Deconstructing PPI-Associated Risks with Nearly 8 Billion Data Points and More on COVID-19 GI Symptoms (Video)

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Link: 22 minute video —COVID-19 and the GI Tract -What We Know Right Now

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A recent study (C Ma et al. Gastroenterol 2020; 158: 780-82) used cross-sectional data from the National Ambulatory Medical Care Survey (NAMCS) (2006-2015) with a total 7,872,115,883 weighted observations.  They used this data to evaluate medication exposures and outcomes.

Key findings:

  • There was no association between PPI use and dementia, pneumonia, or intestinal infections.  There was a trend towards intestinal infections (AOR 1.48, CI 0.80-2.71) but this did not reach statistical significance. “Sensitivity analysis showed an association between PPI use and C difficile.”
  • There was an association with chronic kidney disease (CKD) (AOR 1.26); however, this was seen with a multitude of drug classes including statins, calcium channel blockers, and beta-blockers.

Discussion:

  • This study notes that a recent large randomized controlled trial found no statistically significant differences between those receiving PPIs and those receiving placebo except for intestinal infections.
  • With regard to CKD, “it is extremely unlikely that all of these medications increase the risk of CKD, and therefore, it is likely that these findings are due to residual confounding.”

My take: With the exception of C difficile/intestinal infections, this study provides further evidence of the safety of PPIs and a lack of association between these medications and purported PPI-related adverse events.  That said, it is still a good idea to limit use for appropriate indications.

Related blog posts:

Also, IOIBD recommendations for IBD patients and COVID-19 have been published.

Here is link as well:

IOIBD (International Organization for the Study of Inflammatory Bowel Disease) Recommendations (#76) for IBD Patients with Regard to COVID-19:

Full link: IOIBD Update on COVID19 for Patients with Crohn’s Disease and Ulcerative Colitis (3/26/20)

 

NY Times: How Will We Know When to Reopen the Country? & Timely Tweets

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A good read from Aaron Carroll/NY Times: How Will We Know When to Reopen the Country?

Here is an excerpt:

Everyone wants to know when we are going to be able to leave our homes and reopen the United States. That’s the wrong way to frame it.

The better question is: “How will we know when to reopen the country?”…

 A recent report by Scott Gottlieb, Caitlin Rivers, Mark B. McClellan, Lauren Silvis and Crystal Watson staked out some goal posts.

  • Hospitals in the state must be able to safely treat all patients requiring hospitalization, without resorting to crisis standards of care.
  • A state needs to be able to test at least everyone who has symptoms.
  • The state is able to conduct monitoring of confirmed cases and contacts.
  • There must be a sustained reduction in cases for at least 14 days…

These four criteria are a baseline…Until we get a vaccine or effective drug treatments, focusing on these major criteria, and directing efforts toward them, should help us determine how we are progressing locally, and how we might achieve each goal.

Related blog posts/links:

 

 

C difficile three-fer: Overdiagnosis with Multiplex Testing, Fidaxomicin Pediatric Approval, & Changing Incidence

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Queen Elizabeth II -picture for the pandemic

JM Cotter et al. (J Pediatr 2020; 218: 157-65) reviewed 1214 C difficile positive results from a total of 6841 C difficile tests 2013-15 & 2015-17). Key findings:

  • In the later era of multiplex tests, there was a much higher rate of C difficile detection (1.7-2.3 times higher) and a much higher rate of detection.
  • However, 31% of the multiplex tests identified another organism which indicates a high likelihood of a false-positive test (C difficile colonization)
  • Many of these “C difficile infections” were detected simply due to ease of test ordering.  In addition, the test results should be viewed with suspicion particularly in low-risk individuals.
  • Nearly one-third of the C difficile infected patients were oncology patients who are known to have high rates of asymptomatic colonization.
  • In patients known to have high risk of asymptomatic colonization (eg. young, oncology, IBD), detection of C difficile infection may lead to anchoring bias resulting in diagnostic delays for other disorders.

