NUTRITION ISSUES IN GASTROENTEROLOGY

Propofol Related Infusion Syndrome:Implications for Nutrition in the Intensive Care Unit

August 2021 • Volume XLV, Issue 8
Matthew Hulse

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Propofol is an intravenous anesthetic agent widely used for a variety of indications in both the operative and critical care settings. Propofol’s ability to produce rapid sedation with a short duration of action makes it an especially appealing agent within the critical care population. While propofol’s beneficial prosperities have been widely exploited in the past several decades, the drug can also be associated with undesirable side effects such as hypotension, hypoventilation, bradycardia, and hyperlipidemia. Rarely, propofol is also linked to the development of severe lactic acidosis, bradycardia, rhabdomyolysis, renal failure, hepatomegaly, hyperlipidemia, cardiovascular collapse and ultimately death. These severe adverse events when combined are referred to under the umbrella of “propofol related infusion syndrome” (PRIS) which can occur in the setting of prolonged, high dose infusions. In this review, we will discuss the pharmacokinetics and pharmacodynamics of propofol and the potential mechanisms for the development of PRIS. Importantly, new evidence suggests that a thoughtful nutritional strategy focusing on carbohydrate administration may help avoid the development of this feared complication.

INTRODUCTION

Developed by James Baird Glen in 1980 and approved by FDA in 1989, propofol (Diprivan) is now the most commonly used anesthetic agent around the world. Due to its poor solubility in water, propofol is formulated at 1% in an oil/water emulsion containing 10% soybean oil, 2.25% glycerol and 1.2% egg lecithin (contains long-chain triglycerides). Given the medium for preparation, bacterial contamination of propofol solution is possible and care should be taken to avoid long delay in administration when vials are open. Presence of EDTA in propofol formulation, a bacteriostatic agent, delays bacterial growth; other propofol formulations (generic) contain sodium metabisulfite as an antibacterial agent. Allergic reactions to propofol have been a cause for concern due to the egg and soy components. Original formulations contained cremophor but were withdrawn because of high incidence of anaphylactic reactions observed in both animals and humans.1 It was once assumed that patients with egg, soybean, or peanut allergy could not receive propofol, however this was subsequently disproven in both children and adults.2,3

Propofol exerts its main activity through interaction with the γ-Aminobutyric acid type A (GABAA) receptors in the central nervous system. GABAA is the main inhibitory transmitter in the brain and when GABAA receptors are activated, chloride conductance increases leading to hyperpolarization of post-synaptic cell membrane and subsequent neuronal inhibition.

Propofol is highly protein bound and is removed from the plasma via hepatic and non-hepatic pathways. Hepatically, propofol is metabolized via cytochrome P-450 to inactive sulfates and glucuronic acid metabolites which are subsequently eliminated by the kidneys. The half-life of propofol after a single injection is very short, with the initial half-time of approximately 2 minutes. A more important consideration is the context sensitive half-time (CST) of propofol, the time required for the drug plasma concentration to decrease by 50%, which is a major consideration in the critical care setting when prolonged infusions are more likely to be used. It is estimated the CST can approach 45 minutes after prolonged infusions.4

Propofol Related Infusion Syndrome

Propofol infusion syndrome is a rare and potentially fatal condition first reported in children in 1990 and more recently in adults receiving longterm (>48 h), high dose (>4/mg/kg/h) propofol infusions.5 The first pediatric patients described experiencing the syndrome were characterized by profound metabolic acidosis, bradycardia, and other dysrhythmias eventually leading to cardiac arrest.6 Since that time, PRIS is now characterized by a constellation of symptoms which involves nearly every organ system. Other commonly reported biochemical and clinical features include rhabdomyolysis, lactemia, and acute kidney injury (AKI). Table 1 summarizes the reported clinical features associated with PRIS.7

Despite initially being considered a syndrome associated only in the pediatric population, it is now clearly evident that it can occur in adults as well. While difficult to estimate, the incidence of PRIS remains rare, likely less than 2% of those being treated with propofol, but continues to be associated with high mortality, up to 80%.8 The incidence of PRIS has been decreasing in recent years due to improved education surrounding the condition, as well as improvements in recognition of the clinical features of the disease process and predisposing conditions. A prolonged and relatively high dose propofol infusion remains a necessary, but not necessarily sufficient, mechanism to induce PRIS. For instance, 68% of the cases from the MEDWATCH database involved propofol infusion rate exceeding 83 mcg/kg/minute (5 mg/kg/hour); 54% of the cases received propofol for over 48 hours.9 Various predisposing factors for PRIS have been suggested by different researchers. Vasile et al. proposed the notion of “priming factors” and “triggering factors” for the syndrome. The priming factor is critical illness and the consequences that follow (systemic inflammation and endogenous catecholamine, glucocorticoid, and cytokine production).7 Triggering factors are the concurrent use of high dose propofol, exogenous catecholamines and corticosteroids.

Other authors describe predisposing factors including age, cumulative dose of propofol, severe critical illness of the central nervous system (CNS) or respiratory origin, infusion of catecholamines, infusion of corticosteroids, inadequate delivery of carbohydrates, and subclinical mitochondrial disease.10,11 The pathogenesis of propofol related infusion syndrome is complex and beyond the scope of this article, however, several important mechanisms underlie the syndrome (Table 2).

While the pathologic cellular energetics which underlie the development of PRIS are complex, it is important to broadly review these topics in order to understand how nutritional therapies can be exploited to potentially prevent the syndrome. Early theories about the cause of acidosis in PRIS included impaired hepatic lactate metabolism caused by the lipid present in propofol leading to lactate accumulation and acidosis, accumulation of inactive propofol metabolites, and lipid microembolization. However, recent research has focused on impaired mitochondrial respiratory chain function being one of the primary mechanisms. Free fatty acids (FFA) are derived from catecholaminemediated lipolysis of adipose tissues and are the most important fuel for the myocardium and skeletal muscle tissues under fasting conditions or in critical illness. Any obstacle to FFA utilization determines various degrees of metabolic acidosis and resultant myocytolysis. Cray et al. supported the theory that a propofol metabolite caused a direct biochemical inhibition which disrupts the respiratory chain causing a failure of adenosine triphosphate (ATP) production, cellular hypoxia, and metabolic acidosis.12 Mehta et al. demonstrated a reduced complex IV activity in the mitochondria,13 and Wolf et al. has implicated the disruption of mitochondrial fatty-acid oxidation.14 Long-term propofol infusion is associated with an increase in malonylcarnitine, which ultimately results in impairment of mitochondrial transport proteins (malonyl coenzyme A and canitine palmitoly transferase I). Consequently, the entry of long chain acylcarnitine esters in the muscle is impaired. Medium and short chain fatty acids diffuse into the mitochondria and inhibit and uncouple the respiratory chain (at complex II) causing a failure of ATP production in the mitochondria, leading to a further buildup of long chain, medium chain, and short chain fatty-acid metabolic by-products.14 Thus, the literature suggests at least two impairments in FFA metabolism level of the mitochondria necessary for the syndrome to occur. Firstly, longchain FFA cannot enter the mitochondria due to inhibition of the active transport, and secondly, while the medium and short-chain FFA, that freely cross the mitochondrial membranes which do not require enzyme-mediated transfer, these cannot be used due to the mitochondrial uncoupling by propofol itself. These biochemical processes which increase FFA combined with the lipid formulation of the drug, drastically increases the medium and long chain triglyceride fat load. As a consequence of the impaired fatty-acid oxidation, a rapid buildup of toxic fatty-acid intermediates results and when coupled with cellular hypoxia, creates a cycle of worsening acidosis and patient decompensation. Excess serum fatty-acid concentrations have been shown to directly contribute to ventricular dysrhythmias, one of the hallmarks of the disease.15

Nutrition and the Role of Carbohydrates

Further attempts to prevent PRIS and optimize cellular energetics in critically ill patients have begun to focus on the role of nutrition and the provided macronutrient profile, especially focusing on dietary carbohydrates. Illustrative of the importance of carbohydrate administration, a case report published in 2004 speculated that PRIS was precipitated by the commencement of a ketogenic diet (high fat, low carbohydrate) as adjuvant therapy for refractory status epilepticus in a 10-year-old boy sedated with propofol.16 The premise of this case report suggests that the dietary fat load, coupled with the propofol-mediated impairment of mitochondrial fatty-acid oxygenation contributed to the metabolic acidosis and clinical decompensation. Furthermore, PRIS mimics the congenital mitochondrial DNA myopathies in which specific defects in the mitochondrial respiratory chain result from a disturbance in the lipid metabolism in cardiac and skeletal muscle. A typical case scenario is a pediatric patient who is well until stressed by infection or starvation, when fat metabolism is needed for energy production. Under such conditions, the patients develop severe rhabdomyolysis, cardiac, and hepatic insufficiency associated with hypoglycemia. Now various guidelines support avoiding propofol in patients known to have these inborn errors in metabolism due to this association.17 These biochemical foundations of altered mitochondrial fat oxidation in the PRIS disease process have lent importance to strategies that focus on nutritional alterations which may modulate the disease state and its predisposition. As evidenced by the above ketogenic diet example, both high lipid loads as well as low-carbohydrate intake have been implicated in the development of PRIS. A major concern with propofol is the lipid load owing to its formulation which increases solubility. A daily intravenous lipid load of 2-3 g/kg/day is regarded as adequate for children on total parenteral nutrition (TPN).18 This is equivalent to a fat load conferred by a 1% propofol infusion running at 4 mg/kg/h. Given that most of the case reports documenting PRIS were associated with infusion rates greater than 4 mg/kg/hr, it is postulated that the excessive lipid load may be a significant contributory factor. Considering the lipid load and resultant hyperlipidemia noted in PRIS, the importance of carbohydrate substrates in the process of normal lipid metabolism in the liver cannot be understated. Ahlen et al. have postulated that as a result of the depletion of carbohydrate stores in the critically ill patient, lipid accumulation associated with the high propofol infusion rate is not a direct implication of the toxicity of propofol, rather a consequence of the exhaustion of carbohydrate stores.19 Carbohydrate depletion can, in turn, lead to a reduction in citric acid levels, which slows lipid metabolism.20 Although further research is necessary, some evidence suggests early adequate intake of a source of carbohydrate may reduce the risk of developing PRIS by preventing the switch to fat metabolism. The larger carbohydrate stores in adults may partially explain the lower incidence of the syndrome in adults. Wolf et al. suggested that a carbohydrate intake of 6-8 mg/kg/min can suppress fat metabolism in critically ill children and thus prevent PRIS.14

