to placebo, so the authors conducted a network meta-analysis to compare outcomes among the various medication classes and medications identified in the systematic review:

Our network meta-analysis identified 11 current drug classes for the treatment of panic disorder, highlighting benzodiazepines, tricyclic antidepressants, and SSRIs as the highest ranked treatments for remission based on SUCRA values. Although benzodiazepines were associated with the lowest probability of dropout, they were also associated with the highest risk of adverse events. Overall, SSRIs provided high benefit (remission) with low risk of adverse events. Across individual SSRIs, sertraline and escitalopram were identified as the most efficacious agents with low risk of adverse events.

The researchers also evaluated included studies for risk of bias, and they noted that "[t]he findings were...based on studies of moderate to very low certainty levels of evidence, mostly as a result of within study bias, inconsistency, and imprecision of the findings reported." Nevertheless, this study's comprehensive and rigorous comparisons may still help guide treatment decisions for patients presenting with panic disorder.

Medications are a useful tool for treating panic disorder, but cognitive behavioral therapy is very effective as well (number needed to treat for complete remission of panic after 3-4 months = 2). Accessing support resources can be beneficial; I included a list of mental health resources developed during the pandemic in this blog post from 2020, and I especially like this one from the World Health Organization that emphasizes the importance of simple self-care habits. 

It's also important to precisely diagnose patients to guide treatment recommendations. This 2015 AFP article on "Diagnosis and Management of Generalized Anxiety Disorder and Panic Disorder in Adults" includes diagnostic criteria for both Generalized Anxiety Disorder and panic disorder along with an overview of treatment options - both pharmaceutical and non-pharmaceutical - to discuss with patients. There's also an AFP By Topic on Anxiety Disorders if you'd like to read more. 

Is COVID-19 vaccination beneficial in persons with past infection?

 - Kenny Lin, MD, MPH

Since the first COVID-19 vaccine received authorization for emergency use in December 2020, physicians and the public have vigorously debated whether infection-acquired ("natural") or vaccine-mediated immunity provides better protection against future infection and severe illness. The answer may never be known for certain, as observational studies are limited by confounding and it's hard to imagine a research ethics committee approving a trial that randomizes one group to intentional exposure to a potentially lethal infection. A more important clinical question is: does getting vaccinated after recovery from COVID-19 provide additional benefits? Currently, the Centers for Disease Control and Prevention recommends routine vaccination in all persons aged 5 years or older, regardless of their history of past infection.

Two large cohort studies published last week provided the strongest evidence to date that the answer is yes. The first study used electronic medical records from a health care organization covering more than half of the population of Israel to identify 149,000 patients age 16 years or older who had recovered from documented SARS-CoV-2 infection at least 100 days earlier and had not yet received COVID-19 vaccination as of March 1, 2021. 56% of these persons received at least one dose of BNT162b2 (Pfizer-BioNTech) vaccine by November 26, 2021. 2,168 of those who remained unvaccinated (3.3%) were reinfected during the study, compared to 354 of the vaccinated patients (0.4%). After adjustment for sociodemographic factors and coexisting illnesses, the estimated vaccine effectiveness was 82% for patients aged 64 years or younger and 60% for patients aged 65 years or older. A secondary analysis showed no difference in protection between one or two vaccine doses.

A second study in a highly vaccinated cohort of 35,768 health care workers in the United Kingdom tracked primary infections and reinfections between December 7, 2020 and September 21, 2021. Most participants received two doses of BNT162b2 (Pfizer-BioNTech) vaccine; 8% received the single-dose ChAdOx1 nCoV-19 vaccine (AstraZeneca). In previously uninfected participants who received the second dose of BNT162b2 six weeks or more after the first dose, adjusted vaccine effectiveness was 85% up to 73 days after the second dose but declined to 51% after 200 days. In comparison, adjusted effectiveness of the ChAdOx1 nCoV-19 vaccine was only 58% up to 73 days. In 6,169 participants who had COVID-19 prior to the study, long-term (>1 year) protection against re-infection was 69% in unvaccinated persons but remained high at 94% in persons who received one or two doses of BNT162b2.

Acknowledging some differences between the populations and the predominant variants circulating during the respective study periods, the results support the following conclusions. First, re-infection in unvaccinated persons is relatively uncommon during the first 9 months after a primary infection (1 in 30 in the Israeli study) but becomes more likely after 1 year (per the U.K. study). Similarly, the effectiveness of the initial two doses of BNT162b2 vaccine in preventing COVID-19 declines after 6-7 months, supporting booster doses. However, patients with past infections who subsequently receive one or two doses of BNT162b2 have sustained high levels of protection ("hybrid immunity") against re-infection for at least one year. In an editorial in The Guardian, Dr. Eric Topol recently argued that these and other data support re-defining "fully vaccinated" to include recovery from past infection plus a single dose of an mRNA vaccine.