Case 327.

HISTORY: A 58-year-old man who was an active smoker was admitted twice to the intensive care unit (ICU) of a tertiary referral thoracic center for severe hypercapnic acute respiratory failure and persistent bilateral chest radiograph opacities that were unchanged over the course of the two ICU admissions within a 3-month period (Fig 1). He had obesity (body mass index, 36 kg/m2), stage 3 vascular chronic renal insufficiency, and hebephrenic schizophrenia treated with haloperidol, carbamazepine, and cyamemazine. He reported chronic dyspnea on exertion, which worsened for 6 months. At the second ICU admission, he was afebrile, with a blood pressure of 160/72 mm Hg and pulse oximetry of 93% on 6 L/min oxygen therapy through a nonrebreathing mask. Physical examination showed signs of respiratory failure with wheezing and active abdominal expiration, bilateral pulmonary crackles without chest pain, hemoptysis, clubbing, or signs of cardiac failure. He had no peripheral lymphadenopathy and no enlarged spleen. Blood gases (on 6 L/min oxygen) showed respiratory acidosis (pH, 7.15 [normal range, 7.38-7.42]; Pao2 level, 67 mm Hg [normal range, 80-100 mm Hg]; Paco2 level, 102 mm Hg [normal range, 38-42 mm Hg]; Hco3- level, 29 mmol/L [normal range, 22-27 mmol/L]). Noninvasive ventilation was initiated. Imaging performed during the second ICU hospitalization included noncontrast chest CT (Fig 2), MRI of the chest without contrast enhancement (Fig 3), and fluorine 18 fluorodeoxyglucose PET/CT (Fig 4).

ICU admission for solid cancer patients treated with immune checkpoint inhibitors.

BACKGROUND: Immune checkpoint inhibitors (ICI) have revolutionized the management of cancer. They can induce immune-related adverse events (irAE) leading to intensive care unit (ICU) admission. We aimed to describe irAEs for ICU admissions in solid cancer patients treated with ICIs. METHODS: This prospective multicenter study was conducted in France and Belgium. Adult patients with solid tumor and treated with systemic ICIs within the last 6 months, requiring non-programmed ICU admission were included. Patients admitted for microbiologically documented sepsis were excluded. Imputability of irAEs in ICU admissions was described according to the WHO-UMC classification system at ICU admission and at ICU discharge. The use of immunosuppressant treatment was reported. RESULTS: 115 patients were eligible. Solid tumor was mainly lung cancer (n = 76, 66%) and melanoma (n = 18, 16%). They were mainly treated with an anti-PD-(L)1 alone (n = 110, 96%). Main ICU admission reasons were acute respiratory failure (n = 66, 57%), colitis (n = 14, 13%), and cardiovascular disease (n = 13, 11%). ICU admission was considered "likely" associated with irAE for 48% (n = 55) of patients. Factors independently associated with irAE were a good ECOG performance status (PS) (ECOG-PS of 0 or 1 vs. ECOG-PS of 2-3, odds ratio [OR] = 6.34, 95% confidence interval [95% CI] 2.13-18.90, and OR = 3.66, 95% CI 1.33-10.03, respectively), and a history of irAE (OR = 3.28, 95% CI 1.19-9.01). Steroids were prescribed for 41/55 (75%) patients with ICU admission "likely" related to irAE. Three patients were subsequently treated with immunosuppressants. CONCLUSION: IrAEs accounted for half of ICU admissions in cancer patients receiving ICIs. They could be treated with steroids. Identifying the imputability of irAEs in ICU admissions remains a challenge.

Spontaneous pneumomediastinum: a surrogate of P-SILI in critically ill COVID-19 patients.

Spontaneous pneumomediastinum (SP) has been described early during the COVID-19 pandemic in large series of patients with severe pneumonia, but most patients were receiving invasive mechanical ventilation (IMV) at the time of SP diagnosis. In this retrospective multicenter observational study, we aimed at describing the prevalence and outcomes of SP during severe COVID-19 with pneumonia before any IMV, to rule out mechanisms induced by IMV in the development of pneumomediastinum.Among 549 patients, 21 patients (4%) developed a SP while receiving non-invasive respiratory support, after a median of 6 days [4-12] from ICU admission. The proportion of patients requiring IMV was similar. However, the time to tracheal intubation was longer in patients with SP (6 days [5-13] vs. 2 days [1-4]; P = 0.00002), with a higher first-line use of non-invasive ventilation (n = 11; 52% vs. n = 150; 28%; P = 0.02). The 21 patients who developed a SP had persisting signs of severe lung disease and respiratory failure with lower ROX index between ICU admission and occurrence of SP (3.94 [3.15-5.55] at admission vs. 3.25 [2.73-4.02] the day preceding SP; P = 0.1), which may underline potential indirect signals of Patient-self inflicted lung injury (P-SILI).In this series of critically ill COVID-19 patients, the prevalence of SP without IMV was not uncommon, affecting 4% of patients. They received more often vasopressors and had a longer ICU length of stay, as compared with their counterparts. One pathophysiological mechanism may potentially be carried out by P-SILI related to a prolonged respiratory failure, as underlined by a delayed use of IMV and the evolution of the ROX index between ICU admission and the day preceding SP.

