Daily Archives: January 7, 2025
ATS Guidelines on Invasive Pulmonary Aspergillosis and Antifungal Strategies in Critically Ill Adults
7 Jan, 2025 | 12:29h | UTCIntroduction: This summary provides an overview of a recent American Thoracic Society clinical practice guideline addressing two core questions in adult pulmonary and critical care practice. First, it examines whether combination therapy with a mold-active triazole (most data concern voriconazole, though newer agents such as isavuconazole or posaconazole may also be considered) plus an echinocandin (specifically caspofungin, micafungin, or anidulafungin) offers added benefit over mold-active triazole monotherapy for patients with proven or probable invasive pulmonary aspergillosis (IPA). Second, it evaluates whether routine use of prophylactic or empiric antifungal agents against Candida species is advisable in critically ill, nonneutropenic, nontransplant patients at risk of invasive candidiasis (IC). By synthesizing available evidence using the GRADE approach, this guideline aims to support clinicians in optimizing therapeutic strategies and improving patient outcomes in these complex infections.
Key Recommendations:
Initial Combination Therapy vs. Monotherapy for IPA
- For patients with proven or probable IPA, the guideline makes a conditional recommendation, meaning the best choice isn’t entirely clear. Both initial combination therapy (mold-active triazole + echinocandin) and monotherapy (mold-active triazole alone) are considered reasonable options.
- Evidence stems primarily from studies in hematologic malignancy (HM) or hematopoietic stem cell transplant (HSCT) recipients, with mixed findings in observational cohorts and a key randomized trial favoring combination therapy, particularly in a subgroup diagnosed by positive galactomannan assays.
- When critical illness or triazole resistance is a concern, combination therapy may be considered, but there is insufficient evidence to categorically endorse one approach over the other.
Prophylactic or Empiric Antifungal Therapy for Candida in Critically Ill Patients
- In nonneutropenic, nontransplant adult ICU patients at risk for IC, the guideline makes a conditional recommendation against routinely using prophylactic or empiric antifungal therapy. This means the benefits of withholding these treatments likely outweigh the risks, but there’s still some uncertainty.
- Low-quality evidence from multiple randomized controlled trials showed no significant mortality benefit in administering antifungals prophylactically or empirically compared with placebo.
- Although IC carries substantial morbidity and mortality, its overall incidence in this population remains low, and ongoing surveillance or targeted diagnostics may be preferable to universal antifungal administration.
Conclusion: The panel emphasizes that these recommendations should be applied with clinical judgment, especially in patients with severe disease, likely high fungal burden, or concerns for antifungal resistance. Combination therapy for IPA may be particularly relevant when critical illness or limited triazole efficacy is suspected. Meanwhile, prophylactic or empiric anti-Candida therapy in the broader ICU setting does not appear to substantially reduce mortality. Continued advances in rapid diagnostics, close monitoring of local resistance patterns, and new antifungal agents may further refine best practices. Future research should focus on validating these findings in diverse patient populations, exploring novel combination regimens, and establishing more precise risk assessments for IC in the ICU.
Reference: Epelbaum O, Marinelli T, Haydour Q, Pennington KM, Evans SE, Carmona EM, Husain S, Knox KS, Jarrett BJ, Azoulay E, Hope WW, and others. “Treatment of Invasive Pulmonary Aspergillosis and Preventive and Empirical Therapy for Invasive Candidiasis in Adult Pulmonary and Critical Care Patients: An Official American Thoracic Society Clinical Practice Guideline.” American Journal of Respiratory and Critical Care Medicine (2025). https://doi.org/10.1164/rccm.202410-2045ST
RCT: Assessing Procalcitonin-Based Antibiotic Management in Critically Ill Patients With Sepsis
7 Jan, 2025 | 14:00h | UTCBackground: Optimal antibiotic duration for sepsis remains uncertain. Procalcitonin (PCT) and C-reactive protein (CRP) are thought to support shorter courses, but prior research was small-scale or at risk of bias. This multicenter, randomized trial (ADAPT-Sepsis) evaluated whether daily PCT- or CRP-guided protocols could reduce antibiotic use without increasing 28-day all-cause mortality in critically ill adults with suspected sepsis.
Objective: To determine if daily biomarker-guided (PCT or CRP) strategies decrease total antibiotic days among critically ill adults while maintaining acceptable 28-day mortality, compared with standard care.
