Why It is Still Not a Good Idea to Test Healthy Children for Enteric Pathogens & Infant Mortality Rates Rising in Georgia (& much of U.S.)

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BR Lee et al. J Pediatr 2023; 261: 113551. A Comparison of Pathogen Detection and Risk Factors among Symptomatic Children with Gastroenteritis Compared with Asymptomatic Children in the Post-rotavirus Vaccine Era

Patients (<11 yrs old) with acute gastroenteritis (AGE, n=2503) and healthy controls (HC, n=537) old enrolled in the New Vaccine Surveillance Network study between December 2011 to June 2016. Key findings:

  • One or more organisms was detected in 1159 of 2503 children (46.3%) with AGE compared with 99 of 537 HC (17.3%).
  • Norovirus was detected most frequently among AGE (n = 568 [22.7%]). The other frequent pathogens detected were rotavirus 7.8% (despite ~75% vaccinated population), adenovirus 4.8%, C difficile 5.3%, Salmonella 6.4%, and Shigella 4.5%. 63.5% of all pathogens detected were viruses.
  • C difficile was detected more frequently in the HC population (7% vs 5.3%). E coli infections, likewise, were very commonly observed in the HC population (2.1% vs 1.1%). The false positive rates for C difficile pathogenicity would have been higher if the authors had not restricted their analysis to >12 months for C diff. The rates of Norovirus and Rotavirus in the HC group was 6.8% and 2.6% respectively.
  • Codetection of multiple pathogens was common. For example, with norovirus, 20.8% had a copathogen detected. Salmonella and C difficile had the highest codection rates of 53.5% and 54.5% respectively.

This study shows substantial improvement in rotavirus infections with a drop from 26% in detection prior to vaccine era to 6% afterwards.

My take: These muliplex molecular assays are quite useful and have improved our ability to determine underlying infections. This is particularly useful in children with underlying diseases (eg. IBD, malignancy). However, this report serves as a cautionary note that many pathogens, including C diff and E coli, are frequently identified with PCR assays in healthy children

Related blog posts:

In 2022, 892 infants died in Georgia, an increase of 116 from prior year. About 7 infants dying for every 1000 births. AJC 11/1/23: CDC: Georgia’s infant mortality increase is among the worst in U.S.

Bromelia

Increasing Prevalence of Steatotic Liver Disease in Adolescents

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P Hartmann et al. Hepatology 2023; 78: 1168-1181. Open Access! Global and national prevalence of nonalcoholic fatty liver disease in adolescents: An analysis of the global burden of disease study 2019

The authors  analyzed data from the Global Burden of Disease Study 2019 to compare global, continental, and national prevalence rates of adolescent (15-19 yrs of age) NAFLD.

Key finding:

  • The global NAFLD prevalence in adolescents increased from 3.73% in 1990 to 4.71% in 2019 (a relative increase of 26.27%). NAFLD is now termed metabolic dysfunction-associated steatotic liver disease (MASLD).
  • High body mass index and not type 2 diabetes mellitus correlated with NAFLD prevalence in adolescents globally. 

In the associated editorial (S Xanthakos, Hepatology 78(4):p 1017-1019, October 2023, Rising tide of NAFLD in youth: A warning bell and call to action), some of the key points:

  • “The Global Burden of Disease (GBD) Study is the most comprehensive and long-standing effort to systematically and scientifically collate data on hundreds of diseases and injuries across the globe, including related clinical outcomes. Beginning in 1990, the GBD Study initially collected data on 106 conditions and 10 risk factors, across 5 age groups.1 Over time, the GBD Study has expanded through serial iterations to involve >9000 international researchers collecting data on 369 diseases and injuries across 204 countries and territories in the most recent 2019 report.1“
  • ” From the GBD Study, we learned that NAFLD is the most rapidly rising cause of chronic liver disease in adolescents and adults,2 and the fastest-growing contributor to cirrhosis, liver cancer, and liver-related deaths globally.”
  • “The global prevalence of NAFLD in adolescents shows no sign of abating, rather has continued to increase steadily from 3.7% in 1990 to 4.7% in 2019.”
  • “As with all epidemiological research, the GBD study faces the primary limitation of relying on data sources that employ varying and less accurate measures of NAFLD prevalence (alanine aminotransferase and/or ultrasound primarily). However, the rigorous methodological approach employed by the GBD including frequent assessment of face validity, and the tremendous input of data sources (>80,000 in 2019) nonetheless results in the most comprehensive global data set available.”