My take: We know that we are approaching the diagnosis of C difficile infection the wrong way (see IDSA guidelines below), but it is so quick and easy.

Related blog posts:

  • Clostridium difficile Guidelines The diagnosis of CDI… Molecular tests (eg, nucleic acid amplification tests [NAATs], such as polymerase chain reaction), which do not differentiate colonization and infection, are now the most commonly used test for CDI among US hospitals. NAATs have the potential to misdiagnose patients with colonization as having CDI, particularly when used in patients with low likelihood of CDI. Thus, this guideline strongly reinforces the importance of practicing good diagnostic stewardship and limiting C difficile testing to patients with new-onset, unexplained, and clinically significant (ie, at least 3 unformed stools in a 24-hour period) diarrhea…formed stools should not be tested for C difficile, nor should patients be retested within 7 days of a previous negative C difficile test. In pediatric populations, because of the unclear role of C difficile as a cause of diarrhea in infants, children less than 12 months of age should not be tested…If diagnostic stewardship is not an achievable goal, use of NAAT alone is likely to lead to frequent misdiagnosis of CDI among patients with C difficile colonization. In these cases, NAAT alone should be avoided and a multistep algorithm that incorporates toxin testing is recommended.

From MDEdge Pediatrics: full link: FDA approves fidaxomicin for treatment of C. difficile-associated diarrhea

An excerpt:

Approval [by FDA] was based on results from SUNSHINE, a phase 3, multicenter, investigator-blind, randomized, parallel-group study in 142 pediatric patients aged between 6 months and 18 years with confirmed C. difficile infection who received either fidaxomicin or vancomycin for 10 days. Clinical response 2 days after the conclusion of treatment was similar in both groups (77.6% for fidaxomicin vs. 70.5% for vancomycin), and fidaxomicin had a superior sustained response 30 days after the conclusion of treatment (68.4% vs. 50.0%)…

The fidaxomicin pediatric trial was the first randomized, controlled trial of C. difficile infection treatment in children,” Larry K. Kociolek, MD

AY Guh et al. NEJM 2020; 382: 1320-30. The authors examined the U.S. Burden of CDI by using the Emerging Infections Program (35 counties in 10 states). Key findings:

  • 15,461 cases of CDI in 2011 and 15,5512 in 2017 detected which extrapolates to 476,000 national cases in 2011 and 462,400 national cases in 2017
  • When accounting for increased use of PCR assays, the authors estimate that the C difficile infectious burden decreased by 24% from 2011 to 2017 (due to a drop in health care-associated infections.

My wife has been receiving a lot of compliments for her daily jokes which she decided to post for all of the neighborhood walkers: “If number two pencils are so popular, why are they still number 2?”

Dark Side of Zoom and Zoombombing

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The video conferencing available via Zoom has been enormously helpful during this sheltering-in place.  However, it has received attention for privacy concerns (thanks to my sister for the following references).

From NPR (4/3/20) A Must For Millions, Zoom Has A Dark Side — And An FBI Warning

An excerpt:

“a new form of harassment known as “Zoombombing,” in which intruders hijack video calls and post hate speech and offensive images such as pornography. It’s a phenomenon so alarming that the FBI has issued a warning about using Zoom…

Researchers have turned up flaws in Zoom’s software that could let hackers spy through a computer’s webcam or microphone. Zoom says it released fixes for these issues on Wednesday…The website Motherboard found that Zoom was sharing data with Facebook, even data on people who are not Facebook users.”

FBI Warning: FBI Warns of Teleconferencing and Online Classroom Hijacking During COVID-19 Pandemic

“The following steps can be taken to mitigate teleconference hijacking threats:

  • Do not make meetings or classrooms public. In Zoom, there are two options to make a meeting private: require a meeting password or use the waiting room feature and control the admittance of guests.
  • Do not share a link to a teleconference or classroom on an unrestricted publicly available social media post. Provide the link directly to specific people.
  • Manage screensharing options. In Zoom, change screensharing to “Host Only.”
  • Ensure users are using the updated version of remote access/meeting applications. In January 2020, Zoom updated their software. In their security update, the teleconference software provider added passwords by default for meetings and disabled the ability to randomly scan for meetings to join.
  • Lastly, ensure that your organization’s telework policy or guide addresses requirements for physical and information security.