Diagnosis and prognosis of acute respiratory distress syndrome related to diffuse pneumonic-type adenocarcinoma: a single-center case series study.

Background: The absence of diagnosis of acute respiratory distress syndrome (ARDS) concerns 20% of cancer patients and is associated with poorer outcomes. Diffuse pneumonic-type adenocarcinoma (P-ADC) is part of these difficult-to-diagnose ARDS, but only limited data are available regarding critically ill patients with diffuse P-ADC. We sought to describe the diagnosis process and the prognosis of P-ADC related ARDS patients admitted to the intensive care unit (ICU). Methods: Single-center observational case series study. All consecutive patients admitted to the ICU over a two-decade period presenting with (I) histologically or cytologically proven adenocarcinoma of the lung and (II) ARDS according to Berlin definition were included. Clinical, biological, radiological and cytological features of P-ADC were collected to identify diagnostic clues. Multivariate logistic regression analyses were performed to assess factors associated with ICU and hospital mortality. Results: Among the 24 patients included [70 (61-75) years old, 17 (71%) males], the cancer diagnosis was performed during the ICU stay in 19 (79%), and 17 (71%) required mechanical ventilation. The time between the first symptoms and the diagnosis of P-ADC was 210 days (92-246 days). A non-resolving pneumonia after 2 (2 to 3) antibiotics lines observed in 23 (96%) patients with a 34 mg/L (19 to 75 mg/L) plasma C-reactive protein level at ICU admission. Progressive dyspnea, bronchorrhea, salty expectoration, fissural bulging and compressed bronchi and vessels were present in 100%, 83%, 69%, 57% and 43% of cases. Cytological examination of sputum or broncho-alveolar lavage provided a 75% diagnostic yield. The ICU and hospital mortality rates were 25% and 63%, respectively. The time (in days) between first symptoms and diagnosis [odds ratio (OR) 1.02, 95% confidence interval (95% CI): 1.00-1.03, P=0.046] and the Simplified Acute Physiology Score II (OR 1.16, 95% CI: 1.01-1.33, P=0.040) were independently associated with ICU mortality. Conclusions: Non-resolving pneumonia after several antibiotics lines without inflammatory syndrome, associated with progressive dyspnea, salty bronchorrhea, and lobar swelling (i.e., fissural bulging, compressed bronchi and vessels) were suggestive of P-ADC. Delayed diagnosis of diffuse P-ADC seemed an independent prognostic predictor and disease timely recognition may contribute to prognosis improvement.

Prevalence, characteristics and outcome of cardiac manifestations in critically-ill antiphospholipid syndrome patients.

AIMS: Antiphospholipid syndrome (APS) is a rare autoimmune disease defined by thrombotic events occurring in patients with persistent antiphospholipid antibodies. Cardiac manifestations in critically-ill APS patients are poorly investigated. We conducted a study to assess the prevalence, the characteristics and the prognosis of cardiac manifestations in thrombotic APS patients admitted to intensive care unit (ICU). METHODS AND RESULTS: A French, national, multicentre, retrospective study, conducted, from January 2000 to September 2018, including all APS patients admitted to 24 participating centres' ICUs with any new thrombotic (arterial, venous or microvascular) manifestation. Cardiac manifestations were defined as any new cardiac abnormalities relying on clinical examination, cardiac biomarkers, echocardiography, cardiac magnetic resonance (CMR) and coronarography. One hundred and thirty-six patients (female 72%) were included. Mean age at ICU admission was 46 ± 15years. Cardiac manifestations were present in 71 patients (53%). In patients with cardiac involvement, median left ventricular ejection fraction (LVEF) was 40% [28-55], troponin was elevated in 93% patients, coronary angiogram (n = 19, 27%) disclosing a coronary obstruction in 21%. CMR (n = 21) was abnormal in all cases, with late gadolinium enhancement in 62% of cases. Cardiac manifestations were associated with a non-significant increase of mortality (32% vs. 19%, p = 0.08). After 1-year follow-up, median LVEF was 57% [44-60] in patients with cardiac involvement. CONCLUSION: Cardiac involvement is frequent in critically-ill thrombotic APS patients and may be associated to more severe outcome. Increased awareness on this rare cause of myocardial infarction with or without obstructive coronary artery is urgently needed.

