Respiratory failure: a patient's perspective and clinical cases

The major morbidity and mortality from COVID-19 is due to acute viral pneumonitis that evolves to ARDS. Furthermore, COVID-19 patients may be affected by extrarespiratory involvement, including cardiac, renal, neurological and vascular complications. Different hospitals reorganised their logistical structures to optimise the care of COVID-19 patients and ensure infection control, and the public health scenario worldwide was characterised by the rapid spread of multidisciplinary units specifically dedicated to COVID-19 patients. This chapter describes the personal experience and clinical case of a previously healthy and active patient who suffered from severe COVID-19. Two other cases of patients hospitalised because of severe acute respiratory failure due to COVID-19 are also discussed.Copyright © ERS 2021.

Humoral and cell-mediated immune responses to BNT162b2 vaccine against SARS-CoV-2 in people with cystic fibrosis.

People with cystic fibrosis (pwCF) were considered to be clinically vulnerable to COVID-19 and were therefore given priority in the vaccination campaign. Vaccines induced a humoral response in these patients that was comparable to the response observed among the general population. However, the role of the cell-mediated immune response in providing long-term protection against SARS-CoV-2 in pwCF has not yet been defined. In this study, humoral (antibody titre) and cell-mediated immune responses (interferon-γ release) to the BNT162b2 vaccine were measured at different time points, from around 6-8 months after the 2nd dose and up to 8 months after the 3rd dose, in 118 CF patients and 26 non-CF subjects. Subjects were sampled between November 2021 and September 2022 and followed-up for breakthrough infection through October 2022. pwCF mounted a cell-mediated response that was similar to that observed in non-CF subjects. Low antibody titres (<1st quartile) were associated with a higher risk of breakthrough infection (HR: 2.39, 95 % CI: 1.17-4.88), while there was no significant association with low INF-γ levels (<0.3 IU/mL) (HR: 1.38, 95 % CI: 0.64-2.99). Further studies are needed in subgroup of pwCF receiving immunosuppressive therapy, such as organ transplant recipients. This data is important for tailoring vaccination strategies for this clinically vulnerable population.

Post-COVID-19 sequelae

This chapter explores the currently available knowledge (as at October 2021) about the long-term clinical consequences of COVID-19. Distinction between cardiorespiratory and extra-cardiorespiratory sequelae can facilitate understanding of the post-COVID sequelae problem and may aid the clinical management of patients. The strength of the recommendations is highlighted at the end of each paragraph.Copyright © ERS 2021.

Safety and Immunogenicity of the AntiCOVID19 Vaccines in a Cohort of Lung Transplant Recipients

Lung transplant recipients (LuTxR) are at greater risk of COVID-19 and have attenuated response to vaccinations. In Italy, immunocompromised patients received the indication to be administered mRNA vaccines only. We aimed to evaluate the safety and immunogenicity of these vaccines in our cohort of LuTxR;we are now presenting the preliminary data of their serologic responses. We conducted a single-center observational prospective study including all consecutive LuTxR who were administered two doses of mRNA antiCOVID19 vaccine at our institution in March 2021;NCT05116748. We investigated the incidence of systemic and local adverse events and, in order evaluate immunogenicity, we used ImmunoAssay in ECLIA for the quantitative detection of anti-protein S1 (spike) antibodies (including IgG) on venous blood samples at 60 and 80 (+/- 10) days from the vaccine administration. 116 patients were enrolled, 52 females. Table 1 summarizes the basic characteristics of our population. Figure 1 focalizes on different serologic responses based on immunosuppressive regimens. No serious adverse events were reported. The most common solicited adverse events were fever (52% of our patients), headache, fatigue, myalgia, chills, and injection-site pain. Our initial findings are reassuring. Humoral SARS-CoV-2 specific immunity in our cohort of patients tended to be stronger than expected. mRNA vaccines appeared to be safe in the transplant population, and have not raised serious concern about the possible onset of graft dysfunction or other serious adverse events in the first period after their administration. [ABSTRACT FROM AUTHOR] Copyright of Journal of Heart & Lung Transplantation is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Insights into the lung microenvironment after severe COVID-19