If you were a victim of a teleconference hijacking, or any cyber-crime for that matter, report it to the FBI’s Internet Crime Complaint Center at ic3.gov. Additionally, if you receive a specific threat during a teleconference, please report it to us at tips.fbi.gov or call the FBI Boston Division at (857) 386-2000.”

Advice to avoid hackers from stealing user credentials:  Don’t click on links in Zoom chats from people that you don’t know or when they start with double slashes “\\”.

COVID-19 Posts

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My wife has been receiving a lot of compliments for her daily jokes which she decided to post for all of the neighborhood walkers. “A lot of people cry when they cut an onion. The trick is not to form an emotional bond.”

This coronavirus disease has caused incredible upheaval & misery throughout the world.  In addition, it has created an “infodemic.”  This blog post is intended to collate my previous related posts/& many of the referenced links into one location, to provide GI society guidelines for PPE/endoscopy as well as to place a good image at the bottom:

Aslo, recommendations from GI societies -AGA, ACG, ASGE and AASLD

  1. Use of Personal Protective Equipment in GI Endoscopy
  2. Endoscopic Procedure Guidance
JOINT GASTROENTEROLOGY SOCIETY MESSAGE: COVID-19
Use of Personal Protective Equipment in GI Endoscopy
RECOMMENDATIONS:
  1. General measures of physical distancing and adequate hand hygiene are of critical importance and need to be practiced diligently, independent of other protective measures.
  2. All elective, non-urgent procedures should be postponed until ample supplies of PPE, hospital beds and other resources are available after the COVID-19 surge.
  3. All members of the endoscopy team should wear a full set of PPE, predicated on resource availabilities.
  4. The correct sequence of putting on and taking off PPE (“donning” and “doffing”) is critical and needs to be understood and practiced [17].
  5. All members of the endoscopy team should wear N95 respirators (or devices with equivalent or higher filtration rates) for all GI procedures performed on patients with known SARS-CoV-2 infection and those with high risk of exposure. Given the high rate of infection transmission from pre-symptomatic individuals, all patients undergoing GI endoscopy in an area of community spread need to be considered ‘high risk’.
  6. All healthcare workers should have their N95 respirators fitted by an occupational health specialist prior to the first usage.
  7. Staffing of endoscopy rooms should be reduced to the minimum number of individuals necessary, in order to conserve PPE and other resources.
  8. In some cases, shortages may require extended and limited reuse of N95 respirators. Guidance is available on how to wear, remove and store respirators to minimize contamination [18]. Decontamination of N95 respirators with hydrogen peroxide vapor has been approved by the FDA as a means of reuse in times of limited supply [19].
GASTROENTEROLOGY PROFESSIONAL SOCIETY
GUIDANCE ON ENDOSCOPIC PROCEDURES
DURING THE COVID-19 PANDEMIC
Below is guidance regarding how to manage the clinical procedural needs of patients during the COVID-19 pandemic. Any decisions should be informed by the local situation and available resources. There may be state, local and institutional rules in place that must be considered as well. This guidance is offered until more definitive data-driven information becomes available.
For those patients for whom a procedure or appointment is not deemed immediately necessary, each practice should implement mechanisms to assure appropriate follow-up once the immediate impact of the COVID-19 pandemic has eased or passed.
All Elective Procedures Should Be Delayed
  1. Screening and surveillance colonoscopy in asymptomatic patients ​
  2. Screening and surveillance for upper GI diseases in asymptomatic patients​, including surveillance for esophageal varices in patients with cirrhosis
  3. For patients needing interval endoscopy for obliteration of esophageal varices post-acute bleeding, the individual circumstances of the patient need to be taken into account to determine safety of delay (i.e., size of varices, red wale markings, CTP status of the patient, acute bleed characteristics).
  4. Evaluation of non-urgent symptoms or disease states where procedure results will not imminently (within 4-6 weeks) change clinical management (e.g., EGD for non-alarm symptoms, EUS for intermediate risk pancreatic cysts) ​
  5. Motility procedures – esophageal manometry, ambulatory pH testing, wireless motility capsule testing and anorectal manometry
Urgent/Emergent Procedures Should Not Be Delayed ​
  1. Upper and lower GI bleeding​ or suspected bleeding leading to symptoms
  2. Dysphagia significantly impacting oral intake (including EGD for intolerance of secretions due to foreign body impaction or malignancy (stent placement))
  3. Cholangitis or impeding cholangitis (perform ERCP)​
  4. Symptomatic pancreaticobiliary disease ​(perform EUS drainage procedure if necessary for necrotizing pancreatitis and non-surgical cholecystitis, if patient fails antibiotics)
  5. Palliation of GI obstruction [UGI, LGI (including stent placement for large bowel obstruction) and pancreaticobiliary] ​
  6. Patients with a time-sensitive diagnosis (evaluation/surveillance/treatment of premalignant or malignant conditions, staging malignancy prior to chemotherapy or surgery) ​
  7. Cases where endoscopic procedure will urgently change management (e.g., IBD)
  8. Exceptional cases will require evaluation and approval by local leadership on a case by case basis
Q. Should all emergent EGD patients be intubated?
A. Absent other reasons that present a threat to the airway, intubation is not indicated for all EGDs. Proper use of PPE, including N95 masks is paramount.
Q. Should procedures be performed on patients with intermediate level cases such as Iron Deficiency Anemia (IDA) or mild dysphagia?
A. Decisions regarding cases such as these will need to be made on a case by case basis, taking into account resource availability, level of community infectivity and risk to the patient.