When targeted therapy for cancer leads to ICU admission. RETRO-TARGETICU multicentric study.

PURPOSE: To study prevalence of targeted therapy (TT)-related adverse events requiring ICU admission in solid tumor patients. METHODS: Retrospective multicenter study from the Nine-i research group. Adult patients who received TT for solid tumor within 3 months prior to ICU admission were included. Patients admitted for TT-related adverse event were compared to those admitted for other reasons. RESULTS: In total, 140 patients, median age of 63 (52-69) years were included. Primary cancer site was mostly digestive (n=27, 19%), kidney (n=27, 19%), breast (n=24, 17%), and lung (n=20, 14%). Targeted therapy was anti-VEGF/VEGFR for 27% (n=38) patients, anti-EGFR for 22% (n=31) patients, anti-HER2 for 14% (n=20) patients and anti-BRAF for 9% (n=5) patients. ICU admission was related to TT adverse events for 30 (21%) patients. The most frequent complications were interstitial pneumonia (n=7), cardiac failure (n=5), anaphylaxis (n=4) and bleeding (n=4). At ICU admission, no significant difference was found between patients admitted for a TT-related adverse event and the other patients. One-month survival rate was higher in patients admitted for TT adverse event (OR=5.733 [2.031-16.182] P<0.001). CONCLUSIONS: Adverse events related to targeted therapy accounted for 20% of ICU admission in our population and carried a 16% one-month mortality. Outcome was associated with admission for TT related to adverse event, breast cancer and good performance status.

Identification of bronchoalveolar and blood immune-inflammatory biomarker signature associated with poor 28-day outcome in critically ill COVID-19 patients.

The local immune-inflammatory response elicited by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is still poorly described, as well as the extent to which its characteristics may be associated with the outcome of critical Coronavirus disease 2019 (COVID-19). In this prospective monocenter study, all consecutive COVID-19 critically ill patients admitted from February to December 2020 and explored by fiberoptic bronchoscopy with bronchoalveolar lavage (BAL) were included. Biological assays, including digital ELISA cytokine profiling and targeted eicosanoid metabolomic analysis, were performed on paired blood and BAL fluid (BALF). Clinical outcome was assessed through the World Health Organization 10-point Clinical Progression Scale (WHO-CPS) at the 28th day (D28) following the admission to intensive care unit. A D28-WHO-CPS value higher than 5 defined a poor outcome. Seventy-six patients were included, 45 (59%) had a poor day-28 outcome. As compared to their counterparts, patients with D28-WHO-CPS > 5 exhibited a neutrophil-predominant bronchoalveolar phenotype, with a higher BALF neutrophil/lymphocyte ratio, a blunted local type I interferon response, a decompartimentalized immune-inflammatory response illustrated by lower BALF/blood ratio of concentrations of IL-6 (1.68 [0.30-4.41] vs. 9.53 [2.56-19.1]; p = 0.001), IL-10, IL-5, IL-22 and IFN-γ, and a biological profile of vascular endothelial injury illustrated by a higher blood concentration of VEGF and higher blood and/or BALF concentrations of several vasoactive eicosanoids. In critically ill COVID-19 patients, we identified bronchoalveolar and blood immune-inflammatory biomarker signature associated with poor 28-day outcome.

