The addition of nivolumab to platinum-based chemotherapy improved pathologic complete response rates in patients with resectable stage IIIA or IIIB NSCLC.
Approximately 20% of patients with non–small-cell lung cancer (NSCLC) have stage III disease. Although therapeutic intent is curative for patients with locally advanced disease, historically, treatment outcomes have been poor, and there is lack of consensus on the most appropriate management.
In the industry-sponsored, open-label, multicenter, phase 2 NADIM II trial, 86 treatment-naive patients with resectable stage IIIA or IIIB NSCLC were randomized 2:1 to receive either neoadjuvant nivolumab and paclitaxel plus carboplatin (experimental group) or paclitaxel plus carboplatin alone (control group), followed by surgery. Patients in the experimental group who had R0 resections received adjuvant nivolumab for 6 months.
Pathologic complete response (pCR), the primary endpoint, occurred in 37% of patients in the experimental group compared with 7% in the control group (relative risk, 5.34; 95% CI 1.34–21.23; P=0.02). Progression-free survival at 24 months was 67.2% in the experimental group and 40.9% in the control group (hazard ratio for disease progression, disease recurrence, or death, 0.47; 95% CI, 0.25–0.88).
During neoadjuvant treatment, grade 3 or 4 adverse events occurred in 19% of patients in the experimental group compared with 10% in the control group, most commonly febrile neutropenia (5%) and diarrhea (4%). A higher percentage of patients in the experimental group underwent surgery (93% vs. 69%); there were no delays in surgery due to adverse events. All patients who attained pCR were free from progression at the time of data cutoff.
Comment
In the NADIM II trial, patients with stage IIIA or stage IIIB NSCLC who were treated with neoadjuvant nivolumab and paclitaxel plus carboplatin achieved a higher rate of pCR and longer survival than those treated with chemotherapy alone. These findings add further support for a neoadjuvant chemo-immunotherapy strategy as demonstrated in CheckMate 816 (NEJM JW Oncol Hematol Apr 14 2022 and N Engl J Med 2022; 386:1973) and in KEYNOTE 677 (NEJM JW Oncol Hematol Jun 20 2023 and N Engl J Med 2023 Jun 3; [e-pub]) in a restricted population of patients with stage III NSCLC.
In a phase 3 trial, weekly rezafungin was noninferior to daily caspofungin followed by optional fluconazole regarding 14-day global cure and 30-day all-cause mortality.
Enchinocandin antifungals are the first choice for therapy of invasive candidiasis, although current formulations require daily dosing. Rezafungin, a new echinocandin with a broad range of activity and a half-life of 133 hours, may present advantages over the available echinocandins. A consortium of international investigators performed a multicenter, prospective, double-blind, noninferiority phase 3 study from October 2018 through August 2021 to assess weekly IV rezafungin compared with daily IV caspofungin followed by optional step-down oral fluconazole in adult patients with candidemia or invasive candidiasis. Participants received treatment for a minimum of 14 days. The study was funded by the manufacturer of rezafungin.
Among 187 subjects, global cure rates at day 14 were 59% (rezafungin) and 61% (caspofungin) and all-cause 30-day mortality was 24% and 21%. For both of these predefined endpoints, rezafungin was noninferior to caspofungin. Among those with candidemia, median time to negative culture was 23.9 hours for rezafungin compared with 27.0 hours for caspofungin (p=0.18). Serious adverse events were similar between groups.
Comment
Rezafungin does not have FDA approval at this time, but these data support a future role for its use in the management of invasive candidiasis for patients in whom once-weekly dosing is advantageous.
This document presents the official recommendations of the American Gastroenterological Association (AGA) on the initial management of acute pancreatitis (AP). The guideline was developed by the AGA’s Clinical Practice Guideline Committee and approved by the AGA Governing Board. It is accompanied by a technical review that is a compilation of the clinical evidence from which these recommendations were formulated.
AP is an inflammatory condition of the pancreas that can cause local injury, systemic inflammatory response syndrome, and organ failure. Worldwide, AP is a common gastrointestinal condition that is associated with substantial suffering, morbidity, and cost to the health care system. In the United States, AP is a leading cause of inpatient care among gastrointestinal conditions: >275,000 patients are hospitalized for AP annually, at an aggregate cost of >$2.6 billion per year.
The most common causes of AP remain gallstones and alcohol, which together comprise 80% of cases; the remainder of cases are due to less common causes, including drug reactions, pancreatic solid and cystic malignancies, and hypertriglyceridemia.
The diagnosis of AP requires at least 2 of the following features: characteristic abdominal pain; biochemical evidence of pancreatitis (ie, amylase or lipase elevated >3 times the upper limit of normal); and/or radiographic evidence of pancreatitis on cross-sectional imaging.
Presentations of AP occur along a clinical spectrum, and can be categorized as mild, moderately severe, or severe, based on the recent revised Atlanta classification.
are mild, with only interstitial changes of the pancreas without local or systemic complications. Moderately severe pancreatitis is characterized by transient local or systemic complications or transient organ failure (<48 hours), and severe AP is associated with persistent organ failure.
Necrotizing pancreatitis is characterized by the presence of pancreatic and/or peripancreatic necrosis, and is typically seen in patients with moderately severe or severe AP. Severity of disease factors into several of the recommendations in this guideline. There are 2 overlapping phases of AP, early and late. The early phase of AP takes place in the first 2 weeks after disease onset, and the late phase can last weeks to months thereafter.
In this guideline, we address the initial management of AP within the first 48−72 hours of admission. We focus on the initial management of AP, as this is the period when management decisions can alter the course of disease and duration of hospitalization. The management of AP has evolved slowly during the preceding 100 years. However, emerging evidence challenges many of the long-held management paradigms in AP regarding the benefit of antibiotics, the timing and mode of nutritional support, and the utility and timing of endoscopic retrograde cholangiopancreatography (ERCP) and cholecystectomy. Therefore, we sought to evaluate the sum of the evidence for these and other important questions regarding the management of AP.