Management Considerations

A high index for suspicion for development of disease-state and prompt discontinuation of propofol sedation remains the hallmark of both the diagnosis and treatment of PRIS. The disease commonly presents as unexplained high anion gap metabolic acidosis (HAGMA), rhabdomyolysis, hyperkalemia, AKI, elevated liver enzymes, and cardiac dysfunction (brady or tachydysrhythmias, cardiogenic shock, and asystole). There are no established guidelines for the treatment of propofol infusion syndrome nor is there a specific antidote. The successful management of PRIS relies on the awareness of the condition, the clinical features, and maintaining a high index of suspicion of the development of such symptoms in patients who are at elevated risk. The treatment of the condition must rely firstly on prompt discontinuation of the propofol infusion and selection of an alternative sedative agent, if necessary. Management of the metabolic acidosis in the literature includes volume optimization for optimal cardiac output and renal replacement therapy. Sodium bicarbonate in the management of lactic acidosis is controversial, not universally accepted, and could paradoxically worsen acidemia.21 Hyperkalemia and rhabdomyolysis are strong indications to consider renal replacement therapy for patient with metabolic acidosis due to PRIS. Extrapolating from other guidelines for the treatment of rhabdomyolysis, patients should receive vigorous fluid resuscitation.22 However, euvolemia should be maintained in certain patient populations such as those with traumatic brain injuries or heart failure. Calcium administration, insulin with or without dextrose, beta-2 agonists, sodium bicarbonate, and potassium binding resins can be considered in the treatment of hyperkalemia. Despite these interventions and conventional circulatory support measures in modern critical care medicine, many case reports highlight the refractory nature of the condition to intravenous fluid volume loading and the use of escalating doses of vasopressors and inotropes. Limited success has been achieved with cardiac pacing for dysrhythmias, and there is emerging literature of success with extracorporeal membrane oxygenation (ECMO).23 Table 3 outlines the major management considerations for treatment of suspected PRIS.

CONCLUSION

PRIS is a rare but extremely dangerous complication of propofol administration with high mortality in both the pediatric and adult patient populations. Risk factors for the development of PRIS are described such as: large doses of propofol and prolonged duration of infusions, carbohydrate depletion, critical illness, and concomitant administration of catecholamines and glucocorticoids. The pathophysiology of the condition includes impairment of mitochondrial beta-oxidation of fatty acids, and the disruption of the electron transport chain resulting in metabolic disarray. The disease commonly presents as an otherwise unexplained metabolic acidosis, rhabdomyolysis, hyperkalemia, acute kidney injury, elevated liver enzymes, and cardiac dysfunction. Management of PRIS includes immediate discontinuation of the propofol infusion and problem-driven management which may include hemodialysis, hemodynamic support, optimization of glucose metabolism, nutritional supplementation to include adequate carbohydrate sources, and ECMO in refractory cases. Despite increased awareness of the clinical condition and improvements in the specialty of critical care medicine, mortality remains high. Clinicians should consider alternative sedation agents in patients who are receiving prolonged (>48 h) or high dose propofol infusions (>4/ mg/kg/h) and be aware of the various strategies available to reduce the likelihood of developing the syndrome.

References

1. Briggs LP, Clarke RSJ, Watkins J. An adverse reaction to the administration of disoprofol (Diprivan). Anaesthesia. 1982;37:1099-1101.
2. Asserhøj LL, Mosbech H, Krøigaard M, et al. No evidence for contraindications to the use of propofol in adults allergic to egg, soy or peanut. Br J Anaesth. 2016 Jan;116(1):77-82
3. Sommerfield DL, Lucas M, Schilling A, et al. Propofol use in children with allergies to egg, peanut, soybean or other legumes. Anaesthesia. 2019 Oct;74(10):12521259.
4. Hughes MA, Glass PS, Jacobs JR. Context-sensitive half-time in multicompartment pharmacokinetic models for intravenous anesthetic drugs. Anesthesiology. 1992 Mar;76(3):334-41
5. Kam, P.C.A. and Cardone, D. Propofol infusion syndrome. Anaesthesia. 2007. 62: 690-701.
6. Hatch DJ. Propofol-infusion syndrome in children. Lancet. 1999 Apr 3;353(9159):1117-8.
7. Vasile B, Rasulo F, Candiani A, et al. The pathophysiology of propofol infusion syndrome: a simple name for a complex syndrome. Intensive Care Med. 2003 Sep;29(9):1417-25.
8. Roberts RJ, Barletta JF, Fong JJ, et al. Incidence of propofol-related infusion syndrome in critically ill adults: a prospective, multicenter study. Crit Care. 2009;13(5):R169.
9. Fong JJ, Sylvia L, Ruthazer R, et al. Predictors of mortality in patients with suspected propofol infusion syndrome. Crit Care Med 2008;36:2281-7
10. Smith H, Sinson G, Varelas P. Vasopressors and propofol infusion syndrome in severe head trauma. Neurocrit Care 2009;10:166-72.
11. Otterspoor LC, Kalkman CJ, Cremer OL. Update on the propofol infusion syndrome in ICU management of patients with head injury. Curr Opin Anaesthesiol 2008;21:544-51
12. Cray SH, Robinson BH, Cox PN. Lactic acidemia and bradyarrhythmia in a child sedated with propofol. Crit Care Med. 1998 Dec;26(12):2087-92.
13. Mehta N, DeMunter C, Habibi P, et al. Short-term propofol infusions in children. Lancet. 1999 Sep 4;354(9181):866-7.
14. Wolf A, Weir P, Segar P, et al. Impaired fatty acid oxidation in propofol infusion syndrome. Lancet. 2001 Feb 24;357(9256):606-7.
15. Jorens PG, Van den Eynden GG. Propofol infusion syndrome with arrhythmia, myocardial fat accumulation and cardiac failure. Am J Cardiol. 2009 Oct 15;104(8):1160-2.
16. Baumeister FA, Oberhoffer R, Liebhaber GM, et al. Fatal propofol infusion syndrome in association with ketogenic diet. Neuropediatrics. 2004 Aug;35(4):250-2.
17. Hsieh VC, Krane EJ, Morgan PG. Mitochondrial Disease and Anesthesia. Journal of Inborn Errors of Metabolism and Screening. January 2017.
18. Goulet, O.J., Cai, W, Seo, J. Lipid Emulsion Use in Pediatric Patients Requiring Long-Term Parenteral Nutrition. Journal of Parenteral and Enteral Nutrition. 2020. 44: S55-S67.
19. Ahlen K, Buckley CJ, Goodale DB, et al. The ‘propofol infusion syndrome’: the facts, their interpretation and implications for patient care. Eur J Anaesthesiol. 2006 Dec;23(12):990-8.
20. Mirrakhimov AE, Voore P, Halytskyy O, et al. Propofol Infusion Syndrome in Adults: A Clinical Update. Crit Care Res Pract. 2015;2015:260385.
21. Kim HJ, Son YK, An WS. Effect of sodium bicarbonate administration on mortality in patients with lactic acidosis: a retrospective analysis. PLoS One. 2013;8(6):e65283. Published 2013 Jun 5.
22. Vanholder R, Sever MS, Erek E, et al. Rhabdomyolysis. J Am Soc Nephrol. 2000 Aug;11(8):1553-1561.
23. Mayette M, Gonda J, Hsu JL, et al. Propofol infusion syndrome resuscitation with extracorporeal life support: a case report and review of the literature. Ann Intensive Care. 2013;3(1):32. Published 2013 Sep 23.

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Safety of FMT Treatment for Recurrent C. Difficile Infection

Fecal microbiota transplantation (FMT) is highly effective for treating recurrent Clostridioides difficile infection (CDI). A prospective surveybased study was conducted from September 2012 to June 2018 in patients undergoing FMT for recurrent CDI.

