key: cord-0931730-e0ms9573
authors: Sagnelli, Caterina; Celia, Benito; Monari, Caterina; Cirillo, Salvatore; De Angelis, Giulia; Bianco, Andrea; Coppola, Nicola
title: Management of SARS‐CoV‐2 Pneumonia
date: 2020-08-28
journal: J Med Virol
DOI: 10.1002/jmv.26470
sha: a49fa0a753a41d0048b9463ad2539ab8d08f9074
doc_id: 931730
cord_uid: e0ms9573

Severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) infection has rapidly spread throughout the world since December 2019 to become a global public health emergency for the elevated deaths and hospitalizations in Intensive Care Units. The severity spectrum of SARS‐CoV‐2 pneumonia ranges from mild to severe clinical conditions. The clinical course of SARS‐CoV‐2 disease is correlated with multiple factors including host characteristics (genetics, immune status, age and general health), viral load and, above all, the host distribution of the airways and lungs of the viral receptor cells. In this review, we will briefly summarize the current knowledge on the characteristics and management of COVID‐19‐pneumonia. However, other studies are needed to better understand the pathogenetic mechanisms induced by SARS‐Cov‐2 infection, and to evaluate the long‐term consequences of the virus on the lungs. This article is protected by copyright. All rights reserved.

Severely ill patients may exhibit lymphopenia and interstitial pneumonia with high levels of inflammatory cytokines (cytokine storm) characterized by elevated concentrations of IL-2, IL-6, IL-7, IL-10, TNFα, G-CSF, IP-10, MCP-1 and MIP-1α. The massive cytokine release probably plays a significant part in the induction of respiratory failure and ARDS. Some data support the evidence for hyperactivation of macrophages and monocytes and a resulting increase in neutrophils, IL-6, C reactive protein and a decrease in lymphocytes. Concerning the adaptive immune system, activation of the Th1/Th17 response might contribute to inflammation, while the production of specific antibodies by B-lymphocytes may be directed to neutralize the virus [29] .

In the pathogenesis of pneumonia, it is interesting to evaluate the dynamics of the antibody response, anti-SARS-CoV-2. Evidence from SARS-CoV and MERS-CoV infections indicate that in SARS-CoV infection IgM could be detected in serum 3-6 days after disease onset and IgG after 8 days while seroconversion in MERS-CoV infection occurs at the second or third week; for both types of coronavirus infection severe outcomes were observed in patients with a delayed and weaker antibody response [29] . On the contrary, an observational cohort study on 23 SARS-CoV-2 patients reported that serum antibody levels are not correlated with clinical severity, observing that deceased patients developed faster peak antibody anti-spike responses compared with recovered patients. Antispike IgG could cause immunopathological lung injury by binding Fcγ receptor on wound-healing macrophages [30] .

Finally, there is growing interest on the pathogenetic involvement of lung vascular coagulopathy in the respiratory failure of COVID-19 patients [31] [32] [33] . However, higher quality studies are needed to better understand and confirm the pathogenetic mechanisms induced by the SARS-Cov-2 infection.

Accepted Article currently unknown. In critical cases, the lesions may progress to "white lung" and acute ARDS [44] . CT semi-quantitative and quantitative scoring methods to estimate the proportion of GGO and consolidation have also been proposed. The quantitative method appears to correlate well with the conventional semi-quantitative method and laboratory indexes, and therefore may help the clinician to predict the severity of the SARS-CoV-2 pneumonia [45] .

LUS may have an important role in daily management of SARS-COV-2 patients with pneumonia because it allows a non-invasive assessment without radiation exposure. It is a dynamic observation of the lung and pleural line, a simpler and safer management than CXR and especially HRCT. A disadvantage of LUS is the lack of a "panoramic view" of the chest and the impossibility of peri-hilar lesion visualization [46, 47] .

