Favorable Anakinra Responses in Severe Covid-19 Patients with Secondary Hemophagocytic Lymphohistiocytosis.

Dysregulation of inflammation is hypothesized to play a crucial role in the severe complications of COVID-19, with the IL-1/IL-6 pathway being central. Here, we report on the treatment of eight severe COVID-19 pneumonia patients-seven hospitalized in intensive care units (ICUs) in Greece and one non-ICU patient in the Netherlands-with the interleukin-1 receptor antagonist Anakinra. All patients scored positive for the hemophagocytosis score (HScore) and were diagnosed with secondary hemophagocytic lymphohistocytosis (sHLH) characterized by pancytopenia, hyper-coagulation, acute kidney injury, and hepatobiliary dysfunction. At the end of treatment, ICU patients had less need for vasopressors, significantly improved respiratory function, and lower HScore. Although three patients died, the mortality was lower than historical series of patients with sHLH in sepsis. These data suggest that administration of Anakinra may be beneficial for treating severe COVID-19 patients with sHLH as determined by the HScore, and they support the need for larger clinical studies to validate this concept.

Acute effects of combined high-frequency oscillation and tracheal gas insufflation in severe acute respiratory distress syndrome.

OBJECTIVE: In acute respiratory distress syndrome (ARDS), high-frequency oscillation (HFO) improves oxygenation relative to conventional mechanical ventilation (CMV). Alveolar ventilation is improved by adding tracheal gas insufflation (TGI) to CMV. We hypothesized that combined HFO and TGI (HFO-TGI) might result in improved gas exchange relative to both standard HFO and CMV according to the ARDS Network protocol. DESIGN: Prospective, randomized, crossover study. SETTING: A 30-bed university intensive care unit. PATIENTS: A total of 14 patients with early (<72 hrs in duration), severe (PaO2/FiO2 of <150 mm Hg and prerecruitment oxygenation index of 22.8 +/- 1.9 [mean +/- SEM]), primary ARDS. INTERVENTIONS: Patients were ventilated with HFO without (60 mins) and combined with TGI (6.1 +/- 0.1 L/min, 60 mins) in random order. HFO sessions were repeated in inverse order within 24 hrs. HFO sessions were preceded and followed by ARDS Network CMV. Four recruitment maneuvers were performed during the study period. During HFO sessions, mean airway pressure was set at 1 cm H2O above the point of maximal curvature of the respiratory system expiratory pressure-volume curve. MEASUREMENTS AND MAIN RESULTS: Gas exchange and hemodynamics were determined before, during, and after HFO sessions. HFO-TGI improved PaO2/FiO2 relative to HFO and CMV (174.5 +/- 10.4 vs. 136.0 +/- 10.0 and 105.0 +/- 3.7 mm Hg, respectively, p < .05 for both) and oxygenation index relative to HFO (17.1 +/- 1.3 vs. 22.3 +/- 1.7, respectively p < .05). PaO2/FiO2 returned to baseline within 3 hrs after HFO. During HFO-TGI, shunt fraction and mixed venous oxygen saturation improved relative to CMV (0.36 +/- 0.01 vs. 0.45 +/- 0.01 and 77.8% +/- 1.2% vs. 71.8% +/- 1.3%, respectively, p < .05 for both). PaCO2 and hemodynamics were unaffected by HFO sessions. Respiratory mechanics remained unchanged throughout the study period. CONCLUSIONS: In early onset, primary, severe ARDS, short-term HFO-TGI improves oxygenation relative to standard HFO and ARDS Network CMV.

Immunoparalysis in patients with severe trauma and the effect of inhaled interferon-gamma.

OBJECTIVE: To evaluate the local immune status in patients with severe trauma and the influence of interferon-gamma on patients with immunoparalysis. PATIENTS: Fifty-two mechanically ventilated patients with severe multiple trauma. SETTING: A 14-bed polyvalent intensive care unit. INTERVENTIONS: The local immune status was evaluated by examining bronchoalveolar lavage fluid. Subsequently, the patients were divided into two groups: immunoparalyzed (group 1) and nonimmunoparalyzed (group 2). Immunoparalysis was defined as a decreased level of human leukocyte antigen-DR expression of alveolar macrophages in <30%. Patients with immunoparalysis were treated with 100 microg of inhaled recombinant human interferon-gamma, three times daily (group 1a, 11 patients) or placebo (group 1b, ten patients). A second bronchoalveolar lavage fluid was obtained 3 days after the initiation of therapy. MEASUREMENTS: The alterations in human leukocyte antigen-DR expression, as well as in pro- and anti-inflammatory markers, such as platelet-aggregating factor, phospholipase A2, interleukin-1beta, platelet-aggregating factor acetylhydrolase, and interleukin-10, were evaluated in the bronchoalveolar lavage fluids. RESULTS: In 21 of 52 (40%) patients, immunoparalysis was established. After interferon-gamma administration, the level of human leukocyte antigen-DR expression increased in group 1a from 17 +/- 5% to 46 +/- 9%. In parallel, platelet-aggregating factor and interleukin-1beta as well as the specific activities of phospholipase A2 and platelet-aggregating factor acetylhydrolase significantly increased. In contrast, interleukin-10 decreased after interferon-gamma therapy. In group 1b, no statistically significant changes appeared in the levels of human leukocyte antigen-DR expression or in the concentrations of inflammatory mediators. The incidence of ventilator-associated pneumonia was significantly lower in group 1a than in group 1b. The administration of interferon-gamma did not affect the outcome of the patients. CONCLUSIONS: A significant proportion of multiply injured patients developed immunoparalysis. The administration of interferon-gamma resulted in the recovery of levels of human leukocyte antigen-DR expression in alveolar macrophages, influenced the inflammatory reaction, and decreased the incidence ventilator-associated pneumonia, without affecting the patients' outcome.