Data on demographics and comorbidities were abstracted from medical records. Patients were contacted at 1 week, 1 month, 6 months, 1 year and greater than 2 years post-FMT (longterm). Symptoms and new medical diagnoses were recorded at each time point. Data was weighted to account for survey nonresponse bias. Multivariate logistic regression models for adverse events were built using age, sex, time of survey, and comorbidities.

Overall, 609 patients underwent FMT. Median age was 56 years (18-94), 64.8% were women, and 22.8% had IBD. At short-term followup (N = 609), greater than 60% of patients had diarrhea and 19 (33%) had constipation. At 1 year, 9.5% reported additional CDI episodes. On multivariable analysis, patients with IBD, dialysisdependent kidney disease and multiple FMTs had higher risk of diarrhea; risk of constipation was higher in women and lower in IBD. For long-term follow-up (N = 447), median time of follow-up was 3.7 years (2-6.8). Overall, 73 new diagnoses were reported; 13% gastrointestinal, 10% weight gain, 11.8% new infections deemed unrelated to FMT. Median time to infections was 29 months post-FMT.

It was concluded that FMT appears safe with low risk of transmission of infections. Several new diagnoses were reported that require exploration in future studies.

Saha, S., Mara, K., Pardi, D., and Khanna, S. “Long- Term Safety of Fecal Microbiota Transplantation for Recurrent Clostridioides Difficile Infection.” Gastroenterology 2021; Vol. 160, pp. 1961-1969.

FROM THE LITERATURE

Refractory Reflux Symptoms: A Guide for Discontinuation of PPI Treatment

July 2021 • Volume XLV, Issue 7

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A proportion of patients with gastroesophageal reflux symptoms are refractory to PPI therapy. In order to develop a diagnostic approach to identify candidates appropriate for PPI cessation and to examine the clinical utility of prolonged wireless reflux monitoring to predict the ability to discontinue PPIs, a double-blinded, clinical trial performed over 3 years at 2 centers was carried out.

Adults were enrolled with troublesome esophageal symptoms of heartburn, regurgitation, and/or chest pain and inadequate PPI response. Participants underwent prolonged wireless reflux monitoring (off PPIs for greater than 7 days), and a 3-week PPI cessation intervention. Primary outcome was tolerance of PPI cessation (discontinued or resumed PPIs). Symptom burden was quantified using the reflux symptom questionnaire, electronic diary (RESQ-eD).

Of 128 enrolled, 100 participants met inclusion criteria (mean age 48.6 years; 41 men, 34 participants, 34% discontinued PPIs). The strongest predictor of PPI discontinuation was number of days with acid exposure time (AET) greater than 4%. Participants with 0 days of AET greater than 4% had a 10x increased odds of discontinuing PPI than participants with 4 days of AET greater than 4%. Reduction in symptom burden was greater among the discontinued vs. resumed PPI group.

It was concluded among patients with typical reflux symptoms, inadequate PPI response and absence of severe esophagitis, acid exposure on reflux monitoring predicted the ability to discontinue PPIs without symptom escalation. Upfront reflux monitoring of acid suppression can limit unnecessary PPI use and guide personalized management.

Yadlapati, R., Mishia, M., Gayawali, C., et al. “Ambulatory Reflux Monitoring Guides Proton Pump Inhibitor Discontinuation in Patients with Gastroesophageal Reflux Symptoms: A Clinical Trial.” Gastroenterology 2021; Vol. 160, pp. 174-182, January 2021

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FROM THE LITERATURE

Clinical Features of Both Functional Dyspepsia and Gastroparesis

July 2021 • Volume XLV, Issue 7

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To clarify the pathophysiology of functional dyspepsia (FD) and its relationship with the better understood syndrome of gastroparesis. Adult patients with chronic upper gastrointestinal symptoms were followed up prospectively for 48 weeks in multi-center registry studies. Patients were classified as having gastroparesis if gastric emptying was delayed; if not, they were labeled as having FD if they met Rome III criteria. Study analysis was conducted using analysis of covariance and regression models.

A total of 944 patients were enrolled during a 12-year period; 720 (76%) were in a gastroparesis group and 224 (24%) were in the FD group. Baseline clinical characteristics and severity of upper gastrointestinal symptoms were highly similar. The 48-week clinical outcome was also similar, but at this time, 42% of patients with an initial diagnosis of gastroparesis were reclassified as FD, based on gastric emptying results at this time point. Conversely, 37% of patients with FD were reclassified as having gastroparesis. Change in either direction was not associated with any difference in symptom severity changes. Fullthickness biopsies of the stomach showed loss of interstitial cells of Cajal and CD-206 macrophages in both groups, compared with obese controls.

It was concluded a year after initial classification, patients with FD and gastroparesis as seen in tertiary referral centers at least, are not distinguishable based on clinical and pathologic features, or based on assessment of gastric emptying. Gastric-emptying results are labile and do not reliably capture the pathophysiology of clinical symptoms in either condition. FD and gastroparesis are unified by characteristic pathologic features and should be considered as part of the same spectrum of truly “organic” gastric neuromuscular disorders.

Pasricha, P., Grover, M., Yates, K., et al for the National Institute of Diabetes and Digestive and Kidney Diseases/National Institute of Health Gastroparesis Clinical Research Consortium. “Functional Dyspepsia and Gastroparesis in Tertiary Care are Interchangeable Syndromes With Common Clinical and Pathologic Features.” Gastroenterology 2021; Vol. 160, pp. 2006-2017.

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FROM THE PEDIATRIC LITERATURE

Food to Improve the Microbiome May Help Children with Malnutrition

July 2021 • Volume XLV, Issue 7

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Prior research has demonstrated that children from low- and middle-income countries have a specific microbiome taxa that change in the setting of malnutrition, and such changes may contribute to malnutrition. This study from Bangladesh recruited children between 12 and 18 months of age with moderate acute malnutrition. Such children were randomized to consume either a newly developed microbiota-directed complementary food (MDCF) or a standard ready-to-use supplementary food (RUSF) for three months. The MDCF used in this study was MDCF-2 which is a new formulation that previously has been shown to change the microbiome to beneficial taxa. Anthropometric data was measured every 15 days, and fecal samples were obtained one month after the intervention. Besides anthropometric data, all patients underwent plasma proteomic profiling and gut microbiota determination.

A total of 123 subjects were enrolled (61 received MDCF-2 and 62 received RUSF). No was present regarding anthropometrics and social demographics between the two treatment groups. Both weight-for-length z scores and weight-for-age z scores significantly improved in the MDCF-2 group compared to the RUSF group. Plasma protein analysis showed that 714 proteins significantly increased or decreased in patients receiving MDCF-2 versus 82 proteins which significantly increased or decreased in patients receiving RUSF. Specific proteins that increased significantly in the MDCF-2 group included intermediate layer protein 2 (which improves articular cartilage formation), thrombospondin-4 (which helps develop bone and skeletal muscle), and SFRP4 (which is an osteoclast inhibitor). Fecal analysis demonstrated that 23 bacterial taxa (identified by amplicon sequence variants) were significantly associated with weight-forlength z scores (21 positively associated; 2 negatively associated). Interestingly, 5 of these taxa promoting growth had been identified previously in gnotobiotic mouse studies. Finally, these specific 21 bacterial taxa associated with increased weightfor- length z scores were significantly increased in children receiving MDCF-2 compared to children receiving RUSF and had a positive correlation with 70 plasma proteins associated with improving weight-for-length z scores.

This study demonstrates that changing the fecal microbiome via dietary manipulation may reverse the effects of malnutrition. This finding is intriguing as such effects also could occur in the setting of various types of intestinal inflammation. It is interesting to note that the significant improvements in malnutrition in children receiving MDCF-2 occurred despite this formulation having less caloric density compared to RUSF.

Chen R, Mostafa I, Hibberd M, Das S, Mahfuz M, Naila N, Islam M, Huq S, Alam A, Zaman M, Raman A, Webber D, Zhou C, Sundaresan V, Ahsan K, Meier M, Barratt M, Ahmed T, Gordon J. A microbiotadirected food intervention for undernourished children. N Engl J Med 2021; 384: 1517-1528.

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FROM THE PEDIATRIC LITERATURE

Safety of Biopsy Techniques for Hirschsprung Disease

July 2021 • Volume XLV, Issue 7

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Hirschsprung Disease (HD) is due to aganglionosis of the colon that presents in the distal colon and then proximally. HD typically presents in the first few days of life, and early diagnosis is imperative to provide corrective surgery and to prevent complications such as enterocolitis. Several colonic biopsy techniques exist which help determine the presence of HD, and the authors of this study performed a meta-analysis using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement (PRISMA) for patients younger than 18 years of age with potential HD. All included studies had to include at least 5 patients or at least 5 rectal biopsy specimens. Biopsy types included suction, open surgical, endoscopic, or punch biopsy. Various staining techniques to diagnose HD included hematoxylin and eosin staining, acetylcholinesterase staining, and calretinin staining.

