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Immune-checkpoint inhibitor-induced diarrhea and colitis in patients with advanced malignancies: retrospective review at MD Anderson.
Wang, Y, Abu-Sbeih, H, Mao, E, Ali, N, Ali, FS, Qiao, W, Lum, P, Raju, G, Shuttlesworth, G, Stroehlein, J, et al
Journal for immunotherapy of cancer. 2018;(1):37
Abstract
BACKGROUND Immune checkpoint inhibitors (ICPIs) are gaining increasing popularity as an efficacious treatment for advanced malignancies. ICPI treatment can be complicated by diarrhea and colitis. Systemic steroids are the first line treatment. Infliximab is reserved for severe refractory cases. We aimed to assess the impact of ICPI-induced diarrhea and colitis and their immunosuppressive treatment on patients' outcomes. METHODS This retrospective analysis was conducted in 327 cancer patients who received ICPIs between 2011 and 2017. Patients with ICPI-induced toxicities in other organs were excluded. We collected data about patient demographics, clinical variables, and overall survival. We used descriptive analysis to compare different groups based on the occurrence and the treatment of diarrhea and colitis. Kaplan-Meier and log-rank test were used to estimate and compare overall survival durations between groups. RESULTS Diarrhea was recorded in 117 (36%) patients; 79 (24%) of them required immunosuppressive treatment of either systemic corticosteroid without infliximab (n = 44) or with infliximab (n = 35). Caucasian ethnicity, melanoma, stage 3 cancer, and ipilimumab were predictors of colitis that requires immunosuppression. Patients who required immunosuppressants had better overall survival than those who did not require treatment for colitis or diarrhea (P < 0.001). Immunosuppression for diarrhea or colitis did not affect the overall survival significantly (P = 0.232), nor did the choice of treatment (corticosteroids with vs. without infliximab; P = 0.768). Diarrhea was an independent predictor of a favorable overall survival (P < 0.001), irrespective of treatment need (P = 0.003). We confirmed the same results in a subgroup analysis for patients with stage IV malignancies only. Patients who received long duration of steroid treatment (> 30 days) had numerically higher infection rate than those who received steroid for shorter duration (40.4 vs. 25.8%, P = 0.160). Likewise, long duration of steroid without infliximab was associated with increased risk of infection compared to short duration of steroid with infliximab (42.9% vs. 14.3%, P = 0.089). CONCLUSIONS Patients with ICPI-induced diarrhea or colitis have improved survival outcomes. Diarrhea is an independent predictor of an improved survival regardless of treatment requirement. Immunosuppressive treatment for diarrhea did not significantly affect overall survival, however, infection rates were numerically higher among patients who received steroids for a long duration. Therefore, early non-steroid immunosuppressive therapy may ensure a more favorable overall outcome.
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Study Protocol for a Randomized, Double-Blind, Community-Based Efficacy Trial of Various Doses of Zinc in Micronutrient Powders or Tablets in Young Bangladeshi Children.
Islam, MM, McDonald, CM, Krebs, NF, Westcott, J, Rahman, AE, El Arifeen, S, Ahmed, T, King, JC, Black, RE
Nutrients. 2018;(2)
Abstract
Zinc is essential to supporting growth in young children especially for tissues undergoing rapid cellular differentiation and turnover, such as those in the immune system and gastrointestinal tract. Therapeutic zinc supplementation has been initiated in low-income countries as part of diarrhea treatment programs to support these needs for young children, but the effects of preventive supplemental zinc as a tablet or as a multiple micronutrient powder (MNP) on child growth and diarrheal disease are mixed and pose programmatic uncertainties. Thus, a randomized, double-blind community-based efficacy trial of five different doses, forms, and frequencies of preventive zinc supplementation vs. a placebo was designed for a study in children aged 9⁻11 months in an urban community in Dhaka, Bangladesh. The primary outcomes of this 24-week study are incidence of diarrheal disease and linear growth. Study workers will conduct in-home morbidity checks twice weekly; anthropometry will be measured at baseline, 12 weeks and 24 weeks. Serum zinc and other related biomarkers will be measured in a subsample along with an estimate of the exchangeable zinc pool size using stable isotope techniques in a subgroup. Therapeutic zinc will be provided as part of diarrhea treatment, in accordance with Bangladesh's national policy. Therefore, the proposed study will determine the additional benefit of a preventive zinc supplementation intervention. The protocol has been approved by the Institutional Review Boards (IRBs) of icddr,b and Children's Hospital Oakland Research Institute (CHORI). The IRB review process is underway at the University of Colorado Denver as well.