The SARS-CoV-2 is the betacoronavirus responsible for the coronavirus disease 2019 (COVID-19) pandemic. Severe COVID-19 affects approximately 10-15% of patients and results in prolonged morbidity and mortality. Little is known about the immunophenotypic changes of the lung parenchyma driven by the viral infection in patients who die of severe COVID-19. Ultrasound-guided lung biopsies (LB) were collected (IRB approval#1561/21) within few hours from death in 15 severe COVID-19 patients between November 2020 and January 2021, in two patients who underwent lung transplantation after COVID-19 and in one patient who had surgery for bacterial superinfection during COVID-19 disease. All samples underwent histologic and immunohistochemistry evaluation and molecular profiling using the nCounter Host Response and Coronavirus Panel plus. As controls, lungs from end-stage usual interstitial pneumonia (UIP;n=9) and from lobectomy for lung cancer (Norm;n=5) were used. Eleven lungs (61%) were positive for SARS-CoV-2 RNA. Signs of diffuse alveolar damage (DAD) were observed in 6 patients (30%). COVID-19 lungs showed a marked macrophage infiltration with M2 polarization compared with controls. Globally, COVID-19 lungs showed distinct molecular profiles from UIP or Norm lungs. Specifically, a marked upregulation of interferon-genes that was directly correlated with SARS-CoV-2 genes was seen in COVID-19 lungs. COVID-19-specific genes signatures (Log2FC >1.5;adj p<0.05) obtained using VENN diagram showed impairment of the STAT3-pathway accompanied by the upregulation of the NFkB signaling. Results herein provide new insights into lung alterations induced by severe COVID-19 and suggest novel potential targets for therapeutic intervention.

CPAP-associated changes in oxygenation and clinical outcomes in severe COVID-19 pneumonia

Background: Continuous positive airway pressure (CPAP) can improve oxygenation in severe COVID-19 pneumonia. Objective(s): To assess whether CPAP-associated improvements in oxygenation can inform clinical outcomes in patients with severe COVID-19 pneumonia. Method(s): Retrospective study in patients with severe COVID-19 pneumonia treated with CPAP in three academic respiratory units in Milan, Italy. Arterial gas analysis obtained before and 1 hour after starting CPAP. CPAP failure defined as either death in the respiratory units while on CPAP or need for intubation. Result(s): 211 patients (mean age 64 years, 74% males) were included. Baseline median PaO2was 68 (57-83) mmHg, PaO2/FiO2(P/F) ratio was 129 (91-179) mmHg and alveolar-arterial (A-a) O2 gradient was 310 (177-559) mmHg. On CPAP, PaO2and P/F increased to 100 (79-141) (p<0.001) and 195 (132-257;p<0.001) mmHg and A-a gradient decreased to 240 (188-308;p<0.001) mmHg. 42 (19.9%) patients died in the respiratory units while on CPAP and 51 (24.2%) required intubation. There was a substantial overlap of baseline and CPAP-associated values of PaO2, P/F ratio and A-a gradient in CPAP failures and successes (Figure). CPAP-associated changes in PaO2, P/F ratio and A-a gradient in both groups were similar. Conclusion(s): CPAP-associated improvements in oxygenation cannot be used to inform clinical outcomes of the individual patient with severe COVID-19 pneumonia.

