Beneficial ex vivo immunomodulatory and clinical effects of clarithromycin in COVID-19.

INTRODUCTION: Macrolide antibiotics have immunomodulatory properties which may be beneficial in viral infections. However, the precise effects of macrolides on T cell responses to COVID, differences between different macrolides, and synergistic effects with other antibiotics have not been explored. METHODS: We investigated the effect of antibiotics (amoxicillin, azithromycin, clarithromycin, and combined amoxicillin with clarithromycin) on lymphocyte intracellular cytokine levels and monocyte phagocytosis in healthy volunteer PBMCs stimulated ex vivo with SARS-CoV-2 S1+2 spike protein. A retrospective cohort study was performed on intensive care COVID-19 patients. RESULTS: Co-incubation of clarithromycin with spike protein-stimulated healthy volunteer PBMCs ex vivo resulted in an increase in CD8+ (p = 0.004) and CD4+ (p = 0.007) IL-2, with a decrease in CD8+ (p = 0.032) and CD4+ (p = 0.007) IL-10. The addition of amoxicillin to clarithromycin resulted in an increase in CD8+ IL-6 (p = 0.010), decrease in CD8+ (p = 0.014) and CD4+ (p = 0.022) TNF-alpha, and decrease in CD8+ IFN-alpha (p = 0.038). Amoxicillin alone had no effect on CD4+ or CD8+ cytokines. Co-incubation of azithromycin resulted in increased CD8+ (p = 0.007) and CD4+ (p = 0.011) IL-2. There were no effects on monocyte phagocytosis. 102 COVID-19 ICU patients received antibiotics on hospital admission; 62 (61%) received clarithromycin. Clarithromycin use was associated with reduction in mortality on univariate analysis (p = 0.023), but not following adjustment for confounders (HR = 0.540; p = 0.076). CONCLUSIONS: Clarithromycin has immunomodulatory properties over and above azithromycin. Amoxicillin in addition to clarithromycin is associated with synergistic ex vivo immunomodulatory properties. The potential benefit of clarithromycin in critically ill patients with COVID-19 and other viral pneumonitis merits further exploration.

Comparison of renal replacement therapy and renal recovery before and during the COVID-19 pandemic: a single center observational study.

BACKGROUND: Our objective was to the describe indications, management, complications and outcomes of renal replacement therapy (RRT) in COVID-19 critically ill patients. To contextualize these findings, comparisons were made against 36 non-COVID-19 consecutive patients requiring RRT on ICU. METHODS: We conducted a retrospective single center observational cohort study of patients requiring acute RRT between 1st March and 30th June 2020. Comparison was made against those receiving RRT in the pre-COVID-19 period from January 2019 to February 2020. RESULTS: Of 154 COVID-19 patients, 47 (30.5%) received continuous venovenous hemofiltration (CVVHF), all of whom required mechanical ventilation and vasopressor support. The requirement for RRT was related to fluid balance rather than azotemia. Compared to 36 non-COVID-19 patients, those with COVID-19 were younger (P=0.016) with a lower serum creatinine on hospital admission (P=0.049), and lesser degrees of metabolic acidosis (P<0.001) and lactatemia (P<0.001) before initiation of RRT. In addition, the duration of RRT requirement was longer (P<0.001). Despite lower CVVHF exchange rates with higher serum creatinine levels following RRT initiation in the COVID-19 patients, metabolic abnormalities were corrected. Hospital mortality was 60% among COVID-19 patients requiring RRT, compared to 67% in non-COVID-19 patients (P=0.508), and renal recovery among survivors without pre-existing CKD was similar (P=0.231). CONCLUSIONS: The requirement for RRT in COVID-19 patients was primarily related to fluid balance. Using lower CVVHF exchange rates was effective to correct metabolic abnormalities. Renal recovery occurred in all but one patient by 60 days in the 40% of patients who survived.

Corticosteroids in adult respiratory distress syndrome - an inconvenient truth?