Because of the focus on initial treatment of AP, certain questions pertaining to late complications of AP (eg, management of pancreatic fluid collections) are beyond the scope of this guideline. Additionally, because this guideline focuses on the management of AP, we will not address diagnostic questions, such as the use of laboratory tests or radiographic studies to establish the diagnosis of AP.
The guideline was developed utilizing a process outlined elsewhere.
Briefly, the AGA process for developing clinical practice guidelines incorporates Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology
Optimal understanding of this guideline will be enhanced by reading applicable portions of the technical review. The guideline panel and the authors of the technical review met face to face on July 18, 2017, to discuss the findings from the technical review. The guideline authors subsequently formulated the recommendations. Although the quality of the evidence (Table 1) was a key factor in determining the strength of the recommendations (Table 2), the panel also considered the balance between benefit and harm of interventions, patients’ values and preferences, and resource utilization. The recommendations are summarized in Table 3.
Recommendation 1A. In patients with AP, the AGA suggests using goal-directed therapy for fluid management. Conditional recommendation, very low quality evidence.
Comment: The AGA makes no recommendation whether normal saline or Ringer’s lactate is used.
Table 1Quality of Evidence Categories
Quality of evidence
Interpretation
High
We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate
We are moderately confident in the effect estimate. The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low
Our confidence in the effect estimate is limited. The true effect may be substantially different from the estimate of the effect.
Very low
We have very little confidence in the effect estimate. The true effect is likely to be substantially different from the estimate of effect.
Table 2Interpretation of Strength of Recommendation Categories
Strength of recommendation
Wording in the guideline
For the patient
For the clinician
Strong
“The AGA recommends…”
Most individuals in this situation would want the recommended course of action and only a small proportion would not.
Most individuals should receive the recommended course of action. Formal decision aids are not likely to be needed to help individuals make decisions consistent with their values and preferences.
Conditional
“The AGA suggests…”
The majority of individuals in this situation would want the suggested course of action, but many would not.
Different choices will be appropriate for different patients. Decision aids may be useful in helping individuals in making decisions consistent with their values and preferences. Clinicians should expect to spend more time with patients when working toward a decision.
No recommendation
“The AGA makes no recommendation…”
The confidence in the effect estimate is so low that any recommendation is speculative at this time
Fluid therapy to prevent hypovolemia and organ hypoperfusion is a long-established cornerstone of the initial management of AP. However, the evidence basis for fluid therapy in AP is relatively weak. In the technical review, a total of 7 randomized trials were identified pertaining to fluid resuscitation, with 4 primarily addressing the role of goal-directed targeted therapy.
Goal-directed therapy is generally defined as the titration of intravenous fluids to specific clinical and biochemical targets of perfusion (eg, heart rate, mean arterial pressure, central venous pressure, urine output, blood urea nitrogen concentration, and hematocrit). Use of goal-directed therapy has been shown to lower mortality in sepsis,
a condition with physiologic similarities to AP. Compared to non-targeted therapy, goal-directed therapy did not result in significantly improved mortality, prevention of pancreatic necrosis, or decrease in the rate of persistent multiple organ failure. In this context, though there was not clear randomized controlled trial (RCT)−level evidence of benefit, the panel issued a conditional recommendation suggesting the use of judicious goal-directed fluid therapy vs other methods. However, the panel recognized that overly aggressive fluid therapy can be associated with harms in AP, including respiratory complications and abdominal compartment syndrome.
The overall quality of the evidence was very low due to the inconsistency among reported outcome measures (especially the lack of differentiation between transient and persistent organ failure), the small number of RCTs, outcome assessment (detection bias), and lack of blinding (performance bias). The lack of RCT evidence addressing the optimal initial rate, volume, and duration of fluid resuscitation in AP rendered the panel unable to make specific recommendations in this regard.
Regarding the use of Ringer’s lactate vs normal saline as the optimal fluid solution for resuscitation, the panel could not make a recommendation based on the low quality of evidence. The 2 RCTs specifically addressing this topic used surrogate markers of severity and did not focus on important clinical outcomes, such as organ failure, necrosis, or mortality. The panel recognizes that the current intensive study of this topic may lead to changing this recommendation in the near future.
Recommendation 1B. In patients with AP, the AGA suggests against the use of hydroxyethyl starch (HES) fluids. Conditional recommendation, very low quality evidence.
The technical review revealed few studies that specifically addressed the issue of using HES as a resuscitative fluid in AP.
with mortality not improved compared to fluid resuscitation without HES. Importantly, multiple organ failure was significantly increased in 1 trial with HES fluids (odds ratio [OR], 3.86; 95% confidence interval [CI], 1.24−12.04).
Unfortunately, other important outcomes, such as development of necrosis and/or persistent organ failure were not evaluated in these studies. These findings in AP mirror recent studies in the critical care literature, which have not demonstrated a mortality benefit of HES-containing fluids as resuscitative agents.
Recommendation 2. In patients with predicted severe AP and necrotizing pancreatitis, the AGA suggests against the use of prophylactic antibiotics. Conditional recommendation, low quality evidence.
which included 10 RCTs addressing the role of prophylactic antibiotics in patients with predicted severe AP and necrotizing pancreatitis, demonstrated a reduction in the risk of infected pancreatic and peripancreatic necrosis (OR, 0.56; 95% CI, 0.36−0.86) and a trend toward reduction in mortality (OR, 0.66; 95% CI, 0.42−1.04). However, in a subgroup analysis that included only recent trials published after 2002, no differences in risks of infected pancreatic and peripancreatic necrosis (OR, 0.81; 95% CI, 0.44−1.49) or mortality (OR, 0.85; 95% CI, 0.52−1.8) were noted. Similarly, there were no differences in these 2 critical outcomes among higher-quality studies. Given the higher methodologic quality of the recent studies, the guideline panel placed greater emphasis on results published after 2002 for this recommendation. Prophylactic antibiotics had no impact on the rates of important outcomes, such as persistent single organ failure, multiple organ failure or multiple organ dysfunction of unclear duration, single organ failure of unclear duration, and hospital length of stay. Though this recommendation statement is specific for patients with severe AP, it should be clarified that there is also no role for prophylactic antibiotics in patients with milder forms of AP. The overall quality of evidence was graded as low because of methodologic limitations (ie, risk of bias due to lack of blinding of participants and study personnel and imprecision).