Methods: From 2018 to 2024 (with enrollment paused March–August 2020 due to COVID-19), 2760 adults (≥18 years) on intravenous antibiotics for suspected sepsis (acute organ dysfunction and presumed infection) and likely to continue antibiotics for at least 72 hours were randomized across 41 UK NHS ICUs within 24 hours of antibiotic initiation. They were assigned in a 1:1:1 ratio to (1) daily PCT-guided advice (n=918), (2) daily CRP-guided advice (n=924), or (3) standard care (n=918). Biomarker results were concealed; clinicians received automated daily prompts recommending continuation or discontinuation. The co-primary outcomes were (1) total antibiotic duration (randomization to day 28) and (2) 28-day all-cause mortality. Secondary measures included antibiotic duration for the initial sepsis episode, 90-day mortality, readmissions, and length of stay.
Results: Among 2760 participants (mean age, 60.2 years; 60.3% men; ~50% with septic shock), over 96% provided 28-day data. Patients in the PCT-guided arm had a statistically significant mean reduction in total antibiotic duration vs standard care (9.8 vs 10.7 days; difference, 0.88 days; 95% CI, 0.19–1.58; p=0.01). The PCT strategy met the prespecified 5.4% noninferiority margin for 28-day mortality (20.9% vs 19.4%; absolute difference, 1.57; 95% CI, –2.18 to 5.32; p=0.02), implying noninferiority but not fully excluding a small risk of excess mortality. CRP-guided protocols did not shorten total antibiotic use (10.6 vs 10.7 days; p=0.79) and were inconclusive for noninferiority regarding mortality (21.1% vs 19.4%; difference, 1.69; 95% CI, –2.07 to 5.45; p=0.03). Notably, 90-day mortality also showed no significant differences. A post-trial commentary (PulmCCM) emphasized that some uncertainty remains with the 5.4% margin and warned that patient-level randomization could subtly discourage earlier antibiotic discontinuation in standard care, which received no explicit “stop” prompts.
Conclusions: In critically ill patients with suspected sepsis, a PCT-guided antibiotic discontinuation protocol shortened overall antibiotic use by nearly one day without exceeding the predefined noninferiority threshold for 28-day mortality. However, the chosen 5.4% margin allows for the possibility of clinically relevant harm. A CRP-guided protocol did not reduce total antibiotic use and showed inconclusive mortality findings.
Implications for Practice: Adopting PCT-based stewardship may modestly decrease antibiotic exposure without a clear short-term mortality penalty, potentially limiting antibiotic resistance. Clinicians should remain vigilant, recognizing the risk tolerance implied by the 5.4% margin. PCT results should complement, not replace, comprehensive clinical judgment.
Study Strengths and Limitations: Strengths include the large sample size, multi-center design, blinded biomarker allocation, and distinct emphasis on both effectiveness and safety outcomes. Limitations include the acceptance of a 5.4% potential excess mortality as the noninferiority threshold, uncertainty about rare but significant harms, and the possibility of bias introduced by patient-level randomization. Generalizability to lower-resource settings may also be limited.
Future Research: Further randomized trials with lower noninferiority margins or cluster-level allocation are needed to better define the safety and efficacy of PCT-guided strategies for reducing antibiotic duration in sepsis. Additional investigations are needed for long-term patient-centered outcomes, cost-effectiveness, and the role of alternative biomarkers or combined strategies in sepsis care.
Reference:
Dark P, Hossain A, McAuley DF, et al. Biomarker-Guided Antibiotic Duration for Hospitalized Patients With Suspected Sepsis: The ADAPT-Sepsis Randomized Clinical Trial. JAMA. 2024; published online December 9. DOI: http://doi.org/10.1001/jama.2024.26458
PulmCCM Commentary: “Is procalcitonin ‘safe’ to guide antibiotic use in patients with sepsis? ADAPT-Sepsis tests the strategy in the U.K., with global ambitions.” Jan 02, 2025. https://www.pulmccm.org/p/is-procalcitonin-safe-to-guide-antibiotic
Phase 2b/3 QUASAR Program: Guselkumab for Induction and Maintenance Therapy in Moderate-to-Severe Ulcerative Colitis
7 Jan, 2025 | 13:00h | UTCBackground: Ulcerative colitis (UC) is a chronic inflammatory condition affecting the colon’s mucosal surface, frequently accompanied by debilitating symptoms such as bloody diarrhea, urgency, and abdominal discomfort. Despite the availability of corticosteroids, immunosuppressants, and advanced biologic or small-molecule therapies, many patients still experience suboptimal outcomes. Targeting interleukin (IL)-23, a critical cytokine in the inflammatory cascade, has gained increasing attention. Guselkumab, a human IgG1 monoclonal antibody against the IL-23p19 subunit, has shown clinical promise in psoriasis, psoriatic arthritis, and Crohn’s disease. This article reports findings from the phase 2b/3 QUASAR clinical development program evaluating guselkumab in UC.