OBJECTIVES: Recent studies have demonstrated mortality benefits from corticosteroid use in COVID-19 patients requiring respiratory support. However, clinical practice may warrant the use of corticosteroids outside the context of a clinical trial. Such data are rarely, if ever, reported. We explored the use of corticosteroids for adult respiratory distress syndrome (ARDS) indications in patients with non-COVID ARDS. METHODS: We retrospectively studied patients with moderate-to-severe ARDS, admitted to our intensive care unit (ICU) between January 2018 and March 2020. KEY FINDINGS: Of the 91 patients with ARDS identified, 80% were treated with a corticosteroid during their ICU admission. Of these, 73 (82%) had corticosteroids administered for reasons other than ARDS. CONCLUSIONS: Corticosteroid use for non-ARDS indications is commonplace in ARDS patients in our ICU. The use of corticosteroids outside a randomisation process in randomised clinical trials may be more common than appreciated and needs to be routinely reported.

Convalescent plasma for COVID-19: a meta-analysis, trial sequential analysis, and meta-regression.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific antibodies, particularly those preventing interaction between the viral spike receptor-binding domain and the host angiotensin-converting enzyme 2 receptor, may prevent viral entry into host cells and disease progression. METHODS: We performed a systematic review, meta-analysis, trial sequential analysis (TSA), and meta-regression of RCTs to evaluate the benefit of convalescent plasma for COVID-19. The primary outcome was 28-30 day mortality. Secondary outcomes included need for mechanical ventilation and ICU admission. Data sources were PubMed, Embase, MedRxiv, and the Cochrane library on July 2, 2021. RESULTS: We identified 17 RCTs that recruited 15 587 patients with 8027 (51.5%) allocated to receive convalescent plasma. Convalescent plasma use was not associated with a mortality benefit (24.7% vs 25.5%; odds ratio [OR]=0.94 [0.85-1.04]; P=0.23; I2=4%; TSA adjusted confidence interval [CI], 0.84-1.05), or reduction in need for mechanical ventilation (15.7% vs 15.4%; OR=1.01 [0.92-1.11]; P=0.82; I2=0%; TSA adjusted CI, 0.91-1.13), or ICU admission (22.4% vs 16.7%; OR=0.80 [0.21-3.09]; P=0.75; I2=63%; TSA adjusted CI, 0.0-196.05). Meta-regression did not reveal association with titre of convalescent plasma, timing of administration, or risk of death and treatment effect (P>0.05). Risk of bias was high in most studies. CONCLUSIONS: In patients with COVID-19, there was no clear mortality benefit associated with convalescent plasma treatment. In patients with mild disease, convalescent plasma did not prevent either the need for mechanical ventilation or ICU admission. CLINICAL TRIAL REGISTRATION: CRD42021234201 (PROSPERO).

Defining Potential Therapeutic Targets in Coronavirus Disease 2019: A Cross-Sectional Analysis of a Single-Center Cohort.

OBJECTIVES: Multiple mechanisms have been proposed to explain disease severity in coronavirus disease 2019. Therapeutic approaches need to be underpinned by sound biological rationale. We evaluated whether serum levels of a range of proposed coronavirus disease 2019 therapeutic targets discriminated between patients with mild or severe disease. DESIGN: A search of ClinicalTrials.gov identified coronavirus disease 2019 immunological drug targets. We subsequently conducted a retrospective observational cohort study investigating the association of serum biomarkers within the first 5 days of hospital admission relating to putative therapeutic biomarkers with illness severity and outcome. SETTING: University College London, a tertiary academic medical center in the United Kingdom. PATIENTS: Patients admitted to hospital with a diagnosis of coronavirus disease 2019. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Eighty-six patients were recruited, 44 (51%) with mild disease and 42 (49%) with severe disease. We measured levels of 10 cytokines/signaling proteins related to the most common therapeutic targets (granulocyte-macrophage colony-stimulating factor, interferon-α2a, interferon-ß, interferon-γ, interleukin-1ß, interleukin-1 receptor antagonist, interleukin-6, interleukin-7, interleukin-8, tumor necrosis factor-α), immunoglobulin G antibodies directed against either coronavirus disease 2019 spike protein or nucleocapsid protein, and neutralization titers of antibodies. Four-hundred seventy-seven randomized trials, including 168 different therapies against 83 different pathways, were identified. Six of the 10 markers (interleukin-6, interleukin-7, interleukin-8, interferon-α2a, interferon-ß, interleukin-1 receptor antagonist) discriminated between patients with mild and severe disease, although most were similar or only modestly raised above that seen in healthy volunteers. A similar proportion of patients with mild or severe disease had detectable spike protein or nucleocapsid protein immunoglobulin G antibodies with equivalent levels between groups. Neutralization titers were higher among patients with severe disease. CONCLUSIONS: Some therapeutic and prognostic biomarkers may be useful in identifying coronavirus disease 2019 patients who may benefit from specific immunomodulatory therapies, particularly interleukin-6. However, biomarker absolute values often did not discriminate between patients with mild and severe disease or death, implying that these immunomodulatory treatments may be of limited benefit.