My take (borrowed from editorial): Without intervention, “the increase in adolescent NAFLD certainly portends a future increase in NAFLD-related cirrhosis and liver-related deaths in young adults in the coming decades, and a likely escalation in cardiovascular and diabetes-related morbidity.

Related blog posts:

Flu Shots & Other Vaccines Linked to Lower Rates of Dementia

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10/26/23 Washington Post: Flu shots may protect against the risk of Alzheimer’s, related dementias

An excerpt:

A number of studies have found that people receiving vaccinations for flu and several other infectious diseases appear less likely than the unvaccinated to develop dementia, although scientists aren’t sure why…

In the flu study, the researchers took participants from a national patient database, two groups of 935,887 each, one group vaccinated, the other not. To avoid the potential influence of various factors that could affect the results, the scientists ensured that each group shared many of the same characteristics… found that an annual flu vaccination for three consecutive years reduced the dementia risk 20 percent over the next four to eight years, while six shots doubled it to a 40-percent reduction…

“All this requires further studies, but vaccination, along with good diet, exercise, intellectual and emotional stimulation are key factors for healthy aging,” Hotez said.

The article notes reductions in dementia with Shingles vaccine, Tdap or Td, and pneumococcal vaccines.

These cliffs of the calanques (near Cassis, France) are about 260 meters in elevation

Upadacitinib Works Quickly and with High Response

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D Ahuja et al. Am J Gastroenterol 2023; Open Access! Comparative Speed of Early Symptomatic Remission With Advanced Therapies for Moderate-to-Severe Ulcerative Colitis: A Systematic Review and Network Meta-Analysis Thanks to Ben Gold for this article.

Key findings:

  • On network meta-analysis of 14 RCTs, upadacitinib was more effective than all agents in achieving symptomatic remission at weeks 2 (range of RR, 2.85–6.27), 4 (range of RR, 1.78–2.37), and 6 (range of RR, 1.84–2.79). 

This study has a number of limitations including the following:

  • Potential differences in patient-level characteristics between these trials
  • Symptoms may not always correlate with endoscopic findings
  • Data from some medications (eg. tofacitinib) were incomplete and not included

My take: This study indicates an impressive early symptomatic response to upadacitinib compared to other agents for ulcerative colitis.

Related blog posts:

Three-fer on Steatotic Liver Disease

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  1. JJ Wattacheril, MF Abdelmalek et al. Gastroenterol 2023; 165: 1080-1088. Open Access! AGA Clinical Practice Update on the Role of Noninvasive Biomarkers in the Evaluation and Management of Nonalcoholic Fatty Liver Disease: Expert Review

This article offers best practice advice -here are two of them:

#2: A Fibrosis 4 Index score <1.3 is associated with strong negative predictive value for advanced hepatic fibrosis and may be useful for exclusion of advanced hepatic fibrosis in patients with NAFLD.

#8 Patients with NAFLD and NITs (noninvasive tests) results suggestive of advanced fibrosis (F3) or cirrhosis (F4) should be considered for surveillance of liver complications (eg, hepatocellular carcinoma screening and variceal screening per Baveno criteria). Patients with NAFLD and NITs suggestive of advanced hepatic fibrosis (F3) or (F4), should be monitored with serial liver stiffness measurement; vibration controlled transient elastography; or magnetic resonance elastography, given its correlation with clinically significant portal hypertension and clinical decompensation.