Typical imaging features include B line patterns (focal, multifocal, and confluent) due to interlobular septa thickening, hazy opacities or sub-pleural consolidations and thickened pleural line. The lesion distribution is typically bilateral and multifocal [45] . The diagnostic efficacy of bedside LUS seems higher in severe disease cases than the mild ones [46] but could be useful to detect early lung involvement during the paucisymptomatic phase in confirmed cases.

Semi-quantitative ultrasound methods to score lung involvement have been proposed in the past, for example, to monitor ventilated patients in ICU settings [47] . Soldati et al. [48] proposed a similar scoring method for SARS-CoV-2 scanning fourteen areas of the patient's chest (three posterior, two lateral, and two anterior) with a standard sequence of evaluations; a score from zero to three is assigned to each evaluated area [48] . [57, 58] , in vitro studies have demonstrated that both these agents decreased viral replication of SARS-CoV-2 in a concentration-dependent manner [59] . Several retrospective observational studies aimed at describing the efficacy of CQ or HCQ against SARS-COV-2 have been conducted with controversial results. A recent retrospective observational study compared 811 hospitalized patients who received hydroxychloroquine (600 mg twice on day 1, then 400 mg daily for a median of 5 days) with 565 patients who did not.

Patients receiving HCQ were more severely ill at baseline than those in the control group [60] . No significant association between HCQ and a lower risk of intubation or death was observed, even after a propensity score adjusted analysis (HR 1.04; 95% CI 0.82-1.32). Moreover, a multinational registry analysis (i.e. 671 hospitals in 6 continents) has recently been published with surprising results regarding the use of HCQ or CQ, with or without a macrolide, in hospitalized patients with COVID-19 [61] . The registry included 96,032 patients with a positive laboratory finding for SARS-CoV-2. Of these, 14,888 subjects were included in the treatment group (1,868 patients treated with CQ, 3,783 with CQ plus a macrolide, 3,016 with HCQ and 6,221 with HCQ with a macrolide) and started the therapy within 48 hours from the diagnosis, whereas 81,144 patients were included in the control group. The authors reported that chloroquine and hydroxychloroquine, alone or in combination with a macrolide, were independently associated with both a higher in-hospital mortality rate compared to the control group and an increased risk of ex-novo ventricular arrhythmia compared to the control group (0.3%) [61] . However, since these results have raised several concerns, the paper has been retracted from the authors.

Nevertheless, HCQ arm has been recently ceased in two large randomized control trials, Solidarity trial by WHO [62] and Recovery trial by the Oxford University in UK [63] , because of the lack of its efficacy in a cohort of hospitalized patients with COVID-19.

As well, the DisCoVeRy trial, a multicentre, adaptive, randomized open clinical trial, aiming to evaluate clinical efficacy and safety of 4 treatment arms (remdesivir, LPV/r, Interferon-beta 1A,

HCQ) in addition to the usual standard of care, has temporarily stopped the HCQ arm since the 24th of May 2020 [64, 65] .

Lopinavir/ritonavir (LPV/r) is an oral combination agent approved for the treatment of HIV infection; LPV is a protease inhibitor and ritonavir a booster of LPV by inhibiting cytochrome P450. Studies in vitro have demonstrated an antiviral activity of LPV against SARS-CoV and MERS-CoV through the inhibition of 3-chymotrypsin-like protease [66] [67] [68] [69] . Choy et al. [70] reported an antiviral effect of LPV but not ritonavir against SARS-CoV-2 in vitro [70] . There are few clinical studies regarding LPV/r activity against human coronaviruses, mostly conducted on SARS-CoV-1 infection, with promising results [67, 71] . One study demonstrated that the combination LPV/r and ribavirin had a synergistic effect for the treatment of SARS, in the early phase of infection [71] .