Tocilizumab in COVID-19: a meta-analysis, trial sequential analysis, and meta-regression of randomized-controlled trials.

PURPOSE: Interleukin-6 (IL-6) levels discriminate between patients with mild and severe COVID-19, making IL-6 inhibition an attractive therapeutic strategy. We conducted a systematic review, meta-analysis, trial sequential analysis (TSA), and meta-regression of randomized-controlled trials to ascertain the benefit of IL-6 blockade with tocilizumab for COVID-19. METHODS: We included randomized-controlled trials (RCTs) allocating patients with COVID-19 to tocilizumab. Our control group included standard care or placebo. Trials co-administering other pharmacological interventions for COVID-19 were not excluded. Primary outcome was 28-30 day mortality. Secondary outcomes included progression-to-severe disease defined as need for mechanical ventilation, intensive-care unit (ICU) admission, or a composite. RESULTS: We identified 10 RCTs using tocilizumab, 9 of which reported primary outcome data (mortality), recruiting 6493 patients with 3358 (52.2%) allocated to tocilizumab. Tocilizumab may be associated with an improvement in mortality (24.4% vs. 29.0%; OR 0.87 [0.74-1.01]; p = 0.07; I2 = 10%; TSA adjusted CI 0.66-1.14). Meta-regression suggested a relationship between treatment effect and mortality risk, with benefit at higher levels of risk (logOR vs %risk beta = -0.018 [-0.037 to -0.002]; p = 0.07). Tocilizumab did reduce the need for mechanical ventilation and was associated with a benefit in the composite secondary outcome but did not reduce ICU admission. CONCLUSIONS: For hospitalized COVID-19 patients, there is some evidence that tocilizumab use may be associated with a short-term mortality benefit, but further high-quality data are required. Its benefits may also lie in reducing the need for mechanical ventilation.

Plasma exchange for COVID-19 thrombo-inflammatory disease.

Severe COVID-19 disease is a hyperinflammatory, pro-thrombotic state. We undertook plasma exchange (PEX) to determine its effects on organ function and thrombo-inflammatory markers. Seven critically ill adults with severe COVID-19 respiratory failure (PaO2:FiO2 ratio < 200 mm Hg) requiring invasive or noninvasive ventilatory support and elevated thrombo-inflammatory markers (LDH >800 IU/L and D-dimer >1000 µg/L (or doubling from baseline) received PEX, daily, for a minimum of 5 days. No other immunomodulatory medications were initiated during this period. Seven patients matched for age and baseline biochemistry were a comparator group. Coagulation screening revealed no evidence of coagulopathy. However, von Willebrand Factor (VWF) activity, antigen and VWF antigen: ADAMTS13 ratio, Factor VIII and D-dimers were all elevated. Following 5 days of PEX, plasma levels of all the above, and ferritin levels, were significantly reduced (P < .05) while lymphocyte counts normalized (P < .05). The PaO2:FiO2 ratio increased from a median interquartile range (IQR) of 11.6 (10.8-19.7) kPa to 18.1 (16.0-25.9) kPa (P < .05). Similar improvements were not observed in controls. Acute kidney injury (AKI) occurred among five patients in the control arm but not in patients receiving PEX. PEX improved oxygenation, decreased the incidence of AKI, normalized lymphocyte counts and reduced circulating thrombo-inflammatory markers including D-Dimer and VWF Ag:ADAMTS13 ratio.

COVID-19 and non-COVID ARDS patients demonstrate a distinct response to low dose steroids- A retrospective observational study.

Patients with COVID-19 ARDS have distinct physiological and immunological phenotypes compared to patients with non-COVID ARDS. Patients with COVID-19 ARDS (n = 32) had a significant improvement in PaO2: FiO2 ratio (p = 0.046) following low-dose steroid treatment, unlike patients with non-COVID ARDS (n = 16) (p = 0.529). Patients with COVID-19 ARDS had a greater fall in CRP compared to patients with non-COVID ARDS, albeit not statistically significant (p = 0.07). Our novel findings highlight differences in the underlying physiological and immunological phenotypes between COVID-19 and non-COVID ARDS, with implications for future ARDS studies.