 

FMT Warning & “Get Your Butt in Gear” –Less Than 10% of Kids Meeting Guidelines for Healthy Movement

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To lessen obesity, three health risk behaviors have been targeted:

  • Sedentary behavior -goal is to limit to 2 hours of screen time in 24 hours
  • Physical activity -goal is 1 hour (or more) of moderate to vigorous activity
  • Sleep duration -goal is 9-12 hours (ages 6-12 years) and 8-10 hours (13-18 years)

A recent study (X Zhu et al. J Pediatr 2020; 218: 204-9) shows that <10% of U.S. kids meet these goals.  The authors examined data (2016-17) from the National Survey of Children’s Health (NSCH) dataset (n=71,811)

Key findings:

  • 80.9% did NOT meet physical activity goal
  • 76.2% did meet screen time goal
  • 581% did meet sleep goal
  • However, only 9.4% met all 3 goals
  • Not meeting these ‘movement’ guidelines was associated with obesity, particularly in females (aOR 4.97 compared to aOR 3.99 for males)

My take: We are all made to be different shapes and sizes.  Nevertheless, we should strive for healthy behaviors and healthy eating which could improve outcomes.

Autoimmune Hepatitis Outcomes, Grand Rounds on Splenomegaly, Hydroxychloroquine for SARS-CoV-2 & Zantac Warning

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Here’s a commentary explaining why hydroxychloroquine is NOT proven effective:

Annals of Internal Medicine -Link: A Rush to Judgment? Rapid Reporting and Dissemination of Results and Its Consequences Regarding the Use of Hydroxychloroquine for COVID-19

Some of the key points:

  • While the study suggested more rapid clearance of SARS-CoV-2 virus at day 6 in those treated with hydroxychloroquine/azathioprine (n=20), the authors excluded 6 from the treatment group including one patient who died and three who were transferrred to the ICU.  In addition, the treatment group had a lower viral load at the start of treatment.
  • Other viral infections, including influenza, have also had in vitro data suggesting efficacy with hydroxychloroquine but this did not translate into clinical efficacy in clinical trials.
  • “The hydroxychloroquine shortage not only will limit availability to patients with COVID-19 if efficacy is truly established but also represents a real risk to patients with rheumatic diseases who depend on HCQ for their survival.”