Involvement of the contact pathway in COVID-19 coagulopathy

Background: A novel acquired coagulopathy characterized by a severe procoagulant imbalance is common in COVID-19 patients and is associated with the clinical severity of the disease. Aim(s): Our study aims to elucidate the underlying mechanisms of coagulation activation in COVID-19 patients. Method(s): Symptomatic COVID-19 patients during Milan first wave were consecutively enrolled and stratified into 3 groups based on the intensity of care: Low, requiring only high-flow oxygen by nasal cannula;intermediate, requiring continuous positive airway pressure;high, requiring mechanical ventilation. Blood samples were tested for markers of activation of the intrinsic pathway (FXIa, FXIIa) together with its physiologic inhibitor (C1-inhibitor), of the extrinsic pathway (FVIIa), of global activation of the coagulation cascade (D-dimer, FDP, FM) and of fibrinolysis (plasminogen, t-PA, alpha2-antiplasmin, PAI-1). Result(s): 111 patients were included: 26 at low, 42 intermediate and 43 high care-intensity. Median age was 59 +/- 12 (34 patients >65 years);32 patients (29%) developed a venous thrombosis and 12 (11%) died (Table). Median D-dimer, FDP and FM plasma levels were higher in COVID-19 patients compared to controls, with a gradient of increase across the three care intensities, while all the fibrinolytic pathway parameters were in the normal range. Median plasma levels of FVIIa were lower in COVID-19 patients (27.5 mU/ml) than in controls (40.1 mU/ml) while median plasma levels of FXIIa and FXIa were higher in COVID-19 patients (11.2 and 11.3 mU/ml) than in controls (7.2 and 5.5 mU/ml), with a gradient of increase across the three care intensities. C1-inhibitor plasma levels were above the normal range in all the 3 COVID-19 patients' groups (Figure). Conclusion(s): Our study showed a prevalent activation of the contact pathway over the extrinsic pathway of the coagulation cascade in COVID-19 patients, which is proportional to the clinical severity of the infection, opening the possibility for targeted anticoagulant therapies. (Table Presented).

Reduced circulating FABP2 in patients with moderate to severe COVID-19 may indicate enterocyte functional change rather than cell death.

The gut is of importance in the pathology of COVID-19 both as a route of infection, and gut dysfunction influencing the severity of disease. Systemic changes caused by SARS-CoV-2 gut infection include alterations in circulating levels of metabolites, nutrients and microbial products which alter immune and inflammatory responses. Circulating plasma markers for gut inflammation and damage such as zonulin, lipopolysaccharide and ß-glycan increase in plasma along with severity of disease. However, Intestinal Fatty Acid Binding Protein / Fatty Acid Binding Protein 2 (I-FABP/FABP2), a widely used biomarker for gut cell death, has paradoxically been shown to be reduced in moderate to severe COVID-19. We also found this pattern in a pilot cohort of mild (n = 18) and moderately severe (n = 19) COVID-19 patients in Milan from March to June 2020. These patients were part of the first phase of COVID-19 in Europe and were therefore all unvaccinated. After exclusion of outliers, patients with more severe vs milder disease showed reduced FABP2 levels (median [IQR]) (124 [368] vs. 274 [558] pg/mL, P < 0.01). A reduction in NMR measured plasma relative lipid-CH3 levels approached significance (median [IQR]) (0.081 [0.011] vs. 0.073 [0.024], P = 0.06). Changes in circulating lipid levels are another feature commonly observed in severe COVID-19 and a weak positive correlation was observed in the more severe group between reduced FABP2 and reduced relative lipid-CH3 and lipid-CH2 levels. FABP2 is a key regulator of enterocyte lipid import, a process which is inhibited by gut SARS-CoV-2 infection. We propose that the reduced circulating FABP2 in moderate to severe COVID-19 is a marker of infected enterocyte functional change rather than gut damage, which could also contribute to the development of hypolipidemia in patients with more severe disease.