Although an initial analysis by text and abstract screening produced 469 articles, only 159 articles met inclusion criteria after full-text review. A total of 300 patients in the meta-analysis underwent endoscopic biopsy while 3369 patients underwent open biopsy, 1507 underwent punch biopsy, and 20,775 patients underwent suction biopsy. The mean age of patients ranged from 27.84 months (suction biopsy group) to 50.40 months old (punch biopsy group). Interestingly, although no significant difference was present between the conclusive rate result of the various biopsy techniques, the heterogeneity between meta-analysis of biopsy types (using the I2 statistic) was significant (P<0.001). Funnel plot analysis for suction biopsy and open biopsy suggested a possible publication bias.

There was no difference in age (defined as less than 36 months of age and greater than 36 months of age) for conclusive results for patients undergoing suction rectal biopsy, and not enough evidence was available to determine effectiveness of results using the other rectal biopsy techniques. No difference was seen between the various staining techniques in determining conclusive results for HD; however, there was significant study heterogeneity between staining types (P<0.001). Various staining techniques were not significantly different for patients undergoing open surgical biopsy for HD although significant heterogeneity existed between the study groups (P<0.001) while no significant heterogeneity existed for patients undergoing suction rectal biopsy. Finally, the pooled complication rate for the various biopsy techniques was 2% with a significant rate of complications noted for patients receiving punch biopsy versus those receiving suction biopsy.

This study demonstrates that all biopsy techniques for the diagnosis of HD likely are equal in their capacity to generate conclusive results. The authors state that the safety of suction rectal biopsy (including the potential lack of need of sedation) makes it a first-line method for diagnosing HD in children.

Comes G, Ortolan E, Moreira M, de Oliveira Junior W, Angelini M, El Dib R, Lourencao P. Rectal biopsy technique for the diagnosis of Hirschsprung disease in children: a systematic review and meta-analysis. Journal of Pediatric Gastroenterologists and Nutrition 2021; 72: 494-500.

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DISPATCHES FROM THE GUILD CONFERENCE, SERIES #38

Therapeutic Drug Monitoring of Biologics in Inflammatory Bowel Disease: What, When and Why?

July 2021 • Volume XLV, Issue 7
Divya Ashat,Millie D. Long

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Therapeutic drug monitoring (TDM) of biologics in inflammatory bowel disease (IBD) is useful in various arenas of clinical practice. It involves the measurement of drug concentrations and anti-drug antibody levels to help optimize therapy. The most popular strategy now considered to be standard of care is ‘reactive drug monitoring’ which is done when the patient is symptomatic from their disease. Reactive TDM is both efficacious and cost effective when compared to empiric therapy changes. ‘Proactive drug monitoring’ is an emerging strategy that utilizes a target drug level, often early during an induction period, with adjustments in dosing prior to any development of symptoms. Additional uses of TDM include during de-escalation from combination therapy to biologic monotherapy and re-initiation of biologic therapy after a drug holiday. Prudent use of these assays is essential to reduce costs and avoid unnecessary testing.

Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the gastrointestinal tract and has two subtypes, namely Crohn’s disease (CD) and ulcerative colitis (UC). Immunosuppressive agents used in the treatment of IBD include corticosteroids, immunomodulators [thiopurines or methotrexate], biologic agents [anti-tumor necrosis factor alpha (anti-TNFs), anti-integrin therapies, anti-IL-12/23 inhibitors] and janus kinase inhibitors.

Biologic therapies in IBD are genetically engineered monoclonal antibodies targeted against inflammatory antigens. They have revolutionized IBD treatment and are considered as first-line therapy in moderate-severe IBD patients.1,2 Despite their proven efficacy, almost 50% of biologics require discontinuation due to failure to respond to induction therapy (primary non-response), loss of response over time (secondary non-response) or serious adverse events.3 The concept of therapeutic drug monitoring (TDM) refers to the practice of measuring drug concentrations and anti-drug antibodies to help guide treatment changes and optimize the use of biologics. This article will review recommendations from current guidelines and recent evidence on therapeutic drug monitoring of biologics in IBD.

Drug Assays in Practice

At present, therapeutic classes of biologics we can monitor in IBD include anti-TNFs biologics (infliximab, adalimumab, certolizumab pegol and golimumab) and other biologics (vedolizumab, ustekinumab). Drug assays measure drug concentrations and anti-drug antibody levels for individual biologics.4 Drug concentrations show good correlation amongst assays when measured as trough levels, that is, as close to the next dose as possible within 24 hours.5 Multiple factors both drug-related (route of administration, dose, inherent immunogenicity, presence of anti-drug antibodies, use of concomitant immunomodulators) and patientrelated (such as sex, body mass index, albumin levels, CRP levels) affect the drug concentrations of biologics.6 Low drug concentrations are associated with antibody development, loss of response and overall poor outcomes.5 Higher drug concentrations have been associated with better outcomes and do not necessarily increase the risk of side effects. Anti-drug antibody levels are produced as an immune response to the biologic protein and is one of the major causes for loss of response to biologic therapy. Anti-TNFs are considered to be more immunogenic than other biologics.7 Unlike drug trough levels, there is low agreement across assays on the levels of anti-drug antibody levels.5 It is, therefore, important to check the reference ranges for the assay being used. There are a variety of commercially available assays for measurement of biologics. The choice of assay typically depends on what is available in the area of practice and insurance coverage. Trying to use of the same assay in practice allows one to become familiar with the reference ranges. Costs vary across various commercial assays and should be taken into consideration when these assays are being ordered.

Strategies for TDM in biologics

Over the years, the indications for TDM in biologics have evolved. Its two main uses are in reactive drug monitoring and proactive drug monitoring. Other indications for TDM are in de-escalation and reinitiation of therapy.

Reactive Drug Monitoring

Reactive TDM with biologic use in IBD is now well-established and is considered standard of care.3,5,8,9 It refers to drug monitoring in a patient who is symptomatic from their IBD. This is done by checking drug level and anti-drug antibodies in a patient who is losing response to therapy, as defined by clinical symptoms or by an increase in biomarkers, and allows appropriate therapeutic intervention by either salvaging or switching of therapies.

  • If drug trough levels are undetectable or low with no antibodies, intensification of therapy by increasing the dose or decreasing the interval would be appropriate. Adding an immunomodulator would also be beneficial in reducing immunogenicity and increasing drug levels. Low drug levels are often in the setting of a high inflammatory burden resulting in rapid drug clearance.
  • If drug trough levels are adequate with or without presence of antibodies, it suggests a mechanistic failure of the drug. In other words, the biologic in use is not targeting the appropriate inflammatory pathway for this particular patient. Switching to another drug class of drug with a different mechanism would be the next step.
  • If drug levels are undetectable or low with presence of antibodies, treatment options would be based on whether the antibody levels are low or high. Low antibody titers can be a transient phenomenon, and response may be recaptured with dose escalation or addition of an immunomodulator. If antibody titers are high, then either switching to another biologic within the same class or switching class altogether would be appropriate.

An algorithmic approach helps us to understand the role of reactive TDM and shift gears appropriately based on drug concentration and antibody levels (Figure 1).10 Target trough concentrations of at least 5 mcg/mL for infliximab and 7.5 mcg/mL for adalimumab have been historically considered to be adequate to achieve mucosal healing.5,11 More recent prospective data has suggested slightly higher levels are predictive of response (7.5 mcg/mL for infliximab and 12 mcg/mL for adalimumab). For other biologics, such as ustekinumab and vedolizumab, the data is not as robust and the overall drug exposure and efficacy relationship are less clear.12 Target trough levels of biologics for reactive TDM based on currently available data are summarized in Table 1.3,5,12 Above these levels, there is a low chance of further improvement with dose titration.

Proactive Drug Monitoring

Proactive TDM refers to drug monitoring in a patient who is clinically doing well on a biologic therapy. Dose adjustments are made preemptively based on drug concentration and antibody levels. The goal is to adjust therapy early on and thereby prevent primary or secondary loss of response. Proactive TDM could be done at specific timepoints such as during induction, post induction or during maintenance therapy, though current evidence is most supportive for post induction (post loading) TDM.

Consensus guidelines recommendations on TDM state that proactive drug monitoring could be a consideration during the first year of therapy, though its role was uncertain.3,5,9 Since then, we have more data looking at proactive TDM. An important study is a large prospective cohort study (PANTS study) of nearly 1500 Crohn’s disease patients on infliximab or adalimumab looking at predictors for anti-TNF treatment failure.13 In multivariable analysis, the only factor independently associated with non-response was low drug concentration at week 14. Optimal week 14 (post loading) drug concentrations associated with remission were 7 mcg/mL for infliximab and 12 mcg/mL for adalimumab. Another randomized control trial (PAILOT trial) in pediatric Crohn’s disease patients started on adalimumab showed significantly higher rates of steroid-free clinical remission than reactive monitoring with adalimumab trough concentrations adjusted to achieve trough concentrations of at least 5 mcg/mL.14 With newly emerging data from the aforementioned studies, there seems to be a role of checking a one time early drug concentration (post loading) as a part of active monitoring and dose intensification if needed, which is associated with improved long-term outcomes. Target drug concentrations used for post loading doses should be at least those suggested for reactive TDM monitoring (Table 1) or higher (7 mcg/mL for infliximab and 12 mcg/mL for adalimumab based on the PANTS study). These can be checked at week 12-14 for infliximab and week 6-8 for adalimumab. At present, there is no role for an ultra-proactive approach, that is, measuring drug at every interval and adjusting medications accordingly.