Objective: To assess the efficacy and safety of intravenous (IV) guselkumab induction therapy (200 mg every 4 weeks) compared to placebo, followed by subcutaneous (SC) maintenance regimens (200 mg every 4 weeks or 100 mg every 8 weeks) compared to placebo (withdrawal) in adults with moderately to severely active UC who had inadequate responses or intolerance to at least one conventional or advanced therapy.
Methods: In these double-blind, randomized, placebo-controlled studies within the QUASAR program, adults with a baseline modified Mayo (mMayo) score of 5–9 (which excludes the physician’s global assessment) and evidence of active UC underwent IV induction with either guselkumab or placebo at Weeks 0, 4, and 8. The primary endpoint of the induction trial was clinical remission at Week 12 in the primary analysis population (patients with mMayo score 5-9), defined by improved stool frequency, rectal bleeding, and endoscopic findings. Responders from both the phase 2b and phase 3 induction studies then entered the maintenance study, randomized to SC guselkumab (either 200 mg Q4W or 100 mg Q8W) or placebo (withdrawal, meaning patients who had previously responded to guselkumab). The primary endpoint for the maintenance phase was clinical remission at Week 44 in the primary analysis population. Key secondary outcomes included endoscopic improvement, histological remission, corticosteroid-free remission, and patient-reported measures.
Results: A total of 701 patients with a baseline mMayo score of 5-9 (primary analysis population) were evaluated in the phase 3 induction study. By Week 12, a higher proportion of those receiving IV guselkumab (23%) achieved clinical remission compared to placebo (8%; p<0.0001). Patients also demonstrated improvement in endoscopic outcomes and had early symptomatic relief (notably a reduction in rectal bleeding as early as Week 1). In the subsequent maintenance phase, 568 guselkumab induction responders from both phase 2b and phase 3 studies (primary analysis population) were randomized. At Week 44, clinical remission was significantly more frequent in patients receiving guselkumab SC (50% on 200 mg Q4W, 45% on 100 mg Q8W) vs 19% on placebo (both p<0.0001). Endoscopic and histological indices indicated improved mucosal healing with active therapy. Most patients in remission were free of corticosteroids, highlighting a significant steroid-sparing effect.
Conclusions: Guselkumab induction (200 mg IV every 4 weeks) followed by either of the two SC maintenance regimens (200 mg Q4W or 100 mg Q8W) demonstrated substantial efficacy in adults with moderate-to-severe UC, with improved clinical, endoscopic, and histological endpoints relative to placebo. No new safety concerns were observed compared to the known safety profile of guselkumab.
Implications for Practice: Guselkumab offers a new therapeutic option for UC, particularly for individuals who have not responded to, or could not tolerate, other treatments. The study suggests that guselkumab can be considered for both biologic-naive and biologic-experienced patients. As with any novel therapy, careful patient selection and close follow-up are advisable.
Study Strengths and Limitations: Strengths include the rigorous, global, phase 2b/3 design with objective assessments of clinical, endoscopic, and histological response. The large population permitted detailed subgroup analyses (e.g., efficacy was observed in both biologic-naive and biologic-experienced populations). Limitations include the exclusion of certain therapy-refractory cases and lack of active comparator arms. The randomized-withdrawal maintenance design means only induction responders were evaluated further, potentially enhancing observed effect sizes.
Future Research: Extended follow-up will elucidate the durability of remission beyond one year and clarify long-term safety considerations. Head-to-head trials against other IL-23 antagonists or advanced therapies could further guide treatment algorithms. Real-world evidence evaluating diverse populations will be instrumental in determining broader applicability.
Reference: Rubin DT, Allegretti JR, Panés J, Shipitofsky N, Yarandi SS, Huang K-HG, Germinaro M, Wilson R, Zhang H, Johanns J, Feagan BG, Hisamatsu T, Lichtenstein GR, Bressler B, Peyrin-Biroulet L, Sands BE, Dignass A; QUASAR Study Group. Guselkumab in patients with moderately to severely active ulcerative colitis (QUASAR): phase 3 double-blind, randomised, placebo-controlled induction and maintenance studies. The Lancet. 2025;405(10472):33–49. DOI: http://doi.org/10.1016/S0140-6736(24)01927-5
RCT: Camrelizumab Increases Pathological Complete Response in Early or Locally Advanced Triple-Negative Breast Cancer
7 Jan, 2025 | 12:00h | UTCBackground: Triple-negative breast cancer (TNBC) accounts for approximately 15% of all breast malignancies and is known for its aggressive clinical course and limited therapeutic options. Neoadjuvant chemotherapy has become standard of care for many patients with stage II or III TNBC, aiming to downstage tumors and enhance surgical outcomes. Recent trials suggest that adding immune checkpoint inhibitors, such as anti–programmed death 1/ligand 1 (PD-1/PD-L1) agents, to anthracycline- and platinum-based regimens can further improve response rates. Camrelizumab, a humanized monoclonal anti–PD-1 antibody, has shown antitumor activity in various malignancies, including advanced TNBC. This study, the CamRelief trial, evaluated whether camrelizumab combined with intensive chemotherapy (nab-paclitaxel plus carboplatin followed by dose-dense anthracycline-cyclophosphamide) increases pathological complete response (pCR) in patients with early or locally advanced TNBC.
