Tuberculosis and Immune Reconstitution Inflammatory Syndrome in Patients With Inflammatory Bowel Disease and Anti-TNFα Treatment: Insights From a French Multicenter Study and Systematic Literature Review With Emphasis on Paradoxical Anti-TNFα Resumption.

Background: The advent of anti-tumor necrosis factor α (anti-TNFα) has revolutionized the treatment of inflammatory bowel disease (IBD). However, susceptibility to active tuberculosis (TB) is associated with this therapy and requires its discontinuation. The risk of immune reconstitution inflammatory syndrome (IRIS) in this population is poorly understood, as is the safety of resuming anti-TNFα. Methods: This French retrospective study (2010-2022) included all TB cases in patients with IBD who were treated with anti-TNFα in 6 participating centers. A systematic literature review was performed on TB-IRIS and anti-TNFα exposure. Results: Thirty-six patients were included (median age, 35 years; IQR, 27-48). TB was disseminated in 86% and miliary in 53%. IRIS occurred in 47% after a median 45 days (IQR, 18-80). Most patients with TB-IRIS (93%) had disseminated TB. Miliary TB was associated with IRIS risk in univariate analysis (odds ratio, 7.33; 95% CI, 1.60-42.82; P = .015). Anti-TB treatment was longer in this population (median [IQR], 9 [9-12] vs 6 [6-9] months; P = .049). Anti-TNFα was resumed in 66% after a median 4 months (IQR, 3-10) for IBD activity (76%) or IRIS treatment (24%), with only 1 case of TB relapse. Fifty-two cases of TB-IRIS in patients treated with anti-TNFα were reported in the literature, complicating disseminating TB (85%) after a median 42 days (IQR, 21-90), with 70% requiring anti-inflammatory treatment. Forty cases of TB-IRIS or paradoxical reaction treated with anti-TNFα were also reported. IRIS was neurologic in 64%. Outcome was mostly favorable (93% recovery). Conclusions: TB with anti-TNFα treatment is often complicated by IRIS of varying severity. Restarting anti-TNFα is a safe and effective strategy.

Hematological features and alternate diagnoses in critically ill thrombotic antiphospholipid syndrome patients.

OBJECTIVES: Severe thrombotic antiphospholipid syndrome (APS) frequently affects the kidney, heart, and central nervous system. The precise frequency, clinical picture, differential diagnoses, and outcome of APS-related hematological involvement are lacking, especially in patients requiring ICU admission. This study aimed to describe the hematological manifestations associated with critically ill thrombotic APS patients and catastrophic antiphospholipid syndrome. METHODS: This French, national, multicenter, retrospective study, conducted, from January 2000 to September 2018, included all APS patients admitted to 24 participating centers' ICUs with any new thrombotic manifestation. The prevalence of hematological manifestations and their associated outcomes were studied. RESULTS: One hundred and thirty-four patients, female 72%, median [IQR] age 45 [34-56] years, with 152 episodes were included. Anemia was present in 95% of episodes and thrombocytopenia in 93%. The lowest values for hemoglobin and platelets were 7.1 [6.3-8.8] g/dL and 38 [21-60] g/L, respectively. The lowest platelet count below 20 g/L was significantly associated with a higher in-ICU mortality rate (50%, p < 0.0001). A thrombotic microangiopathy syndrome (TMA) syndrome was seen in 16 patients (12%) and was associated with higher in-hospital mortality (p = 0.05). Median ADAMTS-13 levels were 44% [27-74]. Anti-ADAMTS13 antibodies were tested in 11 patients and found negative in all. A suspicion of heparin-induced thrombocytopenia (HIT) was raised in 66 patients but only four patients were classified as definite HIT. Disseminated intravascular coagulation (DIC) was seen in 51% of patients. CONCLUSION: Thrombocytopenia is very frequent in severe APS patients and may be related to TMA, HIT, or DIC. Deciphering the mechanisms of thrombocytopenia is decisive in CAPS patients. Key Points • Thrombocytopenia is the hallmark laboratory finding in CAPS. • A complete thrombotic microangiopathy pattern is infrequent in CAPS patients. • Alternate diagnoses of CAPS, especially heparin-induced thrombocytopenia, need to be adequately investigated.