Recommendation 3. In patients with acute biliary pancreatitis and no cholangitis, the AGA suggests against the routine use of urgent ERCP. Conditional recommendation, low quality evidence.
A total of 8 RCTs addressed the role of urgent ERCP in the management of patients with acute gallstone pancreatitis.
Compared to conservative management, urgent ERCP had no impact on critical outcomes, such as mortality and multiple organ failure, and on important outcomes, such as single organ failure (eg, respiratory or renal), infected pancreatic and peripancreatic necrosis, and total rates of necrotizing pancreatitis. Similar findings were noted in a subgroup analysis of studies that clearly excluded patients with biliary obstruction. The guideline panel acknowledged the results of a single study demonstrating a reduction in hospital length of stay, but the overall body of evidence for this end point is sparse. The overall quality of evidence was graded as low given the inconsistency of results, indirectness of the evidence, and imprecision of results. The panel also acknowledged the limitations of published studies in excluding patients with acute cholangitis (a clear indication for ERCP in patients with or without acute biliary pancreatitis).
Recommendation 4. In patients with AP, the AGA recommends early (within 24 hours) oral feeding as tolerated rather than keeping the patient nil per os. Strong recommendation; moderate quality evidence.
Traditional dogma regarding management of AP prescribed “bowel rest” in an attempt to avoid further stimulation of the inflamed pancreas. However, current evidence demonstrates the benefit of the opposite approach, that is, early feeding. Maintaining enteral nutrition is thought to help protect the gut−mucosal barrier and reduce bacterial translocation, thereby reducing the risk of infected peripancreatic necrosis and other serious AP outcomes.
Combined results of 11 RCTs that addressed the role of early vs delayed feeding demonstrated no difference in mortality for early vs delayed feeding. There was, however, a 2.5-fold higher risk of interventions for necrosis associated with delayed vs early feeding (OR, 2.47; 95% CI, 1.41−4.35), as well as trends observed for higher rates of infected peripancreatic necrosis (OR, 2.69; 95% CI, 0.80−3.60), multiple organ failure (OR, 2.00; 95% CI, 0.49−8.22), and total necrotizing pancreatitis (OR, 1.84; 95% CI, 0.88−3.86) associated with delayed feeding. Based on these studies, the AGA recommends initiation of early oral feeding (generally within 24 hours) instead of keeping patients NPO. While type of diet was not specifically examined in the technical review, success of early feeding has been demonstrated using a variety of diets including low-fat, normal fat, and soft or solid consistency,
and thus starting with a clear liquid diet is not required. The panel recognized that early feeding is not successful in all AP patients due to pain, vomiting, or ileus, and feeding may need to be delayed beyond 24 hours in some cases. Furthermore, some patients who are intolerant of oral feeding may require placement of an enteral tube for nutritional support (see Recommendations 5 and 6). However, routine or empiric orders for nil per os status in patients with AP should generally be avoided in favor of feeding trials. This is a strong recommendation based on the moderate quality evidence underpinning the statement.
Recommendation 5. In patients with AP and inability to feed orally, the AGA recommends enteral rather than parenteral nutrition. Strong recommendation, moderate quality evidence.
The technical review identified 12 RCTs that compared the use of parenteral (ie, total parenteral nutrition) vs enteral (oral or enteral tube) feeding in patients with AP. There was clear evidence to support the benefit of enteral nutrition over total parenteral nutrition with respect to reduced risk of infected peripancreatic necrosis (OR, 0.28; 95% CI, 0.15−0.51), single organ failure (OR, 0.25; 95% CI, 0.10−0.62), and multiple organ failure (OR, 0.41; 95% CI, 0.27−0.63). The AGA issued a strong recommendation based on the overall moderate quality of available evidence, and the likelihood of increased harm associated with the unnecessary use of parenteral nutrition.
Recommendation 6. In patients with predicted severe or necrotizing pancreatitis requiring enteral tube feeding, the AGA suggests either nasogastric or nasoenteral route. Conditional recommendation, low quality evidence.
Three RCTs were identified in the technical review that specifically addressed the issue of nasogastric vs nasoenteral (either nasoduodenal or nasojejunal) feeding in AP.
The trials did not demonstrate a mortality benefit associated with either modality (OR, 1.01; 95% CI, 0.44−2.30), but there were several methodologic issues that made the evidence of low quality, including a small number of RCTs, high risk of performance bias due to participant blinding, and a high risk of detection bias due to issues with outcome assessment. The studies also did not adequately address the issue of safety, including aspiration risk, with either of these modalities. The panel recognizes that safety concerns regarding the risk of aspiration may preclude practitioners from using nasogastric tubes in patients with severe AP.
Recommendation 7. In patients with acute biliary pancreatitis, the AGA recommends cholecystectomy during the initial admission rather than after discharge. Strong recommendation, moderate quality evidence.
Cholecystectomy can clearly prevent recurrent episodes of AP after an index case of biliary or gallstone pancreatitis.
However, the appropriate timing of cholecystectomy in patients with biliary or gallstone pancreatitis has been the subject of vigorous debate. The primary argument in favor of earlier intervention is that patients with biliary pancreatitis who are discharged without a cholecystectomy have a significant risk of recurrent biliary events.
However, those who advocate delayed cholecystectomy argue that performing surgery at a later time point when the acute inflammatory state of AP has subsided may be safer and associated with better surgical outcomes.