Reports regarding LPV/r activity against SARS-CoV-2 mostly derive from case-reports or small non-randomized, retrospective studies, with controversial results. Therefore, they do not allow the direct efficacy of LPV/r to be asserted against SARS-CoV-2 [72] . Recently, Wang et al. [73] evaluated the efficacy of LPV/r compared to the standard of care in 199 patients hospitalized with severe SARS-CoV-2, without significant differences in time to clinical improvement or in 28-day mortality rate or in viral clearance. However, LPV/r was administered late during SARS-CoV-2 infection, at a median of 13 days from the onset of symptoms [73] . Nevertheless, in a subgroup analysis among patients who started LPV/r within 12 days from symptom onset, colleagues found no significant difference in clinical improvement [73] . Thus, the timing of administration of antiviral agents seems crucial: the initiation of LPV/r beyond the peak viral replication phase (initial 7-10 days) had no effect on the clinical outcomes [71, 72] . Other HCQ in addition to the usual standard of care [64] .

Nevertheless, the Recovery trial by Oxford University in UK has recently described no clinical benefit from use of LPV/r in hospitalized patients with COVID-19 [64] . As a matter of fact, colleagues found no significant difference in the 28-day mortality between 1,596 patients treated with LPV/r and 3,376 patients randomized to usual of care alone (22.1% LPV/r vs 21.3% usual of care) nor in the risk of progression to mechanical ventilation or length of hospital stay [64] . However, these results may not be applied to severe patients with COVID-19 requiring invasive ventilation, because they could not study a large number of patients on mechanical ventilation. shown that remdesivir has potent antiviral activity against SARS-CoV-2 [76] [77] [78] . In a multicenter, multinational series, 53 patients with severe SARS-CoV-2 received the antiviral drug on a compassionate-use basis for up to 10 days: 68% of them (36/53) had a clinical improvement and of the 30 patients who were mechanically ventilated at baseline 17 (57%) were extubated [79] . A randomized, double blind, placebo-controlled multicenter trial randomized 236 patients with moderate SARS-CoV-2 in a 2:1 ratio either to remdesivir (200 mg 1 st day and then 100 mg for 9 days) or placebo and showed no significant difference between the two groups in the time of

Clinical studies have shown increased levels of cytokines in patients with COVID-19 pneumonia, particularly of IL-6 (but also of IL-1, IL2, IFN-gamma, TNF-alpha, and IL-10) and that high levels of IL-6 correlated with the severity of the disease [105] .

Tocilizumab (TCZ) is a recombinant human monoclonal IL-6 antibody, which binds to soluble and membrane-bound IL-6 receptors blocking IL-6 signaling and mediated inflammatory response. TCZ is approved for treatment of rheumatic diseases, rheumatoid arthritis and for severe life-threatening cytokine release syndrome caused by T-cell immunotherapy of the chimeric antigen receptor (CART). Xiaoling X et al. [106] administered alone TCZ (400 mg once iv) in 20 Chinese patients with SARS-CoV-2 pneumonia, and temperature returned to normal, oxygenation improved (75%) and opacity of lung injury in CT scans resolved (90.5%). Several studies evaluating the safety and efficacy of TCZ in the treatment of severe SARS-CoV-2 pneumonia are ongoing [107] [108] [109] [110] [111] [112] [113] [114] [115] [116] .

Treatment consists of a single dose of 8 mg/kg (up to a maximum of 800 mg/dose) and a second dose equal to the previous one can be administered after 12 hours in case of failure and a third dose after 24-36 hours.

Among the possible side effects of TZV in the treatment of SARS-CoV-2 are osteonecrosis of the mandible [106] , upper airway infections, hypercholesterolemia, leukopenia, neutropenia, abdominal pain, oral ulcers, gastritis, peripheral edema, hypersensitivity, interstitial pneumonia, coughing, wheezing, conjunctivitis, increased liver transaminase, headache, dizziness, hypertension, rash, itching and hives.

Eculizumab is a humanized IgG monoclonal antibody, produced with recombinant DNA technology, which inhibits terminal complement. After binding to the complement C5 protein, it

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