Although respiratory failure and hypoxaemia are the main manifestations of COVID-19, kidney involvement is also common. Available evidence supports a number of potential pathophysiological pathways through which acute kidney injury (AKI) can develop in the context of SARS-CoV-2 infection. Histopathological findings have highlighted both similarities and differences between AKI in patients with COVID-19 and in those with AKI in non-COVID-related sepsis. Acute tubular injury is common, although it is often mild, despite markedly reduced kidney function. Systemic haemodynamic instability very likely contributes to tubular injury. Despite descriptions of COVID-19 as a cytokine storm syndrome, levels of circulating cytokines are often lower in patients with COVID-19 than in patients with acute respiratory distress syndrome with causes other than COVID-19. Tissue inflammation and local immune cell infiltration have been repeatedly observed and might have a critical role in kidney injury, as might endothelial injury and microvascular thrombi. Findings of high viral load in patients who have died with AKI suggest a contribution of viral invasion in the kidneys, although the issue of renal tropism remains controversial. An impaired type I interferon response has also been reported in patients with severe COVID-19. In light of these observations, the potential pathophysiological mechanisms of COVID-19-associated AKI may provide insights into therapeutic strategies.

/pdf/pathophysiology-of-covid-19-associated-acute-kidney-injury-196h6yr0k4.pdf

Pathophysiology of COVID-19-associated acute kidney injury.

https://doi.org/10.1016/j.jacc.2022.02.003

2022 ACC Expert Consensus Decision Pathway on Cardiovascular Sequelae of COVID-19 in Adults: Myocarditis and Other Myocardial Involvement, Post-Acute Sequelae of SARS-CoV-2 Infection, and Return to Play

Abstract Emerging as a new epidemic, long COVID or post-acute sequelae of coronavirus disease 2019 (COVID-19), a condition characterized by the persistence of COVID-19 symptoms beyond 3 months, is anticipated to substantially alter the lives of millions of people globally. Cardiopulmonary symptoms including chest pain, shortness of breath, fatigue, and autonomic manifestations such as postural orthostatic tachycardia are common and associated with significant disability, heightened anxiety, and public awareness. A range of cardiovascular (CV) abnormalities has been reported among patients beyond the acute phase and include myocardial inflammation, myocardial infarction, right ventricular dysfunction, and arrhythmias. Pathophysiological mechanisms for delayed complications are still poorly understood, with a dissociation seen between ongoing symptoms and objective measures of cardiopulmonary health. COVID-19 is anticipated to alter the long-term trajectory of many chronic cardiac diseases which are abundant in those at risk of severe disease. In this review, we discuss the definition of long COVID and its epidemiology, with an emphasis on cardiopulmonary symptoms. We further review the pathophysiological mechanisms underlying acute and chronic CV injury, the range of post-acute CV sequelae, and impact of COVID-19 on multiorgan health. We propose a possible model for referral of post-COVID-19 patients to cardiac services and discuss future directions including research priorities and clinical trials that are currently underway to evaluate the efficacy of treatment strategies for long COVID and associated CV sequelae.

https://academic.oup.com/eurheartj/advance-article-pdf/doi/10.1093/eurheartj/ehac031/42541089/ehac031.pdf

Long COVID: post-acute sequelae of COVID-19 with a cardiovascular focus

BET inhibition blocks inflammation-induced cardiac dysfunction and SARS-CoV-2 infection.

Post-Covid-19 Tachycardia Syndrome: A distinct phenotype of Post-acute Covid-19 Syndrome.