2. AJ Sanyal et al. Clin Gastroenterol Hepatol 2023; 21: 2889-2900. Validation of a Clinical Risk-based Classification System in a Large Nonalcoholic Fatty Liver Disease Real-world Cohort

In this study from U.S., patients (n=2523) were divided into three categories based on FIB-4 scores: (A) Fibrosis-4 (FIB-4) <1.3 and/or liver-stiffness measurement (LSM) measured by Fibroscan <8 kp, (B) FIB-4 1.31‒2.6 and/or LSM 8.1-12.5 kp, and (C) FIB-4 >2.6 and/or LSM >12.5 kp. However, those in class A with aspartate transaminase:alanine transaminase ratio >1 or platelets <150,000/mm3, or class B with aspartate transaminase:alanine transaminase ratio >1 or platelets <150,000/mm3 were upstaged by one class. The data were reviewed retrospectively from a prospective longitudinal cohort (TARGET-NASH)

Key findings: All adverse outcomes including liver and cardiovascular (see below) were correlated with FIB-4 staging.

S Man et al. Gastroenterol 2023; 165: 1025-1040. Open Access! Prevalence of Liver Steatosis and Fibrosis in the General Population and Various High-Risk Populations: A Nationwide Study With 5.7 Million Adults in China

Key findings: The prevalence of steatosis, severe steatosis, advanced fibrosis, and cirrhosis was 44.39%, 10.57%, 2.85%, and 0.87%, respectively in Chinese adults

Limitation: This data was derived from a health checkup cohort which could give different results than a random population sampling. Patients at health checkups may be more health conscious and/or be aware of underlying health concerns.

Prevalence of different grades of liver fibrosis in different age groups.

My take: Steatotic liver disease is a huge worldwide problem. The growing prevalence is going to result in extensive health issues.

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This year’s pumpkin 910/31/23):

It does not look like I will become a professional pumpkin artist anytime soon!

What’s Going on With Refractory Heartburn?

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L Guadagnoli, A Geeraerts et al. Gastroenterol 2023; 165: 848-860. Open Access! Psychological Processes, Not Physiological Parameters, Are Most Important Contributors to Symptom Severity in Patients With Refractory Heartburn/Regurgitation Symptoms

Methods: Consecutive adult patients (n=393) with refractory heartburn/regurgitation symptoms underwent standard 24-hour pH-impedance monitoring and completed questionnaires assessing past and current gastrointestinal and psychological health. Refractory reflux meant that they continued to have symptoms after completing at least 12 weeks of PPI (twice per day) treatment.

Key findings: Psychological symptoms were significantly associated with reflux symptom severity, and physiological reflux variables (eg, number of reflux episodes) were not.

In the discussion, the authors note that ” prior research demonstrates psychological symptoms, including depression, anxiety, and post-traumatic stress, are associated with reflux symptom severity.25, 26, 27 Indeed, psychological processes are believed to impact the brain–gut axis, particularly its central components,28 leading to enhanced esophageal symptom perception and reporting.6,29,30“

My take: Psychological factors (depression, anxiety, post-traumatic stress, and poor sleep) are important factors in refractory reflux and they need to be considered early in the evaluation.

A related article: NY Times Magazine 10/4/23, M Velasques-Manoff. The Mystery of My Burning Esophagus. In this article, the writer describes burning pain associated with his diagnosis of eosinophilic esophagitis. This article has some useful information about eosinophilic esophagitis and about lingering symptoms after responding to treatment.

“My new gastroenterologist had a theory to explain the all-consuming pain under my sternum. Sometimes patients develop a hypersensitivity syndrome, she told me. The original insult — in my case, inflammation of some kind — might be long gone, but the nerves that convey pain can become overactive and begin firing at the slightest provocation…Scientists don’t completely understand how antidepressants help pain syndromes, but certain ones seem to impede pain signals in the nervous system…

Doctors are increasingly aware of these kinds of pain syndromes in many disorders, including GERD. The condition, whose primary symptom is known colloquially as heartburn, is pervasive, afflicting an estimated one in five Americans. Some of these patients continue to feel intense pain even after their stomach acid has been reduced with antacids, a malady most likely caused by a hypersensitivity syndrome similar to mine.”