Objective: To determine if the addition of camrelizumab to a platinum-containing neoadjuvant chemotherapy regimen significantly improves pCR in operable or locally advanced TNBC compared with placebo plus the same chemotherapy backbone.
Methods: This randomized, double-blind, phase 3 trial enrolled 441 female patients aged 18 to 75 years from 40 Chinese centers. Eligible participants had stage II or III TNBC (T2N0-1M0/T3N0M0 or T2N2-3M0/T3N1-3M0) and an Eastern Cooperative Oncology Group performance-status score of 0 or 1. Patients were randomized 1:1 to receive camrelizumab (200 mg) or placebo plus chemotherapy. Chemotherapy consisted of nab-paclitaxel (100 mg/m^2) and carboplatin (area under the curve, 1.5) on days 1, 8, and 15 every 28 days for 16 weeks, then epirubicin (90 mg/m^2) and cyclophosphamide (500 mg/m^2) every two weeks for 8 weeks. Camrelizumab or placebo was administered every two weeks during the 24 weeks of chemotherapy. The primary end point was pCR (ypT0/Tis ypN0), assessed by a local pathologist masked to treatment assignment, at the time of surgery. Secondary end points included event-free survival, disease-free survival, distant disease-free survival, and safety.
Results: Of the 441 randomized patients, 89.2% in the camrelizumab-chemotherapy group and 91.3% in the placebo-chemotherapy group proceeded to surgery. Pathological complete response was observed in 56.8% (95% CI, 50.0%-63.4%) of patients receiving camrelizumab-chemotherapy vs 44.7% (95% CI, 38.0%-51.6%) of those receiving placebo-chemotherapy (rate difference, 12.2% [95% CI, 3.3%-21.2%]; 1-sided P = .004). Serious adverse events occurred more frequently with camrelizumab-chemotherapy (34.7% vs 22.8%), including decreased neutrophil count, decreased platelet count, and decreased white blood cell count, but most immune-related events (eg, reactive capillary endothelial proliferation, hypothyroidism) were low grade and manageable. Longer-term outcomes (event-free survival, disease-free survival, distant disease-free survival) remain immature at a median follow-up of 14.4 months, with hazard ratios of 0.80 (95% CI, 0.46-1.42), 0.58 (95% CI, 0.27-1.24), and 0.62 (95% CI, 0.29-1.33), respectively.
Conclusions: In patients with early or locally advanced TNBC, adding camrelizumab to a platinum-containing, dose-dense anthracycline-cyclophosphamide regimen significantly increased pCR rates compared with placebo plus the same chemotherapy backbone. Safety profiles were consistent with known effects of camrelizumab and dose-dense chemotherapy, with no unexpected toxicities detected.
Implications for Practice: These findings support the integration of camrelizumab into an intensive neoadjuvant regimen for TNBC, potentially offering higher rates of tumor eradication across various nodal stages. Clinicians should, however, anticipate and monitor immune-related adverse events, particularly in higher-risk populations. Given the toxicity profile, patient selection and vigilant supportive care are important.
Study Strengths and Limitations: Strengths include the randomized, double-blind design and the inclusion of higher-risk, node-positive cohorts (including N3). The dose-dense chemotherapy backbone further strengthens the applicability of results in more advanced operable disease. Limitations involve the short follow-up time, which precludes conclusive survival analyses, and the study’s restriction to a single geographic population.
Future Research: Longer follow-up is necessary to determine if improved pCR translates into sustained survival benefits. Biomarker-driven approaches, including further PD-L1 and immunogenomic analyses, may refine patient selection. Studies in broader populations and direct comparisons with other checkpoint inhibitors will help define the optimal immunotherapy-partner regimens in TNBC.
Reference:
Chen L, Li H, Zhang H, et al. Camrelizumab vs Placebo in Combination With Chemotherapy as Neoadjuvant Treatment in Patients With Early or Locally Advanced Triple-Negative Breast Cancer: The CamRelief Randomized Clinical Trial. JAMA. Published online December 13, 2024. DOI: http://doi.org/10.1001/jama.2024.23560
Joensuu H. Neoadjuvant Camrelizumab for Triple-Negative Breast Cancer. Editorial. JAMA. Published online December 13, 2024. DOI: http://doi.org/10.1001/jama.2024.25927