Moderate quality evidence from a single randomized controlled clinical trial
found that cholecystectomy performed during the initial admission for patients with suspected biliary pancreatitis was associated with substantial reductions in a composite outcome of mortality and gallstone-related complications (OR, 0.24; 95% CI, 0.09−0.61), readmission for recurrent pancreatitis (OR, 0.25; 95% CI, 0.07−0.90), and pancreaticobiliary complications (OR, 0.24; 95% CI, 0.09−0.61). Same-admission cholecystectomy did not differ from delayed cholecystectomy with respect to rates of conversion from laparoscopy to open approach or surgical difficulty. The AGA issued a strong recommendation due to the quality of available evidence and the high likelihood of benefit from early vs delayed cholecystectomy in this patient population.
Recommendation 8. In patients with acute alcoholic pancreatitis, the AGA recommends brief alcohol intervention during admission. Strong recommendation, moderate quality evidence.
The technical review identified significant knowledge gaps in this field with a paucity of RCTs addressing the role of alcohol counseling.
The panel’s decision to provide a strong recommendation for a brief alcohol counseling intervention during admission was driven by the following published studies. A single RCT addressed the role of alcohol counseling on recurrent attacks of AP in patients with a first attack of AP with a clear history of alcohol use and exclusion of other possible etiologies.
Patients were randomized to either repeated intervention at 6-month intervals for 2 years at an outpatient gastrointestinal clinic or single intervention at initial hospitalization. There was a strong trend toward a reduction for total hospital admission rates with no statistically significant differences for outcomes, such as second attack of pancreatitis, definite recurrent pancreatitis, or ≥2 recurrent attacks of pancreatitis. The second source of evidence that supports this recommendation was a Cochrane review of alcohol reduction strategies in primary care populations (21 RCTs, n = 7286), although not specifically addressing patients with AP.
This study showed that individuals receiving a brief intervention reduced alcohol consumption compared to the control group (mean difference: −41 g/wk; 95% CI, −57 to −25 g/wk), with substantial heterogeneity in results. Extended intervention compared to brief intervention was associated with a nonsignificantly greater reduction in alcohol consumption. Finally, A follow-up meta-analysis addressing the effectiveness of brief interventions in primary care and differences between efficacy and effectiveness trials demonstrated similar results in reduction in alcohol consumption in participants receiving a brief intervention and no significant difference in effect sizes for efficacy and effectiveness trials.
The overall evidence for this recommendation was graded down to moderate, given the indirectness of evidence, risk of bias associated with lack of blinding, and imprecision of results.
Summary
These practice guideline recommendations for the initial management of AP were developed using the GRADE framework and in adherence with the standards for guideline development set forth by the Institute of Medicine for the creation of trustworthy guidelines.
These guidelines are intended to reduce practice variation and promote high-quality and high-value care for patients with AP. Current evidence supports the benefit of goal-directed fluid resuscitation, early oral feeding, and enteral rather than parenteral nutrition, in all patients with AP. Our evidence profiles also support the benefit of same-admission cholecystectomy for patients with biliary pancreatitis, and brief alcohol intervention for patients with alcohol-induced pancreatitis. In contrast, current evidence does not support a benefit for the routine use of prophylactic antibiotics in predicted severe AP or routine ERCP in patients with AP without accompanying cholangitis.
There are several knowledge gaps in the initial management of AP that have been identified for which RCTs are warranted, as is highlighted in the technical review that accompanies this guideline.
More evidence is needed to deterimine the optimal fluid therapy practice in AP, and to better quantify the benefits and harms of goal-directed therapy vs other approaches. Current evidence does not support a clear benefit of Ringer’s lactate solution compared to normal saline for important outcomes, such as organ failure, necrosis, or mortality. Future RCTs addressing this topic would provide helpful guidance in this regard. Though risk stratification of patients with AP is important to ensure appropriate level of care, there is a dearth of high-quality evidence measuring the actual clinical impacts of using any particular severity prediction tool. High-quality multicenter RCTs are required to determine whether prophylactic antibiotics have a role in specific groups of patients with predicted severe AP and necrotizing pancreatitis. The appropriate timing of ERCP in patients with predicted severe biliary pancreatitis with persistent biliary obstruction also needs to be clarified in future studies. In addition, future research should focus on the impact of alcohol and tobacco cessation interventions on end points, such as recurrent AP, progression to chronic pancreatitis and pancreatic cancer, quality of life, health care utilization, and mortality.
In a phase III trial, the addition of oral clarithromycin to beta-lactam antibiotic treatment improved the clinical response of people with community-acquired pneumonia who had systemic inflammatory response syndrome, findings that support existing guidelines.
In the study, the proportion of patients meeting the primary composite endpoint after 72 hours of treatment — fulfilling criteria for both respiratory symptom improvement and an early dampening of the inflammatory burden — reached 68% of those randomized to clarithromycin atop standard care and 38% of those receiving beta-lactam antibiotics alone (OR 3.40, 95% CI 2.06-5.63), reported Evangelos Giamarellos-Bourboulis, MD, of the National and Kapodistrian University of Athens, Greece, and coauthors.
Additionally, the combination of antibiotics significantly reduced the risk for subsequent organ dysfunction, prevented development of new sepsis, and shortened the time to hospital discharge, according to the double-blind ACCESS trial published in Lancet Respiratory Medicineopens in a new tab or window.
“Our results suggest that clarithromycin should be added to the management of hospitalized patients with community-acquired pneumonia to alleviate the inflammatory burden and to achieve early clinical benefit,” the group wrote.
Serious treatment-emergent adverse events (TEAEs) out to 90 days occurred in similar numbers between groups (43% vs 53%; OR 1.46, 95% CI 0.89-2.35).
Time-to-event curves suggested most of the benefit of the macrolide occurred in the first 8 days. The investigators added that they had indirect evidence of clarithromycin having a strong effect at the level of immune function — given that the clarithromycin group produced more tumour necrosis factor-α and less interleukin-10 in response to lipopolysaccharide stimulation than patients in the placebo group at day 4 — though cautioned that the antibiotic should still be used with caution to avoid emergence of resistance.
“Perhaps the most intriguing aspect of the study was the attempt to assess how clarithromycin modified immune response,” commented Grant Waterer, MD, PhD, of the University of Western Australia and Royal Perth Hospital.