Related blog posts:

Greenville County (SC) Museum of Art

Surgery Compared to Biologic Therapy for Crohn’s Disease

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M Agrawal et al. Gastroenterol 2023; 165: 976-985. Open Access! Early Ileocecal Resection for Crohn’s Disease Is Associated With Improved Long-term Outcomes Compared With Anti-Tumor Necrosis Factor Therapy: A Population-Based Cohort Study

In this study from Denmark (2003-2018) using the Danish National Patient and Prescription Registries, the role of early ileocecal resection (CR), n=581, was compared with anti-TNF treatment, n=698. The primary outcome was a composite of ≥1 of the following: CD-related hospitalization, systemic corticosteroid exposure, CD-related surgery, and perianal CD. Only 178 patients (13.9%) were less than 17 years old. ICR cohort had surgery within 5 months of diagnosis in 85%, and in all within 1 yr of diagnosis. Key findings:

  • The risk of the composite outcome was 33% lower with ICR compared with anti-TNF (adjusted hazard ratio, 0.67; 95% confidence interval, 0.54–0.83). ICR was associated with reduced risk of systemic corticosteroid exposure and CD-related surgery, but not other secondary outcomes
  • Of individuals who underwent ICR, the Kaplan-Meier estimate of the proportion who postoperatively initiated IMM, initiated anti-TNF treatment, underwent another intestinal resection, or were on no treatment at 5 years of postoperative follow-up was 46.3%, 16.8%, 1.8% and 49.7%,
  • Of those who were initiated on infliximab as primary therapy, the Kaplan-Meier estimate of the proportion who underwent ICR, switched to a different biologic agent, or continued infliximab at 5 years of follow-up was 17.7%, 40.8%, and 47.3%

The authors note that their cohort had infrequent complicated disease: “Before ICR, 21% were diagnosed with a stricture, ileus, internal fistula, or abscess, indicative of complicated CD and representative of the real world. In contrast, only 1.7% in the anti-TNF group had complicated CD.”

My take: This study suggests that ICR may be a reasonable option in many cases of Crohn’s disease at an earlier stage rather than reserved for only those with refractory disease and complications. However, in pediatric patients, I would be more reluctant to start with a surgical approach given even longer time frame in which further surgery could be needed.

Related blog posts:

Do We Need to Reimmunize Patients (with IBD or Celiac) with Low Hepatitis B Surface Antibody Levels?

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JA Ulrich et al. Clin Gastroenterol Hepatol 2023; 21: 2901-2907. Open Access! Effectiveness of Hepatitis B Vaccination for Patients With Inflammatory Bowel and Celiac Disease

In 2022, a study in JPGN showed that the rate of Hepatitis B virus (HBV) vaccination and immunity was similar in individuals with and without celiac disease (CD). In addition, there was no increased risk of HBV infection detected in CD patients. Thus, routinely checking hepatitis B status in all patients with CD was no longer justified. (See: Celiac Disease, Hepatitis B and Paul Harvey).

The same researchers in this study expand their findings to inflammatory bowel disease (IBD) and CD. In this retrospective cohort (2000-2019), using the Rochester Epidemiology Project which includes data from 162,847 residents. Key findings:

  • 1264 incident cases of IBD/CD, only 6 HBV infections were diagnosed before the index date; 5 of the 6 had risk factors including IV drug use or living in endemic region.
  • No new HBV infection developed in any of 1258 patients with IBD/CD during a median follow-up of 9.4 years
  • The proportion of patients with HBV-protective titers (≥10 mIU/mL) decreased with time before plateauing, with protective titer rates of 45% at 5 up to 10 years and 41% at 15 up to 20 years after the last HBV vaccination. The control population with protective titers also decreased similarly with time though was consistently higher than the levels of patients with IBD/CD within 15 years after the last HBV vaccination

Context/Discussion:

  • Only 16% of vaccine recipients have measurable protective titers by age 18 years, according to the CDC.32
  • “Time-related waning of Ab levels to HBV after vaccination has unclear clinical significance. Although screening persons for HBV immunity by using anti-HBs titers is widely accepted, prior study results have shown that cellular immunity can also provide long-term HBV protection, even in the setting of nonprotective titers.”
  • Reactivation of HBV is a well-documented complication of immunosuppression in patients with IBD, and screening for dormant infection is of paramount importance at diagnosis
  • Limitations: the study population had a low rate of HBV acquisition; thus, the study findings may not apply to areas with higher risk for HBV.

