key: cord-0756612-cnr9edmf
authors: Lutchmansingh, Denyse D.; Knauert, Melissa P.; Antin-Ozerkis, Danielle E.; Chupp, Geoffrey; Cohn, Lauren; Dela Cruz, Charles S.; Ferrante, Lauren E.; Herzog, Erica L.; Koff, Jonathan; Rochester, Carolyn L.; Ryu, Changwan; Singh, Inderjit; Tickoo, Mayanka; Winks, Vikki; Gulati, Mridu; Possick, Jennifer D.
title: A clinic blueprint for post-COVID-19 RECOVERY: Learning from the past, looking to the future
date: 2020-11-04
journal: Chest
DOI: 10.1016/j.chest.2020.10.067
sha: ee6f646fb34c44b0a09ee782c55829a15527f523
doc_id: 756612
cord_uid: cnr9edmf

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic poses extraordinary challenges. The tremendous number of coronavirus disease 2019 (COVID-19) cases in the United States has resulted in a large population of survivors with prolonged post-infectious symptoms. The creation of multidisciplinary post-COVID-19 clinics to address both persistent symptoms and potential long-term complications requires an understanding of the acute disease and the emerging data regarding COVID-19 outcomes. Experience with severe acute respiratory syndrome and Middle East respiratory syndrome, post-acute respiratory distress syndrome complications, and post-intensive care syndrome also informs anticipated sequelae and clinical program design. Post-COVID-19 clinical programs should be prepared to care for individuals previously hospitalized with COVID-19 (including those who required critical care support), non-hospitalized individuals with persistent respiratory symptoms following COVID-19 infection, and individuals with pre-existing lung disease complicated by COVID-19. Effective multidisciplinary collaboration models leverage lessons learned during the early phases of the pandemic to overcome the unique logistical challenges posed by pandemic circumstances. Collaboration between clinicians and researchers across disciplines will provide insight into survivorship that may shape the treatment of both acute disease and chronic complications. In this review, we discuss the aims, general principles, elements of design, and challenges of a successful multidisciplinary model to address the needs of COVID-19 survivors.

The coronavirus disease 2019 pandemic caused by severe acute 73 respiratory syndrome coronavirus-2 (SARS-CoV-2) has devastated patients, communities, and 74 healthcare systems. More than 170 countries have been affected by the COVID-19 pandemic, 75 with over 6.8 million cases and 200,000 deaths in the United States (US) as of September 23, 76 2020. 1,2 While efforts to manage the ongoing pandemic must remain a priority, our clinical 77 response must also address the needs of a large COVID-19 survivorship. 3 Healthcare systems 78 must develop clinical infrastructures to address the complex needs of COVID-19 survivors 79 experiencing significant persistent respiratory symptoms and must anticipate potential long-term 80 pulmonary and non-pulmonary sequelae. In this review, we touch upon individual risk factors 81 and features of acute disease that impact post-COVID-19 care, explore potential post-COVID-82 fibrosis, pulmonary fibrosis, or active smoking are considered at potentially increased risk 99 pending further study. 7 Additionally, investigators have postulated that the levels of the 100 angiotensin-converting enzyme 2 (ACE-2) receptor, the viral entry point into the cell, and its 101 variable expression in patients with underlying lung disease or smoking exposure may impact 102 susceptibility and disease severity. 9,10 103 104

The primary pulmonary manifestations of SARS-CoV-2 infection include hypoxemia, 106 dyspnea, and cough. Extrapulmonary symptoms vary, with fever, fatigue, headache, myalgia, 107 and diarrhea commonly reported. 11 Though most infections are mild (81%), a subset of 108 individuals develop severe disease manifestations. 12-14 Hallmarks of severe disease include 109 hypoxemic respiratory failure, acute respiratory distress syndrome (ARDS), sepsis, septic 110 shock, and multi-organ dysfunction. 15 111

The predominant reason for hospitalization is hypoxemia. Though many patients with 112 hypoxemic respiratory failure are successfully managed with noninvasive strategies, 16 those 113 with severe respiratory failure require mechanical ventilation along with adjunctive paralytics, 114 sedation, prone positioning, and, in selected cases, extracorporeal membrane oxygenation. 17,18 115 Patients surviving these advanced life support measures are anticipated to have long-term 116 sequelae similar to ARDS survivors and will require post-COVID-19 evaluation and longitudinal 117 care. 118