De-Escalation from Combination Therapy

De-escalation from long-term use of combination therapy (biologic with immunomodulator therapy) is often considered in clinical practice because of safety concerns. Discontinuation of infliximab and continuing immunomodulatory monotherapy (azathioprine or methotrexate) has resulted in nearly 50% relapse rates and lack of maintenance of remission.15 Therefore, once biologic therapy has been initiated, it is important to continue therapy with the biologic unless there is loss of response or an adverse event. On the other hand, de-escalation from combination therapy (biologic with immunomodulator therapy) to biologic monotherapy can be attempted in carefully selected patients.16,17 It is important to assess risk factors associated with poor prognosis and confirm deep (clinical, endoscopic and histological) remission. TDM of biologics to determine if biologic levels are appropriate can help in decision making prior to de-escalation. Drug trough levels similar to those suggested in Table 1 for reactive TDM are considered appropriate prior to withdrawal of an immunosuppressive agent. It is important to note that withdrawal of immunomodulator therapy can drop in biologic drug levels and increase immunogenicity, especially with anti-TNF therapies and increases the risk of relapse. De-escalation should be a shared decision making process. It is important to have a risk-benefit discussion with the patient. It is also important to have a monitoring and rescue strategy in case of a relapse. Post deescalation, drug concentrations and antibody levels can be checked at some point, usually in 6-12 months once the effect of discontinuation of the immunomodulator has worn off, to ensure adequate drug levels persist without development of immunogenicity.

Re-Initiation of Therapy after a Drug Holiday

Reasons for drug holiday or discontinuation of biologic therapy in IBD patients can include elective discontinuation due to infection or surgery, loss of insurance coverage, de-escalation from combination therapy or self-discontinuation by patients. In these situations, the same therapy may need to be restarted. The main concern is of an immunologic reaction to the biologic once it has been withdrawn, especially with the anti- TNF class of drugs that are considered to be highly immunogenic. Studies looking at restarting anti- TNF therapy after a drug holiday (providing no prior significant reaction to the anti-TNF) are promising. Approximately two-thirds of patients are able to recapture response even after a one-year gap.15,18 TDM has a role in determining efficacy and safety of reintroducing anti-TNFs, and if there is a need to switch therapies based on an immunogenic reaction. Institution specific protocols have been described with strategies to re-capture response after a drug holiday.19 These include initiation of a concomitant immunomodulator, premedication with steroids, slow infusion rates for the first few doses and checking antibody levels 7-14 days after the first infusion. It is not useful to check drug antibody levels prior to therapy re-initiation as antibody levels will be negative due to lack of drug exposure and will not be informative.

Conclusion

The field of therapeutic drug monitoring for biologic therapies in IBD is evolving. It is useful in various arenas of clinical practice. Gastroenterology providers taking care of IBD patients should familiarize themselves with its appropriate application. The most common form of TDM used is reactive TDM: checking serum drug levels and anti-biologic antibodies to modify therapy in the setting of active IBD symptoms or a change in biomarkers. Reactive TDM is considered standard of care and should be implemented in one’s practice. This strategy helps avoid empiric therapy changes and decision making is more evidence-based. Trough drug levels (levels checked just before the next dose) are the most interpretable and are consistent amongst different assays. Proactive TDM is emerging as a new therapeutic strategy. Newer prospective data shows the benefit of checking drug levels after completion of induction regimens (post loading) for early adjustment of therapy and improvement in long-term outcomes. Other uses of TDM include in de-escalation from combination to monotherapy and in re-initiation of biologic therapy after a drug holiday. Judicious use of drug assays in the right clinical setting is imperative to improve outcomes, prevent unnecessary testing and to avoid significant out-of-pocket costs to the patient.

References

  1. Feuerstein JD, Isaacs KL, Schneider Y, et al. AGA Clinical Practice Guidelines on the Management of Moderate to Severe Ulcerative Colitis. Gastroenterology. 2020;158(5):1450-1461.
  2. Lichtenstein GR, Loftus EV, Isaacs KL, Regueiro MD, Gerson LB, Sands BE. ACG Clinical Guideline: Management of Crohn’s Disease in Adults. Am J Gastroenterol. 2018;113(4):481-517.
  3. Papamichael K, Cheifetz AS, Melmed GY, et al. Appropriate Therapeutic Drug Monitoring of Biologic Agents for Patients With Inflammatory Bowel Diseases. Clin Gastroenterol Hepatol. 2019;17(9):1655-1668 e1653.
  4. Vande Casteele N. Assays for measurement of TNF antagonists in practice. Frontline Gastroenterol. 2017;8(4):236- 242.
  5. Feuerstein JD, Nguyen GC, Kupfer SS, Falck-Ytter Y, Singh S, American Gastroenterological Association Institute Clinical Guidelines C. American Gastroenterological Association Institute Guideline on Therapeutic Drug Monitoring in Inflammatory Bowel Disease. Gastroenterology. 2017;153(3):827-834.
  6. Ordas I, Mould DR, Feagan BG, Sandborn WJ. Anti- TNF monoclonal antibodies in inflammatory bowel disease: pharmacokinetics-based dosing paradigms. Clin Pharmacol Ther. 2012;91(4):635-646.
  7. Vermeire S, Gils A, Accossato P, Lula S, Marren A. Immunogenicity of biologics in inflammatory bowel disease. Therap Adv Gastroenterol. 2018;11:1756283X17750355.
  8. Mitrev N, Vande Casteele N, Seow CH, et al. Review article: consensus statements on therapeutic drug monitoring of anti-tumour necrosis factor therapy in inflammatory bowel diseases. Aliment Pharmacol Ther. 2017;46(11- 12):1037-1053.
  9. Melmed GY, Irving PM, Jones J, et al. Appropriateness of Testing for Anti-Tumor Necrosis Factor Agent and Antibody Concentrations, and Interpretation of Results. Clin Gastroenterol Hepatol. 2016;14(9):1302-1309.
  10. Sofia MA, Rubin DT. Current approaches for optimizing the benefit of biologic therapy in ulcerative colitis. Therap Adv Gastroenterol. 2016;9(4):548-559.
  11. Ungar B, Levy I, Yavne Y, et al. Optimizing Anti- TNF-alpha Therapy: Serum Levels of Infliximab and Adalimumab Are Associated With Mucosal Healing in Patients With Inflammatory Bowel Diseases. Clin Gastroenterol Hepatol. 2016;14(4):550-557 e552.
  12. Restellini S, Khanna R, Afif W. Therapeutic Drug Monitoring With Ustekinumab and Vedolizumab in Inflammatory Bowel Disease. Inflamm Bowel Dis. 2018;24(10):2165-2172.
  13. Kennedy NA, Heap GA, Green HD, et al. Predictors of anti- TNF treatment failure in anti-TNF-naive patients with active luminal Crohn’s disease: a prospective, multicentre, cohort study. Lancet Gastroenterol Hepatol. 2019;4(5):341-353.
  14. Assa A, Matar M, Turner D, et al. Proactive Monitoring of Adalimumab Trough Concentration Associated With Increased Clinical Remission in Children With Crohn’s Disease Compared With Reactive Monitoring. Gastroenterology. 2019;157(4):985-996 e982.
  15. Louis E, Mary JY, Vernier-Massouille G, et al. Maintenance of remission among patients with Crohn’s disease on antimetabolite therapy after infliximab therapy is stopped. Gastroenterology. 2012;142(1):63-70 e65; quiz e31.
  16. Van Assche G, Magdelaine-Beuzelin C, D’Haens G, et al. Withdrawal of immunosuppression in Crohn’s disease treated with scheduled infliximab maintenance: a randomized trial. Gastroenterology. 2008;134(7):1861-1868.
  17. Fiorino G, Cortes PN, Ellul P, et al. Discontinuation of Infliximab in Patients With Ulcerative Colitis Is Associated With Increased Risk of Relapse: A Multinational Retrospective Cohort Study. Clin Gastroenterol Hepatol. 2016;14(10):1426-1432 e1421.
  18. Baert F, Drobne D, Gils A, et al. Early trough levels and antibodies to infliximab predict safety and success of reinitiation of infliximab therapy. Clin Gastroenterol Hepatol. 2014;12(9):1474-1481 e1472; quiz e1491.
  19. Hughes JT, Herfarth HH, Isaacs KL, et al. Infliximab Re-treatment in Inflammatory Bowel Disease: A Single- Center Routine Clinical Experience. Clin Gastroenterol Hepatol. 2015;13(9):1704-1705.

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MEDICAL BULLETIN BOARD

Arrowhead Presents Additional Clinical Data on Investigational Aro-aat Treatment In Patients with Alpha-1 Liver Disease at Easl International Liver Congress

July 2021 • Volume XLV, Issue 7

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PASADENA, CA– Arrowhead Pharmaceuticals Inc. (NASDAQ: ARWR) presented additional positive interim 48-week liver biopsy results from the ongoing AROAAT2002 study, an openlabel Phase 2 clinical study of ARO-AAT, the company’s second generation investigational RNA interference (RNAi) therapeutic being codeveloped with Takeda Pharmaceutical Company Limited (“Takeda”) as a treatment for the rare genetic liver disease associated with alpha-1 antitrypsin deficiency (AATD), at The International Liver Congress – The Annual Meeting of the European Association for the Study of the Liver (EASL).