Background Troponin elevation is common in hospitalized COVID-19 patients, but underlying aetiologies are ill-defined. We used multi-parametric cardiovascular magnetic resonance (CMR) to assess myocardial injury in recovered COVID-19 patients. Methods and results One hundred and forty-eight patients (64 ± 12 years, 70% male) with severe COVID-19 infection [all requiring hospital admission, 48 (32%) requiring ventilatory support] and troponin elevation discharged from six hospitals underwent convalescent CMR (including adenosine stress perfusion if indicated) at median 68 days. Left ventricular (LV) function was normal in 89% (ejection fraction 67% ± 11%). Late gadolinium enhancement and/or ischaemia was found in 54% (80/148). This comprised myocarditis-like scar in 26% (39/148), infarction and/or ischaemia in 22% (32/148) and dual pathology in 6% (9/148). Myocarditis-like injury was limited to three or less myocardial segments in 88% (35/40) of cases with no associated LV dysfunction; of these, 30% had active myocarditis. Myocardial infarction was found in 19% (28/148) and inducible ischaemia in 26% (20/76) of those undergoing stress perfusion (including 7 with both infarction and ischaemia). Of patients with ischaemic injury pattern, 66% (27/41) had no past history of coronary disease. There was no evidence of diffuse fibrosis or oedema in the remote myocardium (T1: COVID-19 patients 1033 ± 41 ms vs. matched controls 1028 ± 35 ms; T2: COVID-19 46 ± 3 ms vs. matched controls 47 ± 3 ms). Conclusions During convalescence after severe COVID-19 infection with troponin elevation, myocarditis-like injury can be encountered, with limited extent and minimal functional consequence. In a proportion of patients, there is evidence of possible ongoing localized inflammation. A quarter of patients had ischaemic heart disease, of which two-thirds had no previous history. Whether these observed findings represent pre-existing clinically silent disease or de novo COVID-19-related changes remain undetermined. Diffuse oedema or fibrosis was not detected.

/pdf/patterns-of-myocardial-injury-in-recovered-troponin-positive-4ly8auks4n.pdf

Patterns of myocardial injury in recovered troponin-positive COVID-19 patients assessed by cardiovascular magnetic resonance.