Geo-economic Influence on the Effect of Fluid Volume for Sepsis Resuscitation: A Meta-Analysis.

Rationale: Sepsis management relies on fluid resuscitation avoiding fluid overload and its related organ congestion. Objectives: To explore the influence of country income group on risk-benefit balance of fluid management strategies in sepsis. Methods: We searched e-databases for all randomized controlled trials on fluid resuscitation in patients with sepsis or septic shock up to January 2023, excluding studies on hypertonic fluids, colloids, and depletion-based interventions. The effect of fluid strategies (higher versus lower volumes) on mortality was analyzed per income group (i.e., low- and middle-income countries [LMICs] or high-income countries [HICs]). Measurements and Main Results: Twenty-nine studies (11,798 patients) were included in the meta-analysis. There was a numerically higher mortality in studies of LMICs as compared with those of HICs: median, 37% (interquartile range [IQR]: 26-41) versus 29% (IQR: 17-38; P = 0.06). Income group significantly interacted with the effect of fluid volume on mortality: Higher fluid volume was associated with higher mortality in LMICs but not in HICs: odds ratio (OR), 1.47; 95% confidence interval (95% CI): 1.14-1.90 versus 1.00 (95% CI: 0.87-1.16), P = 0.01 for subgroup differences. Higher fluid volume was associated with increased need for mechanical ventilation in LMICs (OR, 1.24 [95% CI: 1.08-1.43]) but not in HICs (OR, 1.02 [95% CI: 0.80-1.29]). Self-reported access to mechanical ventilation also significantly influenced the effect of fluid volume on mortality, which increased with higher volumes only in settings with limited access to mechanical ventilation (OR: 1.45 [95% CI: 1.09-1.93] vs. 1.09 [95% CI: 0.93-1.28], P = 0.02 for subgroup differences). Conclusions: In sepsis trials, the effect of fluid resuscitation approach differed by setting, with higher volume of fluid resuscitation associated with increased mortality in LMICs and in settings with restricted access to mechanical ventilation. The precise reason for these differences is unclear and may be attributable in part to resource constraints, participant variation between trials, or other unmeasured factors.

Herpes Simplex Virus Hepatitis in Patients Requiring Intensive Care Unit Admission: A Retrospective, Multicenter, Observational Study.

The clinical features and short-term prognosis of patients admitted to the intensive care unit for herpes hepatitis are lacking. Of 33 patients admitted between 2006 and 2022, 22 were immunocompromised, 4 were pregnant women, and 23 died. Sixteen patients developed a hemophagocytic syndrome. Acyclovir was initiated a median (interquartile range) of 1 (0-3) day after admission.

FX06 to rescue SARS-CoV-2-induced acute respiratory distress syndrome: a randomized clinical trial.

BACKGROUND: Vascular leakage is a major feature of acute respiratory distress syndrome (ARDS). We aimed to evaluate the efficacy of FX06, a drug under development that stabilizes interendothelial cell junctions, at reducing vascular leakage during SARS-CoV-2-induced ARDS. METHODS: This multicenter, double-blinded, randomized trial included adults with COVID-19-associated ARDS who had received invasive mechanical ventilation for < 5 days and were randomized to receive either intravenous FX06 (400 mg/d, for 5 days) or its vehicle as placebo. The primary endpoint was the lowering-from day 1 to day 7-of the transpulmonary thermodilution-derived extravascular lung-water index (EVLWi). RESULTS: Twenty-five patients were randomized to receive FX06 and 24 the placebo. Although EVLWi was elevated at baseline (median [IQR] 15.6 mL/kg [13.5; 18.5]), its declines from day 1 to day 7 were comparable for FX06 recipients and controls (respectively, - 1.9 [- 3.3; - 0.5] vs. - 0.8 [- 5.5; - 1.1] mL/kg; estimated effect - 0.8 [- 3.1; + 2.4], p = 0.51). Cardiac indexes, pulmonary vascular permeability indexes, and fluid balances were also comparable, as were PaO2/FiO2 ratios and durations of mechanical ventilation. Adverse event rates were similar for the 2 groups, although more FX06 recipients developed ventilator-associated pneumonia (16/25 (64%) vs. 6/24 (24%), p = 0.009). CONCLUSIONS: In this unique-dosing-regimen study, FX06 did not lower SARS-CoV-2-induced pulmonary vascular leakage. Future investigations will need to evaluate its efficacy at earlier times during the disease or using other regimens. Trial registration NCT04618042. Registered 5 November 2020.