The results demonstrate that, in the AROAAT2002 study, investigational AROAAT treatment led to improvements in multiple measures of liver health, including fibrosis, with substantial and sustained reductions in the level of mutant AAT protein (Z-AAT). In addition, AROAAT treatment was generally well tolerated after up to 1 year of treatment.

Javier San Martin , M.D., chief medical officer at Arrowhead, said: “We believe the interim results that were presented today at EASL represent an important breakthrough for the field and are encouraging for patients with alpha-1 liver disease, who currently have no available treatment options other than liver transplant. The data indicate that treatment with investigational ARO-AAT, being developed in collaboration with Takeda as TAK-999, resulted in substantial, sustained, and consistent reductions in the production of the toxic mutant Z-AAT protein, which has been identified as the cause of progressive liver disease in patients with alpha-1 antitrypsin deficiency. This reduction over 6 and 12 months led to multiple important signals associated with healing of patients’ liver disease. Importantly, we believe ARO-AAT is the first investigational therapy to show this type of benefit in patients with alpha-1 liver disease. We want to thank all the investigators and patients for their participation in the study, and we look forward to the availability of additional results from this study and from our ongoing SEQUOIA study of ARO-AAT, which we anticipate will reach full enrollment during the third quarter of 2021.”

Pharmacodynamics and Efficacy

After 24 weeks (cohort 1, n=4) and 48 weeks (cohort 2, n=5) of treatment with investigational ARO-AAT in the AROAAT2002 study, the following results were observed:

  • Serum Z-AAT levels decreased in all patients
  • Median decrease in intra-hepatic Z-AAT levels were:
    • Total Z-AAT -80.1% (range -72 to -97%)
    • Monomer -90% (range -79 to -97%)
    • Polymer -81% (range* -42 to -97%)
    • ■ *Excluding 1 subject in cohort 1 that had very low Z-AAT polymer levels at baseline that increased at week 24
    • Histological globule burden was reduced in all nine patients, with two achieving full resolution (total aggregate globule burden score=0)
  • Six of the nine patients (2/4 after 24 weeks and 4/5 after 48 weeks) achieved a 1 or greater stage improvement in Metavir fibrosis stage, with no worsening of fibrosis in the other three patients
    • Two patients had baseline F4 fibrosis (cirrhosis), with one patient achieving a twostage improvement to F2 and the other patient achieving a one-stage improvement to F3
  • Multiple biomarkers of liver health improved, including liver stiffness (FibroScan), liver enzymes alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT), and PRO-C3, a marker of collagen formation

Safety and Tolerability

In AROAAT2002, investigational ARO-AAT demonstrated an acceptable safety profile and was generally well tolerated after up to 1 year of treatment. There were no treatment-emergent adverse events leading to drug discontinuation, dose interruptions, or study withdrawal. Lung function was assessed throughout the study and there were no clinically meaningful changes in percent predicted forced expiratory volume in 1 second (ppFEV1). Three serious adverse events (SAEs) were reported, but none were considered related to the study drug. All SAEs were moderate in severity and all resolved.

AROAAT2002 (NCT03946449) is a pilot open-label, multi-dose, Phase 2 study to assess the response to investigational ARO-AAT in 16 patients with AATD associated liver disease and baseline liver fibrosis. All eligible participants receive a predose biopsy and an end of study biopsy. Treated participants will also be offered the opportunity to continue treatment in an open-label extension (OLE). Including the OLE, interim assessments will be made after 6 months, 12 months, 18 months, and 24 months of treatment with ARO-AAT.

Presentation Details

Title: ARO-AAT an investigational RNAi therapeutic demonstrates improvement in liver fibrosis with reduction in intra-hepatic Z-AAT burden

Authors: Pavel Strnad , et al.

Type: Late-Breaking Oral Presentation

Date and Time: June 26, 2021 at 12:15 CEST A copy of the presentation materials may be accessed on the Events and Presentations page under the Investors section of the Arrowhead website.

About Arrowhead and Takeda Collaboration

In October 2020, Arrowhead and Takeda announced a collaboration and licensing agreement to develop investigational ARO-AAT. Under the terms of the agreement, Arrowhead and Takeda will codevelop ARO-AAT which, if approved, will be cocommercialized in the United States under a 50/50 profit-sharing structure. Outside the U.S., Takeda will lead the global commercialization strategy and receive an exclusive license to commercialize ARO-AAT with Arrowhead eligible to receive tiered royalties of 20-25% on net sales. Arrowhead received an upfront payment of $300 million and is eligible to receive potential development, regulatory and commercial milestones of up to $740 million.

About Alpha-1 Antitrypsin-Associated Liver Disease

Alpha-1 Antitrypsin-Associated Deficiency (AATD) is a rare genetic disorder associated with liver disease in children and adults and pulmonary disease in adults. AATD is estimated to affect 1 per 3,000-5,000 people in the United States and 1 per 2,500 in Europe. The protein AAT is primarily synthesized and secreted by hepatocytes. Its function is to inhibit enzymes that can break down normal connective tissue. The most common disease variant, the Z mutant, has a single amino acid substitution that results in improper folding of the protein. The mutant protein cannot be effectively secreted and accumulates in globules inside the hepatocytes. This triggers continuous hepatocyte injury, leading to fibrosis, cirrhosis, and increased risk of hepatocellular carcinoma.

Individuals with the homozygous PiZZ genotype have severe deficiency of functional AAT leading to pulmonary disease and liver disease. Lung disease is frequently treated with AAT augmentation therapy. However, augmentation therapy does nothing to treat liver disease, and there is no specific therapy for hepatic manifestations. There is a significant unmet need as liver transplant, with its attendant morbidity and mortality, is currently the only available cure.

About Arrowhead Pharmaceuticals

Arrowhead Pharmaceuticals develops medicines that treat intractable diseases by silencing the genes that cause them. Using a broad portfolio of RNA chemistries and efficient modes of delivery, Arrowhead therapies trigger the RNA interference mechanism to induce rapid, deep, and durable knockdown of target genes. RNA interference, or RNAi, is a mechanism present in living cells that inhibits the expression of a specific gene, thereby affecting the production of a specific protein. Arrowhead’s RNAi-based therapeutics leverage this natural pathway of gene silencing.

For more information, please visit: www.arrowheadpharma.com or follow us on Twitter: @ArrowheadPharma

To be added to the Company’s email list and receive news directly, please visit: http://ir.arrowheadpharma.com/email-alerts

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NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #212

Auto-Brewery Syndrome: A Schematic for Diagnosis and Appropriate Treatment

July 2021 • Volume XLV, Issue 7
Fahad Malik,Prasanna Wickremesinghe,Atif Saleem

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Auto-Brewery Syndrome (ABS), also called Gut Fermentation Syndrome, is a rare, underdiagnosed medical condition. This is caused by fermentation of ingested carbohydrate by gut fungi resulting in endogenous production of ethanol. Though this syndrome has been described in the medical literature for over 50 years, it still remains misunderstood with limited information regarding diagnosis and treatment. The presenting symptoms and signs of ABS can be protean and mimic other clinical entities. This can make diagnosing this condition challenging. We propose the following schematic for diagnosing and treating this unusual entity based on our ongoing study of ABS patients. The initial step in confirming this diagnosis is a standardized carbohydrate challenge test which we have devised and studied in our ongoing cohort of ABS patients.

Introduction

Auto-Brewery Syndrome (ABS), which has also been described as Gut Fermentation Syndrome, is a rare, underdiagnosed medical condition. In this condition, fermentation of ingested carbohydrate results in endogenous production of ethanol. This syndrome was originally described in 1946 in a 5-year-old South African child undergoing emergency laparotomy, during which a 3-inch posterior stomach wall tear was detected and alcohol noted in the stomach.1 Multiple cases of ABS were subsequently described in Japan during the 1970s. In these cases, identified yeast forms were mostly Candida species as the causative agent.2 ABS is more common in patients with chronic medical conditions such as diabetes, inflammatory bowel disease (Crohn’s disease patients with strictures), short bowel syndrome or immunosuppressed subjects. Since then, there have been sporadic case reports of ABS worldwide.3-7 ABS can also occur in healthy individuals. In our cohort of ABS patients prior exposure to antibiotics was universal. Antibotics can alter the gut microbiome allowing fungal elements to proliferate.8,9 Nonetheless, this condition has continued to be regarded as a myth due to limited knowledge on the subject. Initially, only fungi were implicated in the conversion of carbohydrate to alcohol, but a recent large Chinese study also identified certain species of high alcoholproducing bacteria (e.g., Klebsiella species).10

Pathophysiology

Although the initiating or triggering factors resulting in ABS remain uncertain, we propose the following in its causation:
1. Alteration of the gut microbiome: The disruption of gut homeostasis resulting in overgrowth of fungi, and in rare cases, high alcohol-producing bacteria (e.g., Klebsiella species).1,10 All of our patients had prior exposure to antibiotics before developing ABS symptoms.