Telemonitoring: An Opportunity to Improve Multidisciplinary Care in Lung Transplanted Patients

Purpose: Telemedicine has been successfully employed in a wide range of specialties. We hereby present the results of a pivotal study we ran in our centre just before the COVID19 pandemic. Methods: This was a prospective study including all adult cystic fibrosis patients who underwent lung transplant (LuTx) from September 2017 to August 2019. Patients were randomized into two groups;patients assigned to the first arm (intervention) received a home medical assistant (HMA) system device, to which a pulse oximeter and a spirometer with reusable turbine were integrated;they were asked to perform a spirometry and register their SpO2 at rest and on effort on a twice-weekly basis. All the data were digitally transmitted to our centre, where physiotherapists and physicians were able to analyse them real-time. Both the groups received traditional hospital-based follow-up. Results: 32 patients were enrolled, 16 in each group. No statistically significant difference was found between the two groups (see Table 1).With reference to the telemonitoring group:- Adherence to telemonitoring significantly decreased during the 12months period of follow up (see figure 1).- Hospital reported data were consistent with the last being registered with the HMA device.- Of note, two patients were requested to anticipate their hospital routine visit because of a FEV1 decrease being reported on their HMA device, in order to rule out possible acute lung allograft dysfunction.- 13 out of 16 patients reported a high degree of satisfaction with the telemonitoring experience. Conclusion: The COVID19 pandemic highlighted the necessity to investigate alternative practices to treat chronically ill individuals. In our study, telemonitoring proved to be a valuable tool to improve quality health care to LuTx recipients, especially for those who live far from the transplant centre. We are now implementing this approach scheduling online video consultations. Further research should be focused on standardizing quality of telemedicine services.

COVID19 in Lung Transplanted Patients: Chronicles from an Italian Epicenter

Purpose Lombardy was one of the hardest hit regions in Italy during the COVID19 pandemic. We hereby report our experience with SARS-CoV2 infection in lung transplant recipients. Methods We retrospectively collected clinical data on all the consecutive cases of COVID19 in our centre, based in Milan, from March 2020 to August 2021. Diagnosis was always confirmed by a positive nucleic acid amplification test (RT-PCR) for SARS-CoV-2 on nasopharyngeal swab and/or tracheal aspirate. Results 21 patients were diagnosed with COVID19. Figure 1 summarizes the clinical course of these individuals. We reduced immunosuppressive regimen in all these patients, typically holding the antiproliferative agent and augmenting steroids;when hospitalized, everybody received initial empiric antibiotic treatment with piperacillin/tazobactam and high-dose LMWH. Hydroxychloroquine was used only in the "first wave" (4 patients). One patient was compassionately administered anakinra and remdesivir as a “rescue therapy”. Lymphocitopenia was a common presenting sign (14 patients, 66%). Aspergillus co-infection occurred in 5 patients (24%). Mortality rate was 29%;4 out of these 6 patients were affected by CLAD and 3 had chronic kidney disease. Of note, in March 2021, we tested all our patients for anti-SARS-CoV-2 nucleocapsid antibodies before starting vaccinations: we found three additional seropositive patients, who were not included in the present analysis, but had been presumably affected by an asymptomatic/mild form of the disease. Conclusion Apart from immunosuppression, the majority of our patients presented at least one risk factor for mortality in COVID-19 (diabetes, chronic kidney disease, arterial hypertension) and, for this reason, we felt that they should be hospitalized to enable close monitoring and prompt management of possible complications and deterioration. Clinical course seemed favorable in only two thirds of our patients but, for the time being, none of these individuals showed sign of new-onset CLAD after COVID19.

Helmet CPAP treatment in patients with COVID-19 pneumonia: a multicentre cohort study