“If impairment in early downregulation of pro-inflammatory responses is beneficial, this has fundamental implications for our understanding of the pathobiology of severe sepsis. Because most of the trend to benefit in mortality with clarithromycin was observed in the first 6-7 days, primary sepsis was probably driving mortality, not a reduction in secondary infections,” he wrote in an invited commentopens in a new tab or window.
In any case, ACCESS filled the need for a good randomized trial on combining beta-lactam antibiotics and macrolides for community-acquired pneumonia, a practice that has already been recommended by American and European guidelines alike.
ACCESS was conducted at multiple public hospitals within Greece from 2021 to 2023.
Investigators sought adults requiring hospital admission who were experiencing two or more community-acquired pneumonia-related symptoms such as cough, dyspnoea, pleuritic chest pain, or purulent sputum expectoration. Participants were ineligible if they had any history of contact with the hospital environment or with healthcare facilities during the preceding 90 days.
Patients also needed to exhibit two or more criteria for systemic inflammatory response syndrome, have a total Sequential Organ Failure Assessment (SOFA) score of at least 2, and have a procalcitonin concentration of at least 0.25 ng/mL.
A total of 278 patients were enrolled in the trial and randomized to standard care with or without oral clarithromycin (500 mg tablets every 12 hours for a week). Over 60% of the patient population were men, and all of the patients were white.
Individual components of the primary endpoint all favored the clarithromycin group over controls:
Decreases in respiratory symptom severity scores of at least 50% from baseline: 72% vs 48% (OR 2.83, 95% CI 1.70-4.70)
Decrease of 30% or more in SOFA score: 68% vs 41% (OR 3.10, 95% CI 1.88-5.11)
Favorable change in procalcitonin kinetics: 69% vs 54% (OR 1.86, 95% CI 1.12-3.06)
None of the TEAEs were found to be related to the study treatments. The most common events were septic shock, anemia, and SARS-CoV-2 infection, all of which were numerically more frequent among placebo patients.
As for the trial’s limitations, researchers noted that there was a heavy inflammatory burden among the patients enrolled and that the pathogen was ultimately found in 55% of the patient population, distinguishing ACCESS from other studies.
“Questions undoubtedly remain over the role of macrolides in community-acquired pneumonia,” Waterer wrote. “The threshold of severity for mandatory use is unclear and further studies are needed at lower thresholds, acknowledging that many patients with mild community-acquired pneumonia will have good outcomes regardless of the therapy chosen.”
The swallowed capsule detected the presence of blood with a sensitivity and specificity of 92.9% and 90.6%, respectively.
Positive and negative predictive values were 74.3% and 97.9%.
The PillSense System, a novel blood-sensing swallowed capsule device, safely detected blood in patients with clinically suspected upper gastrointestinal bleeding with a sensitivity of 92.9% and a specificity of 90.6%, data showed.
“[Esophagogastroduodenoscopy] is now considered the gold standard for diagnosing and treating [upper GI bleeding (UGIB)], although timely diagnosis and intervention can be challenging from a time, personnel and access perspective,” Karl Akiki, MD, a research fellow in the division of gastroenterology and hepatology at Mayo Clinic College of Medicine and Science, and colleagues wrote in Gastrointestinal Endoscopy. “Hence, an accurate, rapid, easy-to-interpret and noninvasive tool could assist in both diagnosing and offering guidance for clinical decision-making in scenarios of a suspected UGIB.”
Data derived from: Akiki K, et al. Gastrointest Endosc. 2023;doi:10.1016/j.gie.2023.11.051.
In an open-label, single-arm, comparative clinical trial, Akiki and colleagues evaluated the safety and efficacy of the PillSense System (EnteraSense Ltd.), an ingestible capsule that detects blood in the upper GI tract via an optical sensor and transmits data to an external receiver.
They enrolled 126 adults (mean age, 62.4 years; 59.5% men) with suspected UGIB at Mayo Clinic in Rochester between December 2021 and August 2022. Participants underwent esophagogastroduodenoscopy (EGD) within 4 hours of capsule administration and were monitored up to 21 days to confirm capsule passage.
According to results, 110 patients (87.3%) had confirmed capsule passage, with a mean transit time of 3.6 days. The capsule correctly detected the presence of blood in 26 out of 28 cases and the absence of blood in 87 out of 96 cases compared with EGD. The mean PillSense recording time was 6.71 minutes.
Further analysis demonstrated a sensitivity and specificity of 92.9% (95% CI, 76.5-99.1) and 90.6% (95% CI, 82.9-95.6), respectively, as well as positive and negative predictive values of 74.3% and 97.8%. The positive and negative likelihood ratios were 9.9 and 0.08.
Researchers reported no adverse events related to the PillSense System or capsule ingestion.
“Our study demonstrates that a novel blood-sensing swallowed capsule device provides highly accurate and rapid detection of UGIB,” Akiki and colleagues concluded. “The device was simple to deploy, results were easy to interpret and the capsule passed safely through the GI tract in all patients that completed the study.”
They continued: “The PillSense System may assist in efficiently diagnosing UGIB with the goal of improving patient outcomes and may ultimately alter the diagnostic and treatment approach for patients with a suspected UGIB.”
SARS-CoV-2 infected coronary arteries and increased inflammation in atherosclerotic plaques.
The findings suggest how COVID-19 could increase the risk of heart attack and stroke.
Foam cells, which accumulate within arteries to form plaques in atherosclerosis, proved particularly susceptible to infection with SARS-CoV-2. Kateryna Kon / Shutterstock
COVID-19 is known to increase the risk of heart attack and stroke. The intense inflammation that occurs throughout the body in severe cases likely contributes to this increased risk. But it’s not clear whether SARS-CoV-2, the virus that causes COVID-19, also affects blood vessels directly.