Significant acute extrapulmonary manifestations can occur in virtually any organ ( Figure  119 1). This could be due to direct viral injury via the ACE-2 receptor or due to non-specific systemic 120 insults such as poor perfusion, treatment toxicities, or systemic inflammation. 12, [19] [20] [21] The 121 dysregulated pro-inflammatory responses induced by SARS-CoV-2 infection can lead to a 122 maladaptive "cytokine storm" which can contribute to multi-organ dysfunction and death. 22,23 123 There is also growing appreciation for thrombotic complications in patients with Autopsy series have revealed micro-thrombi formation in the pulmonary macro-and 125 microvasculature, as well as skin, cardiac, and renal microvasculature. [24] [25] [26] The involvement of 126 multi-organ vascular beds may represent a different unifying mechanism of multi-organ injury in 127 Though the full spectrum of extra-pulmonary manifestations is beyond the scope of this 129 article, acute cardiac, neurologic, neuromuscular, and hematologic complications have 130 significant implications for post-COVID-19 clinical program design. For example, cardiac 131 complications including arrhythmias, acute coronary syndrome, myocarditis and heart failure 132 have been described. [27] [28] [29] [30] Neurologic and neuromuscular manifestations are another area of 133 significant concern. An early cohort study reported frequent occurrence of acute 134 cerebrovascular disease (6% in severe infection vs. 1% in non-severe), impaired consciousness 135 (15% vs. 2%), and skeletal muscle injury (19 vs. 5%). 20 Coagulopathies and thrombotic 136 complications have also been described. 31 

Multiple centers across the US are creating multidisciplinary ambulatory programs for 246 the post-COVID-19 population. These programs may differ based on local resources and needs 247 but will share common goals, challenges, and design elements. The Yale New Haven Health 248 (YNHH) system, which spans five hospitals across Connecticut and Southern Rhode Island, 249 discharged over 3,500 patients with moderate to severe COVID-19 from March to mid-August. 250

In an observational study of 2154 COVID-19 patients admitted to YNHH, 76% were discharged 251 alive within the study period (March 1 to April 30, 2020); among these survivors, 12% required 252 mechanical ventilation during their admission. 71 The impact of COVID-19 survivorship in our 253 community is substantial. Below, we outline our specific approach to caring for these patients as 254 part of the RECOVERY (CompREhensive Post-COVID CentER at Yale) program developed 255 within our academic pulmonary practice (Figure 2) . 256 257

The primary goals of RECOVERY are to (1) challenges (see below), we have employed expedited telehealth visits, followed shortly 285 thereafter by an in-clinic comprehensive evaluation. This initial telehealth visit allows the 286 physician and patient to review individual case details and identify prominent symptoms 287 or concerns. This information guides selection of subsequent diagnostics, targeted 288 subspecialty referrals, and prioritization of in-clinic assessments. In our experience, most 289 patients, regardless of disease severity, describe persistent dyspnea and exertional 290

limitations. As such, the standard initial diagnostic evaluation includes comprehensive 291 pulmonary symptom assessment, pulmonary function tests (PFTs, including spirometry, 292 lung volumes, diffusion capacity, and 6-minute walk test), physical function assessment 293 with a physical therapist, and repeat imaging (with chest radiograph or HRCT). When 294 extrapulmonary issues are identified, subspecialists are engaged through 295 multidisciplinary case review, electronic/telehealth consults, or formal in-clinic 296 consultations as appropriate. Our program has cultivated COVID-19 specific 297 collaboration with multiple specialties including cardiology, neurology, psychiatry, 298 hematology, otolaryngology, and sleep medicine to date. Additional laboratory and 299 radiological studies are tailored to individual patient course, prior laboratory 300 abnormalities, and active symptoms. For example, we anticipate that cardiopulmonary exercise 301 testing will help differentiate causes of dyspnea in those with otherwise normal PFTs. 302

The optimal role of bronchoscopy and/or surgical lung biopsy in individuals with 303 persistent or evolving infiltrates after COVID infection also remains to be defined and has been 304 approached on a case to case basis. The decision to institute corticosteroids for presumed 305 secondary organizing pneumonia and/or defining the length of therapy for those already on 306 corticosteroids remains uncharted territory. For the subset of patients with evidence of fibrosis, it 307 is unclear if this will persist or progress; as such, the role of antifibrotic therapy remains 308

We emphasize physical therapy in our initial evaluation model based on the symptoms 310 and deficits reported by our earliest patients, and our perception that rehabilitation will play a 311 crucial role in pulmonary and non-pulmonary recovery. Social distancing and ambulatory 312 rehabilitation closures during the COVID-19 pandemic have compounded the sedentarism of 313 acute illness, thereby increasing the risk of skeletal muscle dysfunction in recovering patients. 314

Addressing rehabilitation needs across all illness severity can improve physical function and 315 other aspects of HRQoL. 72 Programs can be implemented using a combination of at-home 316 exercise plans, individual outpatient therapy sessions, or enrollment in pulmonary rehabilitation. 317

Efforts are underway to incorporate telemedicine and wearable devices into pulmonary 318 rehabilitation practice to improve the efficacy of these modalities within COVID-19 pandemic 319

Based on prior experiences with all-cause ARDS, SARS, and MERS, we expect that a 321 subset of patients will require longitudinal pulmonary care, and plan to follow patients regularly 322 Ongoing infection control is, of course, of paramount concern for both patients and staff. 344

The provision of non-emergent clinical care is guided by the CDC time-and symptom-based 345 approaches to discontinuation of isolation. Investigators should also focus on how the intersection of race, socioeconomic status, 366 occupation, and differential healthcare access may contribute to the disproportionate impact of 367 COVID-19 on Black and Latinx communities. 368 RECOVERY program patients may also participate in