Editor—Both deep venous thrombosis (DVT) and pulmonary embolism (PE) are common in critically ill patients on the ICU. Nevertheless, a higher-than-expected incidence of thrombotic complications, particularly in the pulmonary circulation, has been observed in the context of COVID-19 infection,1Helms J. Tacquard C. Severac F. et al.High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study.Intensive Care Med. 2020; 46: 1089-1098Crossref PubMed Scopus (1610) Google Scholar, 2Jiménez D. Garcia-Sanchez A. Rali P. et al.Incidence of VTE and bleeding among hospitalized patients with coronavirus disease 2019: a systematic review and meta-analysis.Chest. 2021; 159: 1182-1196Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar, 3Tufano A. Rendina D. Abate V. et al.Venous thromboembolism in COVID-19 compared to non-COVID-19 cohorts: a systematic review with meta-analysis.J Clin Med. 2021; 10: 4925Crossref PubMed Scopus (11) Google Scholar where in situ thrombosis, as opposed to embolisation from peripheral vessels, is the postulated mechanism for the large thrombotic burden.4Ackermann M. Verleden S.E. Kuehnel M. et al.Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19.N Engl J Med. 2020; 383: 120-128Crossref PubMed Scopus (3004) Google Scholar The high prevalence of thrombosis in COVID-19 has also contributed to a debate about the appropriate intensity of anticoagulation appropriate for this cohort: prophylactic, intermediate or therapeutic.5Spyropoulos A.C. Goldin M. Giannis D. et al.Efficacy and safety of therapeutic-dose heparin vs standard prophylactic or intermediate-dose heparins for thromboprophylaxis in high-risk hospitalized patients with COVID-19: the HEP-COVID randomized clinical trial.JAMA Intern Med. 2021; 181: 1612-1620Crossref PubMed Scopus (156) Google Scholar,6Sadeghipour P. Talazas A.H. Rashidi F. et al.Inspiration InvestigatorsEffect of intermediate-dose vs standard-dose prophylactic anticoagulation on thrombotic events, extracorporeal membrane oxygenation treatment, or mortality among patients with COVID-19 admitted to the intensive care unit: the INSPIRATION randomized clinical trial.JAMA. 2021; 325: 1620-1630Crossref PubMed Scopus (333) Google Scholar At the Royal Free Hospital (London, UK), all patients admitted to ICU were on standard dose thromboprophylaxis with low molecular weight heparin, although practice varied widely across London hospitals at the time. Another uncertainty regards the frequency and distribution of PE within the pulmonary circulation in patients with COVID-19 as well as its association with co-existing DVT.7Lieveld A. Heldeweg M.L.A. Smit J.M. et al.Multi-organ point-of-care ultrasound for detection of pulmonary embolism in critically ill COVID-19 patients — a diagnostic accuracy study.J Crit Care. 2022; 69153992Crossref PubMed Scopus (1) Google Scholar,8Suh Y.J. Hong H. Ohana M. et al.Pulmonary embolism and deep vein thrombosis in COVID-19: a systematic review and meta-analysis.Radiology. 2021; 298: E70-E80Crossref PubMed Google Scholar If peripherally located clot burden within the pulmonary circulation reflects in situ thrombosis, it would less likely be associated with DVT. Conversely, embolisation of clot via the deep veins might be associated with a more centrally located clot burden. To address these questions and facilitate development of local thromboprophylactic guidelines, we performed a service evaluation with the objective of comprehensively capturing the prevalence of PE and DVT in our ICU during the second wave of COVID-19 in the UK. From our experience in the first wave, all mechanically ventilated patients with COVID-19 had computed tomography pulmonary angiograms (CTPA) where clinically feasible. Complementing this, we screened 70 consecutive ICU patients over 1 week for DVT with full-length duplex ultrasonography of both legs. As a service development, the national research ethics committee does not require ethical approval. For the purposes of our evaluation, DVT was grouped into below or above knee; PE into central/lobar or segmental/sub-segmental, consonant with objective radiological and anatomical criteria. The overall prevalence of thrombosis was 47/70 (67%): 30/70 (43%) for PE and 41/70 (59%) for DVT above or below knee (Table 1). The location of PE was evenly divided: 14/30 (49%) were located centrally in a main/lobar pulmonary artery. The remaining 16/30 (51%) were peripheral, segmental/sub-segmental. All above knee DVT associated with PE (four/six) were associated with proximal pulmonary artery thrombus (main trunk or lobar), suggesting an embolic origin. Notably, seven/35 (20%) of patients with below knee DVT also had PE located in main/lobar vessels. The remaining 13/35 (38%) of patients with below knee DVT had concomitant sub-segmental PE.Table 1Comparative table showing relevant clinical and physiological details in patients with and without pulmonary embolism (PE) and with and without deep venous thrombosis (DVT). APACHE II, Acute Physiology and Chronic Health Evaluation II; CVVH, continuous veno-venous haemofiltration.Patient characteristicsTotal (n=70)Pulmonary embolism (n=30)No pulmonary embolism (n=40)Male (%)43 (61.4)20 (66.7)23 (57.5)Average age (yr)6262.961.3BMI (kg m−2)28.927.729.8Co-morbidities, n (%)Cardiovascular disease14 (20)5 (16.7)9 (22.5)Hypertension38 (54.2)12 (40)26 (65)Diabetes mellitus31 (44.2)16 (53.3)15 (37.5)Previous VTE2 (2.8)1 (3.3)1 (2.5)Current cancer6 (8.6)1 (3.3)5 (12.5)Organ support, n (%)Mechanical ventilation66 (94.3)29 (96.7)37 (92.5)Therapeutic paralysis (ever)62 (88.6)27 (90)35 (87.5)Proning (ever)53 (75.8)19 (63.3)34 (85)PO2/Fio2 ratio (kPa)24.0123.924.1Current noradrenaline42 (60)21 (70)21 (52.5)Current inotrope5 (7.1)3 (10)2 (5)Current CVVH12 (17.1)4 (13.3)8 (20)Femoral line26 (37.1)10 (33.3)16 (40)APACHE II14 (11, 17)14 (11,17)14 (11,18)AdmissionAverage length of hospital stay before ICU admission (days)3.43.43.4Average ICU length of stay before Doppler ultrasound (days)18.819.418.4Deep vein thrombosis, n (%)Above knee6 (8.6)4 (13.3)2 (5)Below knee35 (50)20 (66.7)15 (37.5)None29 (41.4)6 (20)23 (57.5) Open table in a new tab This service evaluation of DVT and PE in an ICU cohort is the first (to our knowledge) to document location of PE with location of DVT systematically in all studied patients. We showed that prevalence of both DVT and PE was more than double that previously reported in other COVID-19 patient cohorts.9Mitteldorp S. Coppens M. van Haaps T.F. et al.Incidence of venous thromboembolism in hospitalized patients with COVID-19.J Thromb Haemost. 2020; 18: 1995-2002Crossref PubMed Scopus (884) Google Scholar In addition, below knee DVT was associated with peripherally located PE; 13/16 (81%) of peripheral PE had co-existing below knee DVT whereas more than one-third of below knee DVT was associated with sub-segmental PE. Thus, the presence of a below knee DVT appears to be a marker for in situ thrombosis/COVID-19 thrombotic phenotype. This is a significant observation because below knee DVT is traditionally regarded as of limited clinical relevance in a non-COVID-19 context. Duplex ultrasonography is a readily available technique applicable to all levels of illness acuity, and the utility of a positive scan to inform escalation of anticoagulation to therapeutic dose until a CTPA can be performed should be explored. Those patients with DVT are more likely than not (20/35 [57%] vs 15/35 [43%], unadjusted relative risk [RR]=1.32) to have PE or potentially to develop one over time. Secondly, the complete absence of DVT (29/70) would reassure the clinician that the patient is less likely to have PE (unadjusted RR ∼ ×4 or 23/29 vs six/29 patients) at that time. This service development study may also have implications for more resource-challenged settings where obtaining CTPA to rule out PE is not possible. A duplex scan, which might more easily be performed, could be a useful surrogate marker of clot burden and thrombotic risk, which might trigger a life-saving decision to institute therapeutic anticoagulation. This survey cannot infer causation. The temporal link between PE and DVT is difficult to establish as many patients had duplex scans relatively late into their ICU stay, but the length of ICU stay before duplex scan was the same in both sets of patients with and without PE (19.4 vs 18.4 days). In addition, a large number of patients (23%) had their CT scans >14 days after admission to ICU such that the interval between duplex scan and CT scan would have been closely related. The relative paucity of patients (<100) included precludes a more formal statistical treatment of the data; nevertheless the crude, two-way associations of below knee DVT with sub-segmental PE is a novel and striking observation. Finally, the high proportion of DVT in our survey may call into question the generalisability of our cohort. However, other studies comparing DVT and PE only screened between 10% and 30% of patients within the first 10 days of ICU stay (as opposed to an average of 18 days in our survey) leading to a much lower detected prevalence and the possibility of type II error. We believe that screening 100% of patients in our survey leads to a prevalence that is both accurate and consistent with previous data and in keeping with the biology4Ackermann M. Verleden S.E. Kuehnel M. et al.Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19.N Engl J Med. 2020; 383: 120-128Crossref PubMed Scopus (3004) Google Scholar and known epidemiology of disease, with a risk of DVT present for up to 110 days after COVID-19 diagnosis.10Katsoularis I. Fonseca-Rodriguez O. Farrington P. et al.Risk of deep vein thrombosis and pulmonary embolism, and bleeding after COVID-19: self controlled cases series and matched cohort study.BMJ. 2022; 377e069590PubMed Google Scholar In summary, this service development study shows an association of DVT (both above and below knee) and PE (central vs sub-segmental) in an ICU cohort of patients with COVID-19. We report a very high prevalence of venous thrombosis. There was a notable association between presence of below knee DVT and sub-segmental PE which could have important treatment implications. Below knee DVT should not automatically be assigned as benign and could be a marker for thrombogenicity. Routine duplex ultrasonography scans warrant further exploration as a triage tool to inform intensity of anticoagulation in COVID-19 ICU patients and to expedite prompt investigation of the pulmonary vasculature. The authors declare no conflicts of interest. 

http://www.bjanaesthesia.org/article/S0007091222003944/pdf

Donald Leith

Papers

Patterns of myocardial injury in recovered troponin-positive COVID-19 patients assessed by cardiovascular magnetic resonance.

Prevalence of pulmonary embolism and deep venous thrombosis during the COVID-19 pandemic in an intensive care unit cohort: a service evaluation