Cyclophosphamide added to glucocorticoids in acute exacerbation of idiopathic pulmonary fibrosis (EXAFIP): a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: The use of cyclophosphamide in patients with acute exacerbation of idiopathic pulmonary fibrosis (IPF) is unknown. Our study was designed to evaluate the efficacy and safety of four cyclophosphamide pulses in addition to high-dose methylprednisolone in this population. METHODS: In this double-blind, placebo-controlled trial done in 35 departments across 31 hospitals in France, adult patients (≥18 years) with acute exacerbation of IPF and those with suspected acute exacerbation of IPF were randomly assigned in a 1:1 ratio using a web-based system to receive either intravenous pulses of cyclophosphamide (600 mg/m2) plus uromitexan as haemorrhagic cystitis prophylaxis (200 mg/m2) at the time of cyclophosphamide administration and then again, 4 h later, or placebo at days 0, 15, 30, and 60. Random assignment was stratified according to the severity of IPF and was block-balanced with variable block sizes of four or six patients. Patients receiving mechanical ventilation, with active infection, with active cancer, or who were registered on the lung transplant waiting list were excluded. All patients received standardised high-dose glucocorticoids. The investigators, patients, and the sponsor were masked to the treatment assignments. The primary endpoint was 3-month all-cause mortality, analysed by a χ2 test adhering to an intention-to-treat principle. The trial is now complete and registered with ClinicalTrials.gov, NCT02460588. FINDINGS: Between Jan 22, 2016, and July 19, 2018, 183 patients were assessed for eligibility, of whom 120 patients were randomly assigned and 119 patients (62 [52%] with severe IPF) received at least one dose of cyclophosphamide (n=60) or placebo (n=59), all of whom were included in the intention-to-treat analysis. The 3-month all-cause mortality was 45% (27/60) in patients given cyclophosphamide compared with 31% (18/59) in the placebo group (difference 14·5% [95% CI -3·1 to 31·6]; p=0·10). Similar results were found after adjustment by IPF severity (odds ratio [OR] 1·89 [95% CI 0·89-4·04]). The risk of death at 3 months, independent of the treatment received, was higher with severe than non-severe IPF (OR 2·62 [1·12-6·12]) and was lower with the use of antifibrotic therapy (OR 0·33 [0·13-0·82]). Adverse events were similar between groups by 6 months (25 [42%] in the cyclophosphamide group vs 30 [51%] in the placebo group) and their proportion, including infections, did not differ. Overall infection was the main adverse event and occurred in 20 (33%) of 60 patients in the cyclophosphamide group versus 21 (36%) of 59 patients in the placebo group. INTERPRETATION: In patients with acute exacerbation of IPF, adding intravenous cyclophosphamide pulses to glucocorticoids increased 3-month mortality. These findings provide evidence against the use of intravenous cyclophosphamide in such patients. FUNDING: Programme Hospitalier de Recherche Clinique of the French Ministry of Health (PHRC 2014-502), Roche Pharmaceuticals.

Causes of acute respiratory failure in patients with small-vessel vasculitis admitted to intensive care units: a multicenter retrospective study.

RATIONALE: Acute respiratory failure (ARF) in patients admitted to the intensive care unit (ICU) with known or de novo small-vessel vasculitis (Svv) may be secondary to the underlying immune disease or to other causes. Early identification of the cause of ARF is essential to initiate the most appropriate treatment in a timely fashion. METHODS: A retrospective multicenter study in 10 French ICUs from January 2007 to January 2018 to assess the clinical presentation, main causes and outcome of ARF associated with Svv, and to identify variables associated with non-immune etiology of ARF in patients with known Svv. RESULTS: During the study period, 121 patients [62 (50-75) years; 62% male; median SAPSII and SOFA scores 39 (27-52) and 6 (4-8), respectively] were analyzed. An immune cause was identified in 67 (55%), and a non-immune cause in 54 (45%) patients. ARF was associated with several causes in 43% (n = 52) of cases. The main immune cause was diffuse alveolar hemorrhage (DAH) (n = 47, 39%), whereas the main non-immune cause was pulmonary infection (n = 35, 29%). The crude 90-day and 1-year mortality were higher in patients with non-immune ARF, as compared with their counterparts (32% and 38% vs. 15% and 20%, respectively; both p = 0.03), but was marginally significantly higher after adjusted analysis in a Cox model (p = 0.053). Among patients with a known Svv (n = 70), immunosuppression [OR 9.41 (1.52-58.3); p = 0.016], and a low vasculitis activity score [0.84 (0.77-0.93)] were independently associated with a non-immune cause, after adjustment for the time from disease onset to ARF, time from respiratory symptoms to ICU admission, and severe renal failure. CONCLUSIONS: An extensive diagnosis workup is mandatory in ARF revealing or complicating Svv. Non-immune causes are involved in 43% of cases, and their short and mid-term prognosis may be poorer than those of immune ARF. Readily identified predictive factors of a non-immune cause could help avoiding unnecessary immunosuppressive therapies.

Infectious aetiologies of severe acute chest syndrome in sickle-cell adult patients, combining conventional microbiological tests and respiratory multiplex PCR.