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Acute diarrhea: evidence-based management.
Brandt, KG, Castro Antunes, MM, Silva, GA
Jornal de pediatria. 2015;(6 Suppl 1):S36-43
Abstract
OBJECTIVES To describe the current recommendations on the best management of pediatric patients with acute diarrheal disease. DATA SOURCE PubMed, Scopus, Google Scholar. DATA SUMMARY There has been little progress in the use of oral rehydration salts (ORS) in recent decades, despite being widely reported by international guidelines. Several studies have been performed to improve the effectiveness of ORS. Intravenous hydration with isotonic saline solution, quickly infused, should be given in cases of severe dehydration. Nutrition should be ensured after the dehydration resolution, and is essential for intestinal and immune health. Dietary restrictions are usually not beneficial and may be harmful. Symptomatic medications have limited indication and antibiotics are indicated in specific cases, such as cholera and moderate to severe shigellosis. CONCLUSIONS Hydration and nutrition are the interventions with the greatest impact on the course of acute diarrhea.
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Nutritional consequences of chronic diarrhoea.
Gorospe, EC, Oxentenko, AS
Best practice & research. Clinical gastroenterology. 2012;(5):663-75
Abstract
There is an undeniable link between gastrointestinal disorders and malnutrition. Chronic diarrhoea is one of the most common gastrointestinal conditions that can impact a patient's nutritional status. The nutritional consequences will depend on the cause of the diarrhoea as well as the location and extent of gastrointestinal involvement. In general, malabsorption plays a central role in the interaction between malnutrition and chronic diarrhoea. Malabsorption can result in both nutritional deficits and diarrhoea. With severe malnutrition, chronic diarrhoea can persist due to impaired immune function and poor mucosal recovery. Food intolerance and an inappropriate diet in the setting of malabsorption may also contribute to chronic diarrhoea. Patients may attribute their gastrointestinal symptoms to specific dietary intake, which can lead to self-imposed indiscriminate dietary restrictions. Therefore, disease-specific treatment in conjunction with appropriate nutritional counselling and intervention is recommended in the prevention and treatment of malnutrition in patients with chronic diarrhoea. Specialized nutritional support through enteral or parenteral administration may be required to treat severe caloric and micronutrient deficiencies. In this review, we aim to summarize the mechanism, diagnosis, and treatment of the nutritional consequences of chronic diarrhoea.
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Probiotics have clinical, microbiologic, and immunologic efficacy in acute infectious diarrhea.