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A Di Giorgio et al (J Pediatr 2020; 218: 121-9) provide long-term data (median f/u of 14.5 years) from a retrospective review on 83 children with autoimmune hepatitis (AIH, n=54)/autoimmune sclerosing cholangitis (ASC, n=29). Median age at presentation, between 2000-2004 was 12.1 years

Key findings:

  • 29% had histologic evidence of cirrhosis at diagnosis
  • At a median followup of 14.5 years, 99% were alive, 11 underwent transplantation.  In those who underwent transplantation, 5-year and 10-year survival was 95% and 88% respectively.
  • ASC was associated with IBD in 73% of cases, compared to 33% of AIH patients.
  • Treatment: 95% of all patients had normalization with transaminases with immunosuppressive treatment (most commonly azathioprine with prednisone 2.5-5 mg/day). ASC patients also received ursodeoxycholic acid 15-20 mg/kg/day.
  • Immunologic remission: 47% achieved immunologic remission which required normal IgG levels and negative/low ANA/SMA <1:20 in addition to normal transaminases.
  • Liver transplantation was needed in 28% of ASC compared to 9% of AIH patients; overall, 83% experienced 15-year transplant-free survival. Median age of those needing a liver transplant was 19.3 years.
  • Immunosuppression withdrawal was attempted in 12 patients after a median of 4.5 years of treatment.  9 were able to stay off immunosuppression.
  • An increase in case frequency was noted during the last 4 decades at this center, from 3.6 cases/year to 5.4 case/year.
  • Four patients had isolated infrequent autoantibodies of anti-SLA (n=3) nad antiLC-1 (n=1). SLA =liver soluble antigen, LC-1 =liver cytosol antibody type 1.  Thus, in those with suspected AIH/ASC, testing for these autoantibodies is important in ~5%.
  • Pathology: 18% did not have classical features of interface hepatitis.  Instead, some had lymphocytic/lymphoplasmocytic infiltrate without spillover into the parenchyma.
  • Progression from AIH to ASC occurred in 3 patients on followup cholangiography.
  • ASC would have been overlooked in 41% if one relied on pathology alone -reaffirming need for biliary imaging.

My take: This article has a number of useful points and with an overarching message that long-term outcomes are good for children with AIH/ASC.

Related blog posts:

B Freiberg et al. 2020; 218: 221-31. This grand rounds describes the extensive workup of a 12 year old with splenomegaly ultimately due to splenic vein stenosis.  The report provides a nice review of hepatologic, hematologic, infectious, and other causes of splenomegaly as well as a work-up algorithm. (look for everything).

Initial evaluation per algorithm should start with CBC/d, retic, blood smear, liver biochemistries, GGT, coags, EBV VCA IgM, CMV IgM, Parvovirus IgM, and complete abdominal ultrasound with doppler.

Hepatologic causes of splenomegaly include the following:

  • cirrhosis with portal hypertension
  • autoimmune hepatitis/autoimmune sclerosing cholangitis
  • congenital hepatic fibrosis
  • hepatoportal sclerosis
  • nodular regenerative hyperplasia
  • storage disease and inborn errors of metabolism which includes lipidosis (Gaucher, Niemann-Pick), mucopolysaccharidoses, defects in carbohydrate metabolism (galactosemis, hereditary fructose intolerance), sea-blue histiocyte syndrome
  • anatomic disorders: portal/splenic thrombosis, Budd-Chiari, cysts, hamartomas, hemangiomas, hematoma, peliosis

Other causes of splenomegaly: infecions, hematologic-oncologic, and rheumatic disorders

Related blog posts:

The U.S. Food and Drug Administration today announced it is requesting manufacturers withdraw all prescription and over-the-counter (OTC) ranitidine drugs from the market immediately. This is the latest step in an ongoing investigation of a contaminant known as N-Nitrosodimethylamine (NDMA) in ranitidine medications (commonly known by the brand name Zantac). The agency has determined that the impurity in some ranitidine products increases over time and when stored at higher than room temperatures and may result in consumer exposure to unacceptable levels of this impurity. As a result of this immediate market withdrawal request, ranitidine products will not be available for new or existing prescriptions or OTC use in the U.S.