Early renal recovery after acute kidney injury in patients on venoarterial extracorporeal membrane oxygenation: A retrospective study.

PURPOSE: The impact of VA-ECMO on early renal recovery (within 7 days after ECMO onset) in patients with pre-ECMO acute kidney injury and cardiogenic shock is unknown. MATERIAL AND METHODS: This retrospective single-center study included adult patients with cardiogenic shock rescued by VA-ECMO and severe AKI occurring before ECMO implantation (pre-ECMO AKI). Patients with early renal recovery (defined as at least a 50% decrease in peak serum creatinine or weaning from renal replacement therapy) were compared to patients without early renal recovery. RESULTS: During 7 years, 145 patients with severe pre-ECMO AKI were included. Eighty-two patients had no early renal recovery whereas 63 had early renal recovery within 7 days after VA-ECMO onset. The median time to early renal recovery was 4 (3,6) days. Nephrotoxic antibiotics (HR = 0.35 [95% CI, 0.21-0.59], p < 0.001), median fluid balance during the first 7 days of VA-ECMO (HR = 0.77 [95% CI, 0.64-0.93], p = 0.008), pre-ECMO AKI stage 3 (HR = 0.36 [95% CI, 0.20-0.64], p < 0.001) and median vasoactive-inotropic score (HR = 0.99 [95% CI, 0.98,1.00], p = 0.035) were independently associated with no early renal recovery. CONCLUSIONS: Only 43% of patients with severe pre-ECMO AKI had early renal recovery after VA-ECMO initiation.

Acute circulatory failure in critically ill patients with hemophagocytic syndrome.

BACKGROUND: Hemophagocytic syndrome (HS) is a rare life-threatening condition that can lead to multi organ failure and shock. Acute circulatory failure in these patients has been poorly studied. Objectives of this study were to describe characteristics of HS patients with shock, prognostic factors and impact of etoposide infusion on hemodynamic parameters. This is a monocenter, retrospective, observational cohort study in a French tertiary intensive care unit (ICU). All adult critically ill patients with HS managed in the ICU between 2007 and 2017, requiring vasopressors (norepinephrine) and etoposide infusion. RESULTS: Thirty-four patients were included. Two-third (n = 25) were of male gender and median age was 48 years [IQR 34-62]. Shock (n = 14, 41%) and acute respiratory failure (n = 8, 23.5%) were the main initial reasons for ICU admission. The most common HS trigger was underlying hematological malignancy (n = 26; 76%), followed by infectious diseases in 3 patients (9%) and auto immune diseases in 2 (6%) patients. Median SOFA score at ICU admission was 14 [10-17]. A majority of patients required mechanical ventilation (n = 29, 85%) and initial median lactate level was 3.7 mmol/L [2.9-6.9]. Hospital mortality rate was 53% (n = 18) and was associated with SOFA score and renal replacement therapy in univariate analysis. All patients received broad spectrum antibiotics under suspicion of septic shock. In 17 patients, 21 nosocomial infections were documented, mainly from bacterial origin. Etoposide infusion was followed by decreased norepinephrine doses despite an increase in lactate level, while no degradation in mean arterial pressure, heart rate or renal function were identified. CONCLUSIONS: Hospital mortality remains high in critically ill HS patients with shock, but a significant improvement of hemodynamic parameters is observed following etoposide infusion, suggesting that an aggressive initial supportive care is crucial in these patients.