2. Fungal fermentation: Commercially, Saccharomyces cerevisiae (i.e., brewer’s yeast) has been used for manufacturing beer for centuries.11

Risk Factors

In our ABS cohort of patients, the most common risk factor for its causation has been prior use of antibiotics. Antibiotics may have disrupted the fine homeostatic balance and symbiotic relationship between the different types of gut microbiota causing yeast overgrowth. Several patients with diabetes, short bowel syndrome, intestinal bacterial overgrowth, and inflammatory bowel disease (Crohn’s disease with strictures), have also been described with ABS. Healthy patients may also suffer from ABS if exposed to a precipitating cause.1,4,5-7,12 It is uncertain if any genetic components could have predisposed these patients to ABS.

Symptoms

Patients with ABS are known to present with signs and symptoms of inebriation. Some with psychiatric symptoms (i.e. altered mood, anxiety, dysphoria, changes in affect and depression) or neurological symptoms (i.e. changes in mental status, drowsiness, brain fog, seizures, and ataxia). The patients can also have the smell of alcohol on their breath. The effects of alcohol are the same regardless of whether it is endogenously or exogenously derived, and can increase the risk of fatty liver, cirrhosis of the liver and acute or chronic pancreatitis.10 The legal limit for driving while intoxicated (DWI) is 0.08% in New York and many other states. We have encountered many patients with ABS with 3-4 times this level. These symptoms could also overlap with those of chronic fatigue syndrome, depression, and alcoholism itself.

Diagnosis

Usually, these patients are either identified by a concerned family member or had been arrested for alleged “DWI”. Identifying these patients is difficult as ABS symptoms could masquerade as other entities. The medico-legal implications of DWI are self-evident. When investigating a patient with possible ABS, a complete medical history and a physical examination should be augmented with interrogation of family and friends as they may provide additional vital information. The patient can develop “memory fog” and therefore might have poor recall of past events. Particular attention should be paid to the onset of the condition, inciting factors, prior antibiotic use, mold exposure, and any other useful information available from their previous evaluations. Needless to say, the present or past detailed history of alcohol intake is mandatory, including asking when the patient last drank alcohol, if at all.

Basic laboratory tests, i.e. complete blood count, comprehensive metabolic panel, and stool testing should be performed to rule out other medical conditions (e.g. diabetes, immunosuppression, leukopenia). It is also important to ascertain that the patient is not surreptitiously drinking. Therefore, ideally the validity of the patient’s denial of alcohol consumption has to be corroborated by a family member or a friend. The diagnosis of ABS can only be considered after other conditions which may present with similar symptoms have been ruled out. These patients are advised to purchase a breathalyzer and keep a log of their breathalyzermeasured breath alcohol content (BAC) morning and evening, and at any time when they are symptomatic. Any positive level of breathalyzer BAC measurement needs to be confirmed with a concomitant blood alcohol level and the patient’s physician should also be immediately informed.

Just prior to the carbohydrate challenge test, we initially perform upper and lower endoscopy to obtain gastric, upper small bowel, terminal ileal, and colon secretions. These samples are then tested for pH, gram strain, culture, and antibiotic and antifungal sensitivity in a commercial laboratory. Once a particular fungal species is identified, further antifungal sensitivity testing is conducted to determine the appropriate choice of subsequent therapy. The stepwise process for ABS diagnosis is summarized in Figure 1.

The carbohydrate challenge test should be performed when the patient’s breath and blood alcohol levels are zero. If elevated, the patient will have to wait until it becomes zero prior to testing. Patients have to be under complete observation with no access to alcohol along with zero initial blood alcohol level in order for this test to be performed. A diagnostic standardized carbohydrate challenge test was performed after upper and lower endoscopic evaluation. This test consisted of administering 200g of glucose orally in a supervised setting in an isolation room and testing both breath and blood alcohol levels at baseline (0) and at 0.5, 1, 2, 4, 8 hours after glucose administration. Patient were allowed to eat any meal of their choice after the ingestion of 200g of oral glucose. If alcohol levels are elevated at any time during this evaluation, the test is aborted and considered to be positive. Patients who are still negative at 8 hours are given the option to return for a collection of a 16- and 24-hour sample as some fungi can take longer than 8 hours to ferment carbohydrate. Therefore, a negative 8 hour test cannot exclude this diagnosis due to some fermentation occurring even after 24 hours.

Testing a stool sample can assist in the screening process, but the lower gastrointestinal tract can contain small amounts of fungal colonization which would be considered normal and fermentation here would have little clinical significance. Upper gastrointestinal tract fungal colonization is significant, as the presence of fungi is considered pathological in this location. All of the patients who are currently under treatment for ABS had a positive carbohydrate challenge test and positive stool mycological studies on gut secretions.

Until now there had been no known standardized screening test for ABS. Therefore sensitivity and/ or specificity of this test is unstudied. We are the first to propose a carbohydrate challenge test to identity ABS patients. If BAC or blood alcohol is negative, it is unlikely to see a positive carbohydrate challenge test, even if there is a strong suspicion for ABS. When this carbohydrate challenge test is accepted and used more widely, we would have a better idea of the sensitivity, specificity and validity of this test. In our literature review, we have found less than 100 cases since 1952. We are now studying these patients and might be able provide more statistical information in the future.

Treatment

The same initial treatment protocol used for exogenous alcohol intoxication should be used to treat ABS patients as well. This would include administering appropriate intravenous fluids for hydration, maintaining a clear airway, and correcting calorie and nutritional deficiencies (folate and thiamine). Alcohol withdrawal symptoms if present should also be managed with benzodiazepines. After the resolution of the patient’s acute symptoms and stabilization of the patient’s condition, targeted treatment for the patient’s ABS can be initiated. An interdisciplinary approach is strongly recommended in these situations with the assistance of a Gastroenterologist, Psychiatrist and Nutritionist for optimal care. The mainstay of our dietary treatment should be to keep the patient initially on a carbohydrate free diet for 6 weeks as carbohydrate is the only substrate that is converted to alcohol by fungi. Otherwise, these patients are at liberty to ingest any non-carbohydrate meal. A total elimination of carbohydrate is difficult to to practice. We allowed small amounts of carbohydrate found in fruits or vegetables to be acceptable. Antifungal sensitivity testing should be done on any fungal strains isolated from the gastrointestinal secretions to determine the appropriate choice of antifungal treatment. We used nystatin as a firstline treatment when appropriate, as it has the least amount of side effects and an established safety record. Oral azole compounds (e.g., fluconazole and itraconazole) are our next drugs of choice if the patient is still symptomatic with elevated breath and blood alcohol levels while on nystatin therapy. Finally, intravenous micafungin is used for treatment failure.

In addition to antifungal therapy, these patients are started on a single strain probiotic (Lactobacillus acidophilus). Patients should continue to check their BAC twice a day during, and after the 6 weeks of antifungal treatment, and inform their physicians of any positive results. After successfully completing the 6-week therapy if the patient is asymptomatic with negative BAC, the antifungal therapy is gradually tapered during the next 6 weeks and then discontinued. We continued treatment with the probiotic long-term. It would be ideal to have the patient repeat the carbohydrate challenge test prior to reintroducing carbohydrate in their diet if feasible. If this test is positive then the patient would require further antifungal therapy.

Additionally, the role of probiotic use in ABS needs to be fully investigated. Probiotic strains of Lactobacillus have been studied and found to have inhibitory effects on biofilm formation and filamentation in Candida albicans species. This probiotic has also previously been shown to competitively inhibit gut fungal growth in patients.8,13-15 We had previously postulated that fecal microbiome transplant might be valuable in ABS patients. There has only been a single successful report of using fecal microbiome transplant for the treatment of ABS in Belgium. We await further studies on this treatment modality.17 See Figure 2 for proposed treatment algorithm.

Conclusion

ABS is a rare and underdiagnosed medical condition where ingested carbohydrate is converted to alcohol by fermentation in the gut. This condition should be considered in any patient who has signs and symptoms of inebriation despite denying alcohol intake. This syndrome has been described in the medical literature for over 50 years, but it still remains a condition with limited information regarding diagnosis and treatment. If a physician suspects that a patient has ABS, breathalyzer analysis during the symptomatic episodes could help the clinician determine if this condition might be present. We propose a standardized carbohydrate challenge test to screen patients with suspected diagnosis of ABS. While a positive test is very useful in detecting patients with ABS, a negative test does not definitively rule out ABS, as fungi could take longer than 24 hours to convert carbohydrate to alcohol. The seminal NIH microbiome study from 2007 using genetic methodology has found many fungi are undetected by our usual commercial laboratory culture techniques.15,17 As more research emerges on the gut microbiome, it is hoped that a better understanding of this medical condition will ensue.