My take: This study shows that treating low hepatitis B surface antibody levels with reimmunization is likely NOT needed in either the IBD or the celiac disease population, except perhaps in those at high risk. Checking HBV status prior to immunosuppressive therapy, though, is still needed to prevent reactivation of HBV in those at risk.

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Chalk Art in Sandy Springs:

Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

#NASPGHAN23 Year in Review 2023

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Yesterday’s post was meant to be published on Halloween –will need to fire my editor.

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One of the highlights of NASPGHAN’s annual meeting is the Year in Review lecture. Sandeep Gupta, the editor of JPGN, provided a fantastic review. Here are some of the slides:

AAP has recommended pharmacotherapy and bariatric surgery in selected adolescents at 12 yr and 13 yr respectively. Related blog post: Meds for Obesity: AAP Guidelines
Related blog post: Semaglutide in Adolescent Obesity
Related blog post: Oral GLP-1 Receptor Agonist for Obesity: Orforglipron
etinoids may reduce risk of asparginase-associated pancreatitis
Related blog post: Nonspecific Duodenal Histologic Findings Common in Children with Trisomy 21
Related blog post: Updated Nomenclature for Eosinophilic Gastrointestinal Diseases
Related blog post: I-SEE for Eosinophilic Esophagitis
Related blog post: When to Use Dupilumab for Eosinophilic Esophagitis: Multispecialty Guidelines
Related blog post: Short Bowel Syndrome is a Full Time Job
Related blog post: You No Longer Have Fatty Liver Disease-You Have Steatotic Liver Disease!
Related blog post: RNA Interference (Fazirsiran) for Liver Disease Associated with Alpha-1-Antitrypsin Deficiency
Related blog post: Which Diet is Best for Irritable Bowel Syndrome? A Randomized Trial
Related blog post: Constipation Action Plan: Better Instructions, Fewer Phone Calls
Related blog posts: Foreign Body Retrieval: You Never Know What You Will See, Foreign Bodies in Children -Expert Guidance, Sharp Objects in GI Tract & Good Outcomes

Treats (Tips) and Tricks for Using IBD Drugs in Patients with Hepatobiliary Comorbidities

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S Massironi et al. Inflamm Bowel Dis 2023; 29: 1477-1487. Use of IBD Drugs in Patients With Hepatobiliary Comorbidities: Tips and Tricks

This review article makes a number of useful points:

  • Almost all of the IBD medications (Anti-TNF, Vedolizumab, Ustekinumab, Tofacitinib, Ozanimod) should not be used in patients with untreated hepatitis B surface antigen positivity. Antiviral prophylaxis is recommended even patients with inactive disease (HBV DNA <2000 IU/mL/normal ALT) starting 2 weeks prior to immunosuppression up to 12 weeks after immunosuppression discontinuation.
  • Anti-TNF, Vedolizumab, and Ustekinumab can be safely used in patients with cirrhosis, tofacitinib requires a dose reduction, and ozanimod is NOT recommended
  • Autoimmune hepatitis may be triggered (rarely) by use of anti-TNFs; however, these agents have been uses off-label as a rescue therapy for AIH as well.
  • Anti-TNFs do not appear worsen liver function in PSC and may be associated with improvement in MASH (NASH)
  • Drug-induced liver injury (DILI) is common with anti-TNFs, often seen between the second and fifth doses. It is “generally transient and asymptomatic.” DILI may occur with ustekinumab, tofacitinib and ozanimod.
  • Tofacitinib may have a favorable effect on PSC. A retrospective study with 5 patients reported a 28% and 39% decrease respectively in total bilirubin and alkaline phosphatase within 6 months of starting therapy, A separate study with 42 patients showed a non-significant drop in alkaline phosphatase from 150 U/L to 132 U/L at 12 month followup.
  • The authors note that in patients with cirrhosis and posttransplantation, “vedolizumab and ustekinumab should be preferred due to their safer profile linked to infectious risk.”
  • “Patients with hepatobiliary disorders are often excluded from pivotal trials.” This contributes to a significant knowledge gap for patients with these comorbid conditions which are frequent in patients with IBD

My take: I don’t think I will be too popular if I hand out copies of this article to the kids I see later today –despite the useful advice. (This post was meant to be published on Halloween)

Related blog posts:

Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.