Tracheostomy management in patients with severe acute respiratory distress syndrome receiving extracorporeal membrane oxygenation: an International Multicenter Retrospective Study.

BACKGROUND: Current practices regarding tracheostomy in patients treated with extracorporeal membrane oxygenation (ECMO) for acute respiratory distress syndrome are unknown. Our objectives were to assess the prevalence and the association between the timing of tracheostomy (during or after ECMO weaning) and related complications, sedative, and analgesic use. METHODS: International, multicenter, retrospective study in four large volume ECMO centers during a 9-year period. RESULTS: Of the 1,168 patients treated with ECMO for severe ARDS (age 48 ± 16 years, 76% male, SAPS II score 51 ± 18) during the enrollment period, 353 (30%) and 177 (15%) underwent tracheostomy placement during or after ECMO, respectively. Severe complications were uncommon in both groups. Local bleeding within 24 h of tracheostomy was four times more frequent during ECMO (25 vs 7% after ECMO, p < 0.01). Cumulative sedative consumption decreased more rapidly after the procedure with sedative doses almost negligible 48-72 h later, when tracheostomy was performed after ECMO decannulation (p < 0.01). A significantly increased level of consciousness was observed within 72 h after tracheostomy in the "after ECMO" group, whereas it was unchanged in the "during-ECMO" group. CONCLUSION: In contrast to patients undergoing tracheostomy after ECMO decannulation, tracheostomy during ECMO was neither associated with a decrease in sedation and analgesia levels nor with an increase in the level of consciousness. This finding together with a higher risk of local bleeding in the days following the procedure reinforces the need for a case-by-case discussion on the balance between risks and benefits of tracheotomy when performed during ECMO.

Uncontrolled Innate and Impaired Adaptive Immune Responses in Patients with COVID-19 Acute Respiratory Distress Syndrome.

Rationale: Uncontrolled inflammatory innate response and impaired adaptive immune response are associated with clinical severity in patients with coronavirus disease (COVID-19).Objectives: To compare the immunopathology of COVID-19 acute respiratory distress syndrome (ARDS) with that of non-COVID-19 ARDS, and to identify biomarkers associated with mortality in patients with COVID-19 ARDS.Methods: Prospective observational monocenter study. Immunocompetent patients diagnosed with RT-PCR-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and ARDS admitted between March 8 and March 30, 2020, were included and compared with patients with non-COVID-19 ARDS. The primary clinical endpoint of the study was mortality at Day 28. Flow cytometry analyses and serum cytokine measurements were performed at Days 1-2 and 4-6 of ICU admission.Measurements and Main Results: As compared with patients with non-COVID-19 ARDS (n = 36), those with COVID-19 (n = 38) were not significantly different regarding age, sex, and Sequential Organ Failure Assessment and Simplified Acute Physiology Score II scores but exhibited a higher Day-28 mortality (34% vs. 11%, P = 0.030). Patients with COVID-19 showed profound and sustained T CD4+ (P = 0.002), CD8+ (P < 0.0001), and B (P < 0.0001) lymphopenia, higher HLA-DR expression on monocytes (P < 0.001) and higher serum concentrations of EGF (epithelial growth factor), GM-CSF, IL-10, CCL2/MCP-1, CCL3/MIP-1a, CXCL10/IP-10, CCL5/RANTES, and CCL20/MIP-3a. After adjusting on age and Sequential Organ Failure Assessment, serum CXCL10/IP-10 (P = 0.047) and GM-CSF (P = 0.050) were higher and nasopharyngeal RT-PCR cycle threshold values lower (P = 0.010) in patients with COVID-19 who were dead at Day 28.Conclusions: Profound global lymphopenia and a "chemokine signature" were observed in COVID-19 ARDS. Increased serum concentrations of CXCL10/IP-10 and GM-CSF, together with higher nasopharyngeal SARS-CoV-2 viral load, were associated with Day-28 mortality.