Chen, CC, Kong, MS, Lai, MW, Chao, HC, Chang, KW, Chen, SY, Huang, YC, Chiu, CH, Li, WC, Lin, PY, et al
The Pediatric infectious disease journal. 2010;(2):135-8
Abstract
BACKGROUND Acute infectious diarrhea is a major cause of childhood morbidity and economic burden for families. We evaluate the clinical, microbiologic, and immunologic effects of probiotics in acute infectious diarrhea. METHODS Children (n = 304) aged 3 months to 6 years hospitalized for acute diarrhea were randomized to receive Bio-three (a mixture of Bacillus mesentericus, Enterococcus faecalis, and Clostridium butyricum) or placebo orally 3 times daily for 7 days. Fecal samples were homogenized for bacterial culture and blood cells were isolated for cell culture and cytokine analysis. This study is registered (NCT00463190). RESULTS The mean duration of diarrhea after start of therapy was 60.1 hours in the probiotics group versus 86.3 hours in the placebo group (P = 0.003). Hospital stay was shorter in the probiotics group than in the placebo group (P = 0.009). Counts of Bifidobacteria and Lactobacillus species were elevated in stool culture of the probiotics (Bio-three) group. IL-10 was increased in the serum and supernatants of cell culture in the probiotics group, and tumor necrosis factor-alpha values were down-regulated. Interferon- gamma and IL-12 were mildly elevated in the probiotics group, compared with the placebo group. CONCLUSIONS This probiotics mixture reduced the severity of diarrhea and length of hospital stay in children with acute diarrhea. In addition to restoring beneficial intestinal flora, probiotics may enhance host protective immunity such as down-regulation of pro-inflammatory cytokines and up-regulation of anti-inflammatory cytokines.
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Probiotics as prevention and treatment for diarrhea.
Guarino, A, Lo Vecchio, A, Canani, RB
Current opinion in gastroenterology. 2009;(1):18-23
Abstract
PURPOSE OF REVIEW To critically appraise evidence on probiotic use for prevention and treatment of diarrhea in children and adults. RECENT FINDINGS Several randomized controlled trials and meta-analyses suggested that probiotics are effective in primary and secondary prevention of gastroenteritis and its treatment. Selected Lactobacillus strains had a modest, although significant effect in primary prevention. Saccharomyces boulardii was effective in antibiotic-associated and in Clostridium difficile diarrhea. There is evidence that it might prevent diarrhea in day-care centers. Lactobacillus rhamnosus GG was associated with reduced diarrheal duration and severity, more evident in case of childhood Rotavirus diarrhea. Similar, although weaker, evidence was obtained with S. boulardii. Both strains are included in evidence-based recommendations for gastroenteritis management in children. Data on other Lactobacillus strains are preliminary. Probiotic efficacy was related to cause, early administration and bacterial load, and their mechanisms were associated with antiinfectious action in the intestine or, indirectly, to modulation of innate and adaptive immunity. SUMMARY Probiotics have gained a role as adjunctive treatment of infantile gastroenteritis together with rehydration. Their efficacy is less convincing in adults, but promising in antibiotic-associated diarrhea. However, evidence of efficacy is limited to a few strains.
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The clinical use of probiotics for young children.
Klein, K, Stevens, R
The journal of family health care. 2008;(2):66-8
Abstract
Probiotics are live microorganisms that occur naturally in the human digestive system. They chiefly colonise the colon and benefit the health of the individual by acting as a digestive aid and boosting the immune response. Low levels of beneficial bacteria and microorganisms in the colon provide a greater opportunity for pathogenic bacteria to become established. Probiotics may be beneficial in reducing the severity and incidence of gastroenteritis, diarrhoea, and colic in babies. They can also benefit children's health by supporting the developing immune system but should not be seen as a panacea or as an alternative to a healthy lifestyle or diet. The level of probiotics in the colon can be boosted by a healthy diet containing plenty of grains, fruit and vegetables. It can also be boosted by probiotic supplementation. Supplementation by the probiotic L. reuteri has been studied in major scientific trials and proven to be safe and effective with no reported side effects.
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Enteral-tube-feeding diarrhoea: manipulating the colonic microbiota with probiotics and prebiotics.