To evaluate outcomes of COVID-19 patients with pneumonia-related hypoxaemic acute respiratory failure (hARF) undergoing continuous positive airway pressure therapy (CPAP) treatment, hence, a multicentre, observational, prospective study was conducted between 7 March 2020 and 21 April 2020 in three high-dependency units (HDU) at two hospitals in Milan, Italy. The primary outcome was CPAP failure defined as the occurrence of either intubation or death due to any cause during hospital high-dependency units (HDU) stay while secondary outcomes included the weaning from CPAP to oxygen therapy (CPAP success), all-cause in-hospital and 30-day mortality. A total of 157 patients with hARF (median (IQR) PaO2/FIO2 ratio 142.9 (96.7-203.2)) underwent helmet CPAP with an initial median (IQR) FIO2 of 0.6 (0.5-0.6) and mean positive end-expiratory pressure (PEEP) of 10.8+or-2.3 cmH₂O. The most prevalent comorbidities were arterial hypertension (44.0%), diabetes (22.9%), ischaemic cardiac disease (17.2%) and chronic arrhythmia (10.8%). Hypoxaemia generally improved when CPAP treatment was initiated: median (IQR) values of PaO2/FIO2 ratio at baseline on oxygen therapy (142.9 (96.7-203.2)) significantly improved when helmet CPAP was used after 6 h (205.6 (140.0-271.1), p<0.0001). However, an increase of at least 30% in PaO2/FIO2 ratio during helmet CPAP application in comparison to oxygen therapy was found only in 52% of the population. Median (IQR) duration of helmet CPAP treatment was 6 days. Only 4 patients discontinued helmet CPAP because of intolerance. CPAP failure was observed in 70 (44.6%) patients: 34 (21.7%) were intubated and 36 (22.9%) died during the HDU stay. 87 (55.4%) patients improved during the HDU stay, weaned to oxygen therapy and transferred to the general ward. No patients were intubated during the first hours after CPAP initiation or under high emergency conditions. Among those who died in HDU, pneumonia-related deaths were detected in 26 patients, while non-pneumonia related in 10 patients, including pulmonary embolisms (n=5), end-stage renal failure (n=2), cerebrovascular accident (n=1), end-stage heart failure (n=1) and septic shock (n=1). Among the 34 patients who were intubated in HDU and transferred to the ICU, nine (26.5%) died. A total of 65 (41.4%) patients had a Do-Not-Intubate (DNI) status on HDU admission: 36 died and 29 survived. At the multivariable analysis, CPAP failure was associated with the severity of pneumonia on admission (HR (95% CI) 2.9 (1.3-6.2), p=0.009) and higher baseline values of interleukin-6 (HR (95% CI) 1.0 (1.0-1.0), p<0.009). The all-cause in-hospital and 30-day mortality rates were 28.7% and 28.0%, respectively.

Prevalence of neurological post-COVID-19 manifestations

Background and aims: Although COVID-19 infection predominantly manifests with respiratory symptoms, recent studies have also reported the occurrence of neurological involvement in the acute phase as well as in the follow-up of recovered subjects Methods: Our study focuses on assessing the prevalence of neurological sequelae in COVID-19 patients hospitalized at Ospedale Maggiore Policlinico in Milan. Seventy-five COVID-19 recovered subjects followed a general follow-up protocol including pneumological, infectious and cardiovascular assessment 5-10 months after the onset of SARS-CoV2 infection;among them, a subset of 53 patients was evaluated through a self-administered 18-item questionnaire developed ad-hoc addressing sensory, motor and cognitive neurological symptoms. Results: Collected data has shown that 77.4% patients developed at least one neurological sequela, and 46.3% presented with more than three symptoms. Among symptomatic patients, the most prevalent manifestations were insomnia (65.9%) and daytime sleepiness (46.3%), followed by walking difficulties (31.7%). Other less frequent symptoms were headache (15.1%), hyposmia and hypogeusia (15.1%), and tremor (9.4%). Prevalence of symptoms 18-item questionnare showing the distribution of neurological manifestations Conclusion: Post-COVID-19 manifestations are reported in about 90% of recovered patients. This preliminary study suggests that neurological findings represent a significant part of such manifestations. We are currently expanding the questionnaire to a larger cohort of patients and correlating our findings with patients' demographical and clinical features, as well as with the severity of the previous SARSCoV2 infection. Currently, the same questionnaire is also being validated and administered to age-and sex-matched healthy controls who have not developed symptoms suggestive of Covid-19, and a cohort of non-COVID-19 hospitalized patients.