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

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.

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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.

What is the Current Standard of Care for PPE and Endoscopy Cases?

CC Thompson et al. Gastointestinal Endoscopy (EPUB), in a letter to the editor, respond to two recent studies on SARS-CoV-2 virus/COVID-19 and provide recommendations for PPE use in this era of COVID-19.

Here’s a link to manuscript: COVID-19 in Endoscopy: Time to do more?

Key points:

  • Reduce non-urgent cases. “We have cut our daily endoscopy volume by over 80% and closed our ambulatory endoscopy practice.”
  • Increase the use of telemedicine. “At present, telemedicine or virtual visits make up 91% of our upcoming clinic appointments.”
  • Physical distancing as advocated recently by WHO throughout a patient’s time in the endoscopy unit is stressed in the papers, with a 6-foot minimum between individuals.
  • Suggests “the need for a separate toilet as part of the isolation to minimize spread of infection due to bioaerosols from the toilet plume”
  • Our hospital system has recently changed policy to mandate that all employees wear surgical masks at all times while in the hospital and attest to their wellness online before reporting to work.
  • We suggest labeling each computer so the same provider uses that computer and chair for the entire day, and separating by at least 6 feet.
  • All endoscopic procedures (upper endoscopy, colonoscopy, EUS, ERCP) are aerosol-generating, referencing studies that show contamination of the endoscopist’s face during routine procedures. This makes all endoscopic procedures high risk from an infectious standpoint, and appropriate PPE is
    recommended… It makes little sense for healthcare providers to perform
    aerosolizing procedures, with patients coughing or passing gas on them, while not wearing an N95 mask or better
  • “It is important to use full PPE for all endoscopic procedures while in a pandemic such as this especially in areas with community spread, because no one is truly low risk given our ongoing difficulties with testing.”
  • “The mask can be reused as long as it is functional, not soiled, and not used in a suspected or COVIDpositive patient. It is important to cover the N95 to prevent soiling.”
  • “A study from China showed that no medical staff working in high-risk departments who wore N95s and practiced strict hand hygiene regardless of patient’s infection status became infected.”
  • “Testing all patients before high-risk procedures such as endoscopy is likely the best approach; however, this will depend on significant expansion of testing capabilities. Hopefully, the development of point-of-care testing with rapid results and increasing testing availability will make this a reality soon”

My take (in part from authors): “We are living through an unprecedented time and are all trying our best to protect our patients and ourselves under suboptimal conditions of limited PPE, limited testing, and limited data. ”  The recommendations in this article are based mainly on expert opinion and may need modifications based on new data and circumstances.

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IOIBD (International Organization for the Study of Iinflammatory 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)

 

 

How to Protect Healthcare Workers from COVID-19: Lessons from Hong Kong and Singapore

Atul Gawande has a very pertinent article in the New Yorker:  Keeping the Coronavirus from Infecting Health-Care Workers

An excerpt:

There are lessons to be learned from two places that saw the new coronavirus before we did and that have had success in controlling its spread. Hong Kong and Singapore…

 All health-care workers are expected to wear regular surgical masks for all patient interactions, to use gloves and proper hand hygiene, and to disinfect all surfaces in between patient consults. Patients with suspicious symptoms (a low-grade fever coupled with a cough, respiratory complaints, fatigue, or muscle aches) or exposures (travel to places with viral spread or contact with someone who tested positive) are separated from the rest of the patient population, and treated—wherever possible—in separate respiratory wards and clinics, in separate locations, with separate teams. Social distancing is practiced within clinics and hospitals: waiting-room chairs are placed six feet apart; direct interactions among staff members are conducted at a distance; doctors and patients stay six feet apart except during examinations.

What’s equally interesting is what they don’t do. The use of N95 masks, face-protectors, goggles, and gowns are reserved for procedures where respiratory secretions can be aerosolized. Their quarantine policies are more nuanced, too. What happens when someone unexpectedly tests positive—say, a hospital co-worker or a patient in a primary-care office or an emergency room? In Hong Kong and Singapore, they don’t shut the place down or put everyone under home quarantine. They do their best to trace every contact and then quarantine only those who had close contact with the infected person. In Hong Kong, “close contact” means fifteen minutes at a distance of less than six feet and without the use of a surgical mask; in Singapore, thirty minutes. If the exposure is shorter than the prescribed limit but within six feet for more than two minutes, workers can stay on the job if they wear a surgical mask and have twice-daily temperature checks. People who have had brief, incidental contact are just asked to monitor themselves for symptoms…

Transmission seems to occur primarily through sustained exposure in the absence of basic protection or through the lack of hand hygiene after contact with secretions…

Singapore so far appears not to have had a single recorded health-care-related transmission of the coronavirus, despite the hundreds of cases that its medical system has had to deal with…

For those who cannot stay home, the lesson is that it is feasible to work and stay coronavirus-free, despite the risks….a greater likelihood of staff picking up infections at home than at work. 

“Crushing it:” Two More Pediatric Hepatitis C Trials

Before today’s planned blog post, I wanted to mention a good NY Times article which highlights how long the virus which causes COVID-19 can be present on surfaces:

Full link from NY Times: How Long Will Coronavirus Live on Surfaces or in the Air Around You?

An excerpt:

The virus lives longest on plastic and steel, surviving for up to 72 hours. But the amount of viable virus decreases sharply over this time. It also does poorly on copper and cardboard, surviving four to eight hours; the latter finding suggests packages that arrive in the mail should be safe — unless the delivery person has coughed or sneezed on it or has handled it with contaminated hands.

That the virus can survive and stay infectious in aerosols is also important for health care workers.

For weeks experts have maintained that the virus is not airborne. But in fact, it can travel through the air and stay suspended for that period of about a half-hour.

The virus does not linger in the air at high enough levels to be a risk to most people who are not physically near an infected person. But the procedures health care workers use to care for infected patients are likely to generate aerosols.

The original article from NEJM:  Aerosol and Surface Stability of SARS-CoV-2 as Compared with SARS-CoV-1

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This “C” virus was hard to cure until recently.  More good news from recently published studies for pediatric hepatitis c virus (HCV) treatment:

  • KB Schwarz et al. Hepatology 2020; 71: 422-30. 
  • MM Jonas et al. Hepatology 2020; 71: 456-62.
  • AASLD-IDSA Practice Guidance Panel. Hepatology 2020; 71: 686-721

In the first study of an all oral regimen of ledipasvir-sofosbuvir, sustained virological response at 12 weeks after dosing (SVR12) was achieved in 33 of 34 (97%) of children 3-<6 yrs of age with genotypes 1 or 4 (only 1 with type 4). No serious adverse effects were reported. Dosing: 33.75 mg/150 mg if <17 kg or 45 mg/200 mg if ≥17 kg. The one non-responder discontinued treatment due to drug taste.  Pharmokinetic studies in 13 patients confirmed appropriate medication dosing.

In the second study of glecaprevir/pibrentasvir (G/P), as part of the DORA phase 2/3 nonrandomized, open-label trial, adolescents 12-17 received the ‘adult’ regimen of 300 mg/120 mg daily for 8-12 weeks in accordance with indication duration based on adult data.  Among the 47 patients (genotypes 1, 2, 3, 4), 100% achieved SVR12. Safety profile was consistent with prior studies in adults.

The third publication, which is quite lengthy, highlights updated recommendations for HCV in adults and children (this will be reviewed in tomorrow’s post).

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