New FDA testing and evaluation prompted by information from third-party laboratories confirmed that NDMA levels increase in ranitidine even under normal storage conditions, and NDMA has been found to increase significantly in samples stored at higher temperatures, including temperatures the product may be exposed to during distribution and handling by consumers. The testing also showed that the older a ranitidine product is, or the longer the length of time since it was manufactured, the greater the level of NDMA. These conditions may raise the level of NDMA in the ranitidine product above the acceptable daily intake limit.

Bill Gates: What We Need to Do Now for COVID-19, False-negative testing & Article Describing 3 Stages of Infection

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A recent commentary in Washington Post by Bill Gates states clearly what we need to do now to improve the outcome of this pandemic. Link (may be behind paywall) : Bill Gates: Here’s how to make up for lost time on covid-19

  1. Nationwide stay-at-home.  Given mobility in country, having some states policies lessens the effectiveness of individual state mandates. “Because people can travel freely across state lines, so can the virus. The country’s leaders need to be clear: Shutdown anywhere means shutdown everywhere. Until the case numbers start to go down across America — which could take 10 weeks or more — no one can continue business as usual or relax the shutdown. Any confusion about this point will only extend the economic pain, raise the odds that the virus will return, and cause more deaths.”
  2. Much more testing and quicker turnaround.  This would allow more effective isolation policies and help determine if/when we are truly making progress.
  3. Nationwide coordination for ventilators/supplies.  Competition between states is counterproductive
  4. Preparation for making billions of doses of vaccine (when available)

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From NY Times:  If You Have Coronavirus Symptoms, Assume You Have the Illness, Even if You Test Negative

An excerpt:

Current coronavirus tests may have a particularly high rate of missing infections. The good news is that the tests appear to be highly specific: If your test comes back positive, it is almost certain you have the infection… From a technical standpoint, under ideal conditions, these tests can detect small amounts of viral RNA.  In the real world, though, the experience can be quite different, and the virus can be missed.

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Thanks to Ben Gold for the following article: COVD-19 Illness in Native and Immunosuppressed States: A Clinical-Therapeutic Staging Proposal (HK Siddiqi, MR Mehra. J Heart Lung Transplantation) available at jhltonline.org

This article describes three stages of COVID-19 and associated laboratory/clinical findings.

  1. I -Early stage.  “In patients who can keep the virus limited to this stage of COVID-19, prognosis and recovery is excellent”
  2. II-Pulmonary involvement (IIa) without and (IIlb) with hypoxia
  3. III-Systemic Hyperinflattion

And a reason to wary of hydroxychloroquine in its use for COVID-19:

 

The Problem with Health Share Plans

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Health Share Plans seem appropriate for an April Fools day –if you thought you had health insurance, you may be in for an unpleasant surprise.  The problem with ‘health share’ plans is they often do not provide adequate cost/benefit coverage for those who rely on them.

NY Times: California Cracks Down on Alternative Health Plans

An excerpt:

[California] State insurance regulators accused a ministry offering an alternative to traditional insurance of misleading consumers….

The plans, which have become increasingly popular, rely on pooling members’ contributions to cover their medical expenses, but they are not required to meet standards for traditional insurance plans…

More than one million Americans have joined such groups, attracted by prices that are far lower than the cost of traditional insurance policies, which must meet strict requirements established by the federal health care law, like guaranteed coverage for pre-existing conditions…

State regulators are questioning some of the ministries’ aggressive marketing tactics, saying some consumers were misled or may not understand the lack of comprehensive coverage in the case of a serious illness or conditions that the ministries may not be willing to cover.

From The Onion