References

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  2. Iwata K. A review of the literature on drunken syndromes due to yeasts in the gastrointestinal tract. Tokyo, Japan: University of Tokyo Press; 1972.
  3. Hafez EM, Hamad MA, Fouad M, et al. Auto-brewery syndrome: ethanol pseudo-toxicity in diabetic and hepatic patients. Hum Exp Toxicol. 2017;36:445–50.
  4. Welch BT, Coelho Prabhu N, Walkoff L, et al. Auto-brewery syndrome in the setting of long-standing Crohn’s disease: a case report and review of the literature. J Crohns Colitis. 2016;10:1448–50.
  5. Spinucci G, Guidetti M, Lanzoni E, et al. Endogenous ethanol production in a patient with chronic intestinal pseudoobstruction and small intestinal bacterial overgrowth. Eur J Gastroenterol Hepatol. 2006;18:799–802.
  6. Green AD, Antonson DL, Simonsen KA. Twelve-year-old female with short bowel syndrome presents with dizziness and confusion. Pediatr Infect Dis J. 2012;31(4):425.
  7. Jansson-Nettelbladt E, Meurling S, Petrini B, et al. Endogenous ethanol fermentation in a child with short bowel syndrome. Acta Paediatr. 2006;95:502–4.
  8. Malik F, Wickremesinghe P, Saverimuttu J. Case report and literature review of auto-brewery syndrome: probably an underdiagnosed medical condition. BMJ Open Gastroenterol. 2019;6:e000325.
  9. Painter K, Cordell BJ, Sticco KL. Auto-brewery syndrome (Gut fermentation) [updated 2020 Jun 26]. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/ NBK513346/
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Medical Bulletin Board

Mirikizumab Up-regulates Genes Associated with Mucosal Healing in Ulcerative Colitis for up to One Year in Phase 2 Study

July 2021 • Volume XLV, Issue 7

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INDIANAPOLIS, July 9, 2021 /PRNewswire / – Eli Lilly and Company (NYSE: LLY) announced new Phase 2 data showing that gene expression changes induced by mirikizumab in patients with ulcerative colitis (UC) over a 12-week induction treatment were maintained for up to one year. These gene transcript changes, which were unique among those who responded to mirikizumab compared to placebo, were associated with mucosal healing, indicating that mirikizumab affects a distinct molecular healing pathway, compared to the spontaneous healing that occurred among those who responded to placebo.

Mirikizumab is being studied in Phase 3 trials for UC and Crohn’s disease (CD), two forms of inflammatory bowel disease that can cause serious and debilitating symptoms, and disruptions in daily life.

A separate analysis of patients with moderate to severe UC evaluated meaningful improvement of bowel urgency, a common symptom of UC that is associated with higher levels of disease activity, decreased work productivity and worse quality of life. These results were presented virtually at the Congress of the European Crohn’s and Colitis Organisation (ECCO), July 8-10, 2021.

Mirikizumab Showed Early and Sustained Gene Expression Changes Associated with Mucosal Healing in UC for Up to One Year

In a previously-published Phase 2 study evaluating patients with UC, mirikizumab down-regulated several gene transcripts associated with inflamed mucosa and up-regulated gene transcripts correlated with healthy mucosa and markers of functional healing after 12 weeks, as defined by clinical disease indices of endoscopy and histology.

In this analysis, a set of differentially-expressed gene transcripts were identified in patients who responded to mirikizumab that were not found in those who responded to placebo at 12 weeks. Of the modulated genes, 71% (n=63) were present only in patients who responded to mirikizumab, 5.6% (n=5) were present only in those who responded to placebo, and 23.6% (n=21) were present in both groups. Effect size estimates were also examined to account for differences in sample size and associated power between treatment groups. The set of gene transcripts regulated by mirikizumab correlated with UC disease activity indices, demonstrating consistency of these molecular changes across symptomatic, clinical, endoscopic and histologic indices of UC disease activity.

The results observed at 12 weeks were maintained for up to one year in patients receiving mirikizumab. For methodology, see the “About the Studies” section below.

“In the first clinical study of an anti-IL- 23p19 therapy in ulcerative colitis to evaluate gene expression on this large scale, mirikizumab demonstrated an ability to down-regulate the gene transcripts associated with inflammation and upregulate transcripts associated with mucosal healing in ulcerative colitis, with changes maintained for up to one year,” said Walter Reinisch, Director of the Clinical IBD Study Group, Department of Gastroenterology and Hepatology, Medical University of Vienna. “These results support the continued development of mirikizumab as a potential treatment option for ulcerative colitis, given the importance of mucosal healing and functional healing as key treatment goals for this difficult-to-treat disease.”

Patients with UC Reported on Definition of Meaningful Change in Bowel Urgency

Bowel urgency, the sudden or immediate need for a bowel movement, is one of the most distressing symptoms experienced by patients with UC. In this qualitative study of patients with moderate to severe UC, patients defined both bowel urgency severity and what would be a meaningful improvement in bowel urgency based on an 11-point numeric rating scale (NRS).

In this study, half of patients with UC (50%, n=10) reported that a 1-point change on the urgency NRS would be a meaningful change, indicating improved emotional well-being and greater confidence to leave the home or do their work.

A quarter of respondents (25%, n=5) indicated that a 2-point improvement in the urgency NRS was required to be considered meaningful, and another 25% of respondents (n=5) noted that a 3-point change or more was needed to achieve improvements in quality of life.

Importantly, among the 75% of patients who endorsed a 1 to 2-point change in urgency NRS, initial scores on the urgency NRS ranged from 2 to 9, indicating that this amount of change was meaningful regardless of the severity of an individual’s bowel urgency. For methodology, see the “About the Studies” section below.

“We are very excited to present these findings at ECCO, which provide one of the first analyses from the patient perspective on the impact of bowel urgency and what would constitute a meaningful change,” said Prentice Stovall, Jr., Global Development Leader, Immunology at Lilly. “Given the impact that bowel urgency has on an individual’s ability to work and overall quality of life, this analysis will help us further understand the experience of people with UC and the potential impact of our treatments on this burdensome and debilitating symptom.”

About the Studies

Mirikizumab-Induced Transcriptome Changes in Patient Biopsies at Week 12 are Maintained Through Week 52 in Patients with Ulcerative Colitis

Patients who achieved clinical response at 12 weeks, as measured by a decrease in 9-point Mayo subscore (rectal bleeding, stool frequency, endoscopy) of ≥2 points and ≥35% from baseline, with either a decrease of rectal bleeding subscore of ≥1 or an RB subscore of 0 or 1 continued onto maintenance mirikizumab treatment. Patients given placebo in induction who achieved clinical response continued on placebo in the maintenance period. In this study, colonic biopsies from 52 patients were obtained at Weeks 0, 12 and 52 from the most affected area ≥30 cm from the anal verge (mirikizumab, n=31, placebo, n=7). Of those patients, 31 were 200 mg mirikizumab responders and seven responded to placebo. Transcript changes at Week 12 from baseline in the placebo and mirikizumab arms were clustered into differentially expressed genes using the Bayesian Limma R-package. Differentially expressed genes which maintained their Week 12 expression level through Week 52 in both the placebo and mirikizumab arms were identified and designated as similarly expressed genes. Overall, the safety profile at 52 weeks was consistent with that of mirikizumab in studies of UC and with the class.

A Qualitative Study Exploring Meaningful Improvement in Bowel Urgency among Adults with Moderate to Severe Ulcerative Colitis

In this qualitative study assessing meaningful improvement in bowel urgency based on a NRS, in-depth interviews were conducted in the United States with 20 adults with clinician-confirmed moderate to severe UC. Using an 11-point NRS developed specifically to assess bowel urgency severity, participants were asked to define levels of bowel urgency (where 0=no urgency and 10=worst possible urgency). Participants were also asked to describe what would be a meaningful improvement based on how this change would impact their daily life.

About Mirikizumab

Mirikizumab is a humanized IgG4 monoclonal antibody that binds to the p19 subunit of interleukin 23. Mirikizumab is being studied for the treatment of immune diseases, including ulcerative colitis and Crohn’s disease.

About Ulcerative Colitis

Ulcerative colitis is a chronic inflammatory bowel disease that affects the colon. UC occurs when the immune system sends white blood cells into the lining of the intestines, where they produce chronic inflammation and ulcerations. There is an unmet need for additional treatment options for UC that provide meaningful symptom relief, including bowel urgency, and deliver sustained clinical remission.

About Eli Lilly and Company

Lilly is a global health care leader that unites caring with discovery to create medicines that make life better for people around the world. We were founded more than a century ago by a man committed to creating high-quality medicines that meet real needs, and today we remain true to that mission in all our work. Across the globe, Lilly employees work to discover and bring life-changing medicines to those who need them, improve the understanding and management of disease, and give back to communities through philanthropy and volunteerism.

To learn more about Lilly, please visit us at: lilly.com and lilly.com/newsroom

Lilly Forward-Looking Statement

This press release contains forward-looking statements (as that term is defined in the Private Securities Litigation Reform Act of 1995) about mirikizumab as a potential treatment for patients with ulcerative colitis and/or Crohn’s disease and reflects Lilly’s current beliefs and expectations. However, as with any pharmaceutical product, there are substantial risks and uncertainties in the process of drug research, development, and commercialization. Among other things, there can be no guarantee that future study results will be consistent with study results to date, that mirikizumab will prove to be a safe and effective treatment or that mirikizumab will receive regulatory approvals or be commercially successful. For further discussion of these and other risks and uncertainties, see Lilly’s most recent Form 10-K and Form 10-Q filings with the United States Securities and Exchange Commission. Except as required by law, Lilly undertakes no duty to update forward-looking statements to reflect events after the date of this release.

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