To find out, an NIH-funded research team, led by Dr. Chiara Giannarelli at New York University School of Medicine, analyzed coronary artery tissue samples from eight people who died of COVID-19 between May 2020 and May 2021. Results appeared in Nature Cardiovascular Research on September 28, 2023.
The team found SARS-CoV-2 viral RNA in coronary artery tissue from all patients. They found more viral RNA in the arterial walls than in the surrounding fat tissue. Many of the infected cells were macrophages, a type of white blood cell that ingests pathogens. Samples with more macrophages had more viral RNA.
Macrophages also help remove cholesterol from blood vessels. When macrophages become laden with cholesterol, they are known as foam cells. Accumulation of foam cells within arteries forms plaques that are a hallmark of atherosclerosis. The team confirmed that SARS-CoV-2 could infect human macrophages and foam cells in a petri dish. The foam cells were much more susceptible to infection than the macrophages. This could explain why people with atherosclerosis are more vulnerable to COVID-19.
In both cell types, infection depended on a protein on the surface of the cells called neuropilin. Turning off the gene for neuropilin in these cells reduced infection. So did blocking the virus from binding to neuropilin.
Infection triggered several inflammatory pathways in macrophages and foam cells. The cells also released molecules that are known to contribute to heart attacks and strokes. In arterial plaques that had been surgically removed from patients, the researchers saw an inflammatory response to SARS-CoV-2 infection like that seen in the cultured cells.
The findings suggest that SARS-CoV-2 may increase the risk of heart attacks and stroke by infecting artery wall tissue, including associated macrophages. This provokes inflammation in atherosclerotic plaques, which could lead to heart attack or stroke.
“These results shed light onto a possible connection between preexisting heart issues and Long COVID symptoms,” Giannarelli says. “It appears that the immune cells most involved in atherosclerosis may serve as a reservoir for the virus, giving it the opportunity to persist in the body over time.”
“Since the early days of the pandemic, we have known that people who had COVID-19 have an increased risk for cardiovascular disease or stroke up to one year after infection,” says Dr. Michelle Olive of NIH’s National Heart, Lung, and Blood Institute. “We believe we have uncovered one of the reasons why.”
The authors plan to further investigate the potential link between infection of the arteries and Long COVID. They also aim to see if their results also hold true for newer SARS-CoV-2 variants.
Scientists have uncovered what enzyme turns urine is yellow. Eduardo Ramos Castaneda/Getty Images
Researchers have discovered a new enzyme, bilirubin reductase, that gives urine its yellow color.
These findings could help better understand the connection between the gut and health issues like jaundice and inflammatory bowel disease.
Learning more about bilirubin reductase will help in understanding the breakdown of bilirubin and how it affects other bodily systems.
Urine color can change due to hydration, diet, and medication. But among the average healthy person, it’s a shade of yellow.
According to a new study published this week in Nature Microbiology,Trusted Source researchers have finally uncovered a long-standing mystery, what leads to that yellow color?
Researchers have found that an enzyme called bilirubin reductase (BilR) is what gives urine its yellow color. These results could be used to help study the links between the gut microbiome and health conditions such as jaundice and inflammatory bowel disease.
As red blood cells degrade, the pigment bilirubin is created as a byproduct. Bilirubin is released in the gut to be excreted, but it’s possible to be reabsorbed. If bilirubin builds up in the blood, it can lead to jaundice where the skin and eyes turn yellow.
For more than 125 years, experts have known that compounds in the gut turn bilirubin into the compound urobilin, which is the pigment that results in yellow urine.
But what they didn’t know was what enzyme or collection of enzymes turned bilirubin into urobilin.
“Unfortunately, gut microbes can be challenging to study,” Brantley Hall, PhD, an assistant professor in the University of Maryland’s Department of Cell Biology and Molecular Genetics and study author, told Healthline. “The gut is a low-oxygen environment, and many of the bacteria in our guts can’t survive if too much oxygen is present, making them difficult to grow and perform experiments on in labs. This ultimately meant that only a handful of bacterial species had ever been identified as being able to metabolize bilirubin, limiting the amount of data that was available.”
Hall said advancements in genome sequencing helped them discover this key enzyme.
“Our work to find BilR relied on combining experimental screening with genomic analysis, an approach that has only become possible with the isolation of more gut bacterial species and the advancement of genome sequencing technology,” he said. “So in summary, we unraveled a fundamental aspect of how our gut microbiomes influence our daily lives.”
“Gut microbes encode the enzyme bilirubin reductase that converts bilirubin into a colorless byproduct called urobilinogen,” Hall explained in said in a statement. “Urobilinogen then spontaneously degrades into a molecule called urobilin, which is responsible for the yellow color we are all familiar with.”
“Bilirubin reductase will help in terms of future research to understand the breakdown of bilirubin, which is formed by the breakdown of heme which is present within red blood cells and some other cells within the body,” Dr. Boback Berookhim, a urologist at Northwell Lenox Hill Hospital, stated. “In some disease states high levels of bilirubin may result in brain damage which can be sometimes severe and may even lead to death. This is an important step in better understanding how to treat these disease processes.”
Researchers discovered that bilirubin reductase is present in nearly all healthy adults but not in newborns and adult individuals with inflammatory bowel disease.
Failure of bilirubin breakdown has been clearly associated with jaundice in infants and gallstones in adult patients with inflammatory bowel diseases, Berookhim explained.
For the next research steps, Hall would like to conduct human studies.
“We hope to conduct observational human studies to better understand how bilirubin reduction by gut microbes influences the concentration of bilirubin in circulation,” said Hall. “We are especially interested in looking at premature infants where jaundice rates are high, and the prevalence of bilirubin-reducing microbes is low.”
“The hypothesis is supported by genome-based studies looking at the microbiome of infants with jaundice and inflammatory bowel disease,” he said. “It appears to have validity although confirmatory studies are needed to better support this finding. Biologically, the link is plausible and appears to have validity.”
Urine color can indicate a variety of health issues with patients.
“Yellow, or dark yellow urine may indicate that a person is not adequately hydrated,” said Berookhim. “Red urine usually indicates blood in the urine, which may be associated with kidney stones, enlarged prostates, urinary infections, bladder cancer or kidney cancer.”