Whelan, K
The Proceedings of the Nutrition Society. 2007;(3):299-306
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Abstract
Diarrhoea is a common and serious complication of enteral tube feeding. Its pathogenesis involves antibiotic prescription, enteropathogenic colonization and abnormal colonic responses, all of which involve an interaction with the colonic microbiota. Alterations in the colonic microbiota have been identified in patients receiving enteral tube feeding and these changes may be associated with the incidence of diarrhoea. Preventing negative alterations in the colonic microbiota has therefore been investigated as a method of reducing the incidence of diarrhoea. Probiotics and prebiotics may be effective because of their suppression of enteropathogenic colonization, stimulation of immune function and modulation of colonic metabolism. Randomized controlled trials of probiotics have produced contrasting results, although Saccharomyces boulardii has been shown to reduce the incidence of diarrhoea in patients in the intensive care unit receiving enteral tube feeding. Prebiotic fructo-oligosaccharides have been shown to increase the concentration of faecal bifidobacteria in healthy subjects consuming enteral formula, although this finding has not yet been confirmed in patients receiving enteral tube feeding. Furthermore, there are no clinical trials investigating the effect of a prebiotic alone on the incidence of diarrhoea. Further trials of the efficacy of probiotics and prebiotics, alone and in combination, in preventing diarrhoea in this patient group are warranted.
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Probiotic use in clinical practice: what are the risks?
Boyle, RJ, Robins-Browne, RM, Tang, ML
The American journal of clinical nutrition. 2006;(6):1256-64; quiz 1446-7
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Abstract
Probiotics have been advocated for the prevention and treatment of a wide range of diseases, and there is strong evidence for their efficacy in some clinical scenarios. Probiotics are now widely used in many countries by consumers and in clinical practice. Given the increasingly widespread use of probiotics, a thorough understanding of their risks and benefits is imperative. In this article we review the safety of probiotics and discuss areas of uncertainty regarding their use. Although probiotics have an excellent overall safety record, they should be used with caution in certain patient groups-particularly neonates born prematurely or with immune deficiency. Because of the paucity of information regarding the mechanisms through which probiotics act, appropriate administrative regimens, and probiotic interactions, further investigation is needed in these areas. Finally, note that the properties of different probiotic species vary and can be strain-specific. Therefore, the effects of one probiotic strain should not be generalized to others without confirmation in separate studies. Careful consideration should be given to these issues before patients are advised to use probiotic supplements in clinical practice.
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Effect of nucleotides on diarrhea and immune responses in healthy term infants in Taiwan.
Yau, KI, Huang, CB, Chen, W, Chen, SJ, Chou, YH, Huang, FY, Kua, KE, Chen, N, McCue, M, Alarcon, PA, et al
Journal of pediatric gastroenterology and nutrition. 2003;(1):37-43
Abstract
OBJECTIVES The aim of this study was to compare the effects of an infant formula fortified with nucleotides (NF) with those of a control formula (CF) on the incidence of diarrhea, respiratory tract infections (RTIs), and immune responses in healthy term infants. METHODS This 12-month, double-blind study was conducted on 1- to 7-day-old infants randomized to receive NF or CF exclusively until 12 weeks of age, and fed the assigned formula with solid food until 12 months. NF was supplemented with 72 mg/L of nucleotides, based on the total potentially available nucleotide content of human milk. Subjects were evaluated within 1 week of birth, at 4 weeks, and every 4 weeks thereafter until 48 weeks of age. The primary outcome variable was the incidence of diarrhea. Secondary variables included RTIs, serum immunoglobulin concentrations, and response to hepatitis B vaccine. RESULTS Compared with subjects fed CF (n = 170), those fed NF (n = 166) had a trend toward reduced risk of diarrhea from 8 to 48 weeks of age and a significantly lower risk of 25.4% (P = 0.05) between 8 and 28 weeks. NF subjects had significantly higher serum immunoglobulin A concentrations ( P < 0.05) throughout the 48-week study. The NF group had an increased risk of upper RTIs, the same incidence of lower RTIs, and the same antibody response to hepatitis B vaccination as the CF group, based on one-sided tests. Growth was normal in both groups, and no adverse events were considered to be formula-related. CONCLUSIONS Healthy term infants from 8 to 28 weeks of life are less likely to experience diarrhea and have higher serum immunoglobulin A concentrations with NF compared with formula without added nucleotides.