Acute chest syndrome (ACS) is the most serious complication of sickle cell disease. The pathophysiology of ACS may involve lower respiratory tract infection (LRTI), alveolar hypoventilation and atelectasis, bone infarcts-driven fat embolism, and in situ pulmonary artery thrombosis. One of the most challenging issues for the physicians is to diagnose LRTI as the cause of ACS. The use of a respiratory multiplex PCR (mPCR) for the diagnosis of LRTI has not been assessed in sickle-cell adult patients with ACS. To describe the spectrum of infectious aetiologies of severe ACS, using a diagnostic approach combining conventional tests and mPCR. A non-interventional monocenter prospective study involving all the consecutive sickle-cell adult patients with ACS admitted to the intensive care unit (ICU). Microbiological investigation included conventional tests and a nasopharyngeal swab for mPCR. Altogether, 36 patients were enrolled, of whom 30 (83%) had complete microbiological investigations. A bacterial microorganism, mostly Staphylococcus aureus (n = 8), was identified in 11 patients. There was no pneumonia-associated intracellular bacterial pathogen. A respiratory virus was identified in six patients. Using both conventional tests and nasopharyngeal mPCR, a microbiological documentation was obtained in half of adult ACS patients admitted to the ICU. Pyogenic bacteria, especially S. aureus, predominated.

Pain and dyspnea control during awake fiberoptic bronchoscopy in critically ill patients: safety and efficacy of remifentanil target-controlled infusion.

PURPOSE: Flexible fiberoptic bronchoscopy is frequently used in intensive care unit, but is a source of discomfort, dyspnea and anxiety for patients. Our objective was to assess the feasibility and tolerance of a sedation using remifentanil target-controlled infusion, to perform fiberoptic bronchoscopy in awake ICU patients. MATERIALS, PATIENTS AND METHODS: This monocentric, prospective observational study was conducted in awake patients requiring fiberoptic bronchoscopy. In accordance with usual practices in our center, remifentanil target-controlled infusion was used under close monitoring and adapted to the patient's reactions. The primary objective was the rate of successful procedures without additional analgesia or anesthesia. The secondary objectives were clinical tolerance and the comfort of patients (graded from "very uncomfortable" to "very comfortable") and operators (numeric scale from 0 to 10) during the procedure. RESULTS: From May 2014 to December 2015, 72 patients were included. Most of them (69%) were hypoxemic and admitted for acute respiratory failure. No additional medication was needed in 96% of the patients. No severe side-effects occurred. Seventy-eight percent of patients described the procedure as "comfortable or very comfortable". Physicians rated their comfort with a median [IQR] score of 9 [8-10]. CONCLUSION: Remifentanil target-controlled infusion administered to perform awake fiberoptic bronchoscopy in critically ill patients is feasible without requirement of additional analgesics or sedative drugs. Clinical tolerance as well as patients' and operators' comfort were good to excellent. This technique could benefit patients' experience.

In-Hospital Mortality-Associated Factors in Patients With Thrombotic Antiphospholipid Syndrome Requiring ICU Admission.

BACKGROUND: The antiphospholipid syndrome (APS) is a systemic autoimmune disease defined by thrombotic events that can require ICU admission because of organ dysfunction related to macrovascular and/or microvascular thrombosis. Critically ill patients with thrombosis and APS were studied to gain insight into their prognoses and in-hospital mortality-associated factors. METHODS: This French national, multicenter, retrospective study included all patients with APS and any new thrombotic manifestations admitted to 24 ICUs (January 2000-September 2018). RESULTS: During the study period, 134 patients (male/female ratio, 0.4) with 152 APS episodes were admitted to the ICU (mean age at admission, 46.0 ± 15.1 years). In-hospital mortality of their 134 last episodes was 35 of 134 (26.1%). The Cox multivariable model retained certain factors (hazard ratio [95% CI]: age ≥ 40 years, 11.4 [3.1-41.5], P < .0001; mechanical ventilation, 11.0 [3.3-37], P < .0001; renal replacement therapy, 2.9 [1.3-6.3], P = .007; and in-ICU anticoagulation, 0.1 [0.03-0.3], P < .0001) as independently associated with in-hospital mortality. For the subgroup of definite/probable catastrophic APS, the Cox bivariable model (including the Simplified Acute Physiology Score II score) retained double therapy (corticosteroids + anticoagulant, 0.2 [0.07-0.6]; P = .005) but not triple therapy (corticosteroids + anticoagulant + IV immunoglobulins or plasmapheresis: hazard ratio, 0.3 [0.1-1.1]; P = .07) as independently associated with in-hospital mortality. CONCLUSIONS: In-ICU anticoagulation was the only APS-specific treatment independently associated with survival for all patients. Double therapy was independently associated with better survival of patients with definite/probable catastrophic APS. In these patients, further studies are needed to determine the role of triple therapy.