Some liver dysfunctions can also be related to red urine. Brown urine may also reflect either a liver dysfunction or the presence of old blood in the urinary tract, Berookhim explained.
Along with jaundice and inflammatory bowel disease, the gut microbiome has been associated with numerous health conditions, including arthritis, psoriasis, and allergies.
“The microbiome is a collection of bacteria, fungi and viruses that live in and on the body,” Berookhim stated. “These play a significant role in immune response and help modulate the balance between inflammation and immunity. Within the gut, this can also influence the nervous system, and has been shown to play a role in obesity, type 2 diabetes and coronary artery disease among other issues.”
These organisms tend to be protective of and coexist with our bodies to help break down waste products. Alterations in this microbiome can set off a chain of events that can lead to disease or predisposition to disease throughout the body, Berookhim explained.
Growth of bacterial cultures in Petri dishes [Sylvia Suter, University Hospital Basel]
Clinical bacteriology relies on the ability to identify cultured isolates. However, unknown isolates are common in hospital settings. Now, researchers at the University of Basel, have established a new study algorithm—NOVA (Novel Organism Verification and Analysis)—to analyze bacterial isolates that cannot otherwise be characterized using conventional identification procedures.
The team, which has been collecting and analyzing patient samples containing unknown bacterial isolates since 2014, have discovered more than thirty new species of bacteria, some of which are associated with clinically relevant infections.
In this work, the researchers led by Daniel Goldenberger, PhD, at the University of Basel, analyzed 61 unknown bacterial pathogens found in blood or tissue samples from patients with a wide range of medical conditions. Conventional laboratory methods, such as mass spectroscopy or sequencing a small part of the bacterial genome, had failed to produce results for all these isolates. Researchers sequenced the complete genome of the bacteria.
Out of 61 analyzed bacteria, 35 represent potentially novel species. And 27 of 35 strains were isolated from deep tissue specimens or blood cultures. The authors noted that, “Corynebacterium sp. (n = 6) and Schaalia sp. (n = 5) were the predominant genera. Two strains each were identified within the genera Anaerococcus, Clostridium, Desulfovibrio, and Peptoniphilus, and one new species was detected within Citrobacter, Dermabacter, Helcococcus, Lancefieldella, Neisseria, Ochrobactrum (Brucella), Paenibacillus, Pantoea, Porphyromonas, Pseudoclavibacter, Pseudomonas, Psychrobacter, Pusillimonas, Rothia, Sneathia, and Tessaracoccus.”
Most of the newly identified species belong to the Corynebacterium and Schaalia genera, both gram-positive bacilli. “Many species in these two genera are found in the natural human skin microbiome and the mucosa. This is why they are frequently underestimated, and research into them is sparse,” explained Goldenberger. They can, however, cause infections when they enter into the bloodstream—due to a tumor, for example.
The researchers classified the remaining 26 strains as hard to identify. An evaluation of the patient data showed that seven out of the 35 new strains were clinically relevant, meaning that they can cause bacterial infections in humans. “Such direct links between newly identified species of bacteria and their clinical relevance have rarely been published in the past,” said Goldenberger.
One of the hard-to-identify pathogens might be clinically relevant, too. It was found in the inflamed thumb of a patient after a dog bite. A Canadian research group also recently isolated this bacterium from wounds caused by dog or cat bites. “This has led us to assume that it is an emerging pathogen which we need to monitor,” said Goldenberger. The Canadian researchers appropriately named the bacterium Vandammella animalimorsus (animal bite Vandammella) in 2022.
Naming their new species is the next item on the Basel team’s to-do list, too. They are working closely with Peter Vandamme, a professor from the University of Ghent and a specialist in bacteria classification. Two of the bacteria have been named already. One is Pseudoclavibacter triregionum—referring to Basel’s location near the borders of Switzerland, France, and Germany.
A 60-year-old man incarcerated in Ohio presented to the emergency department after a syncopal episode. He reported recent exposure to COVID-19 but had no fevers, chest pain, cough, dyspnea, or diarrhea. He had unintentionally lost 13.6 kg over 2 years. His temperature was 37 °C (98.5 °F); blood pressure, 124/75 mm Hg; pulse, 123/min; respiratory rate, 22/min; and oxygen saturation, 96% on room air. Findings on physical examination were unremarkable. His white blood cell count was 3300/μL (reference, 4500-11 000/μL) with an absolute lymphocyte count of 200/μL (reference, 1000-4800/μL). Chest radiograph showed bilateral reticulonodular opacities. He was hospitalized and treated with azithromycin, remdesivir, and dexamethasone despite 3 negative SARS-CoV-2 polymerase chain reaction (PCR) test results. Two days after hospital discharge, he presented to the emergency department with recurrent syncope. His temperature was 38.1 °C (100.6 °F); blood pressure, 122/82 mm Hg; pulse, 135/min; and oxygen saturation, 86% on room air. A computed tomography scan revealed diffuse bilateral pulmonary micronodular opacities, a 2.2-cm nodule in the lingula, and mediastinal and hilar lymphadenopathy (Figure 1). Results of HIV testing were positive for HIV-1 antibodies.
Check urine and serum Histoplasma antigen test results
Order a positron emission tomography scan
Perform bronchoscopy with transbronchial biopsy
Treat with 7 days of intravenous cefepime and vancomycin
Discussion
Diagnosis
Disseminated histoplasmosis
What to Do Next
A. Check urine and serum Histoplasma antigen test results
Discussion
The key to the correct diagnosis is recognizing that hypoxemia and diffuse micronodular pulmonary opacities in a patient with HIV is characteristic of disseminated histoplasmosis. A positron emission tomography scan (choice B) is not recommended because it will not provide a definitive diagnosis. Less invasive testing should be pursued prior to bronchoscopy and transbronchial biopsy (choice C). The imaging findings were inconsistent with bacterial pneumonia, so intravenous antibiotics (choice D) are not indicated.
Histoplasma capsulatum is a soil-based fungus associated with bird and bat droppings.1 Exposure occurs via inhalation of fungal spores.1 While endemic in the Ohio and Mississippi River valleys, all US continental states have documented cases of histoplasmosis.2 H capsulatum is endemic in Central and South America, sub-Saharan Africa, and South/Southeast Asia.3 Most patients with acute pulmonary histoplasmosis are asymptomatic or have mild, self-limited cough and remain undiagnosed.4 However, severe pneumonia can occur, especially in patients with immunosuppression or who inhale a large quantity of spores.4 Infants and adults older than 55 years are at higher risk of severe histoplasmosis. Risk factors for dissemination include HIV with CD4 cell count less than 150/mm3, immunosuppressive medications (eg, corticosteroids, tumor necrosis factor inhibitors), hematologic malignancies, and solid organ transplantation.4 Patients with disseminated histoplasmosis typically have fever, fatigue, weight loss, and shortness of breath, and may also have diarrhea, headaches, altered mental status, and rash.5,6 Common laboratory findings include anemia, thrombocytopenia, leukopenia, and elevated liver enzyme and lactodehydrogenase levels.5 The differential diagnosis of disseminated histoplasmosis includes tuberculosis, cryptococcus, coccidioidomycosis, blastomycosis, malignancy, and sarcoidosis.5,6
To diagnose disseminated histoplasmosis, serum and urine tests for Histoplasma antigen are the tests of choice and have sensitivities of 95% and specificities of 97%.7 Disseminated histoplasmosis is fatal if untreated.5 Mild to moderate disseminated histoplasmosis is treated with 200 mg of oral itraconazole 3 times daily, followed by twice-daily dosing for 12 months.7,8 For severe disseminated histoplasmosis (eg, respiratory, circulatory, or kidney failure; neurologic signs; coagulation abnormalities; or symptoms that limit self-care), induction therapy consists of intravenous liposomal amphotericin B for 2 weeks, or for 4 to 6 weeks if there is central nervous system (CNS) involvement.7,8 Recommended maintenance therapy is oral itraconazole for 12 months to lifelong, depending on risk of reinfection or relapse, which occurs most commonly in patients with CNS disease.7,8 Mortality rates in patients with HIV and disseminated histoplasmosis range from 10% to 60%, depending on access to care.9
Patient Outcome
The patient’s urine Histoplasma antigen level was greater than 25 ng/mL and serum Histoplasma antigen level was greater than 20.0 ng/mL (reference positive, >0.20 ng/mL for both). Serum testing revealed negative T-spot, negative Cryptococcus antigen, and negative Coccidioides antibody findings. Results of Mycobacterium tuberculosis PCR and Pneumocystis jirovecii pneumonia PCR of bronchoalveolar lavage (BAL) fluid were negative. Results of brain magnetic resonance imaging were normal. Cerebrospinal fluid cell count, differential, total protein level, and glucose level were normal. HIV viral load was 3.9 million copies/mL, and CD4 cell count was 15/mm3. The patient was treated with 3 days of oral itraconazole (200 mg 3 times daily), followed by twice-daily dosing. Antiretroviral treatment (ART) with bictegravir-emtricitabine-tenofovir alafenamide was started on hospital day 10. On discharge, results of fungal, blood, BAL, and acid-fast bacillus cultures and cerebrospinal fluid Histoplasma antigen testing were pending. He was to continue ART, itraconazole (200 mg twice daily), and trimethoprim-sulfamethoxazole (160-800 mg 3 times per week) for P jirovecii pneumonia prophylaxis.
Twenty days later, the patient was readmitted to the hospital with headaches. Results of prior fungal blood and BAL cultures and CNS Histoplasma antigen testing were positive but had not been reported. He received treatment for CNS histoplasmosis with intravenous liposomal amphotericin B (3 mg/kg/d) for 6 weeks. Bronchoscopy with transbronchial biopsy, performed to evaluate the pulmonary nodule, showed necrotizing granulomas with yeast (Figure 2). After a 44-day hospitalization, the patient was discharged taking ART, itraconazole (200 mg 3 times daily), and trimethoprim-sulfamethoxazole. In clinic 18 months later, he was asymptomatic, with a CD4 count of 182/mm3 and HIV viral load of 100 copies/mL. All of his prior medications were continued, including itraconazole (200 mg twice daily) due to the high risk of reinfection or relapse associated with disseminated histoplasmosis involving the CNS, especially with CD4 cell count less than 200 cells/mm3.
Advanced UC is a very heterogeneous disease, and the identification of molecular pathways potentially implicated in carcinogenesis has been an area of research focus within recent years1
The advent of molecular profiling has allowed comprehensive characterisation of advanced urothelial tumours and further understanding of specific molecular pathways that may be implicated in carcinogenesis, such as TROP-2, NECTIN-4, PD-L1, HER2, and FGFRalt1
The identification of highly ubiquitously expressed antigens may help circumvent these limitations
High expression of TROP-26
A recent study by Bahlinger, et al. ASCO GU 2023 (N=200 cases) found that TROP-2 is:
Highly expressed in advanced UC tumours (>93%)
Not associated with the expression of other antigens like PD-L1, NECTIN-4 or FGFR3
TROP-2 is a cell-surface antigen associated with oncogenic processes8,9
Trophoblast cell-surface antigen 2 (TROP-2) is a transmembrane glycoprotein, calcium signal transducer, involved in oncogenic processes such as cell migration and anchorage-independent growth8,9
TROP-2 is highly expressed in patients with multiple solid tumour types, including:8–11
BLADDER
BREAST
GASTRIC
COLORECTAL
LUNG
CERVICAL/ OVARIAN
Exploring the science of antigens like TROP-2 could bring new possibilities for patients with advanced UC, without the potential need to select patient populations based on molecular screening
BLADDER
BREAST
GASTRIC
COLORECTAL
LUNG
CERVICAL/
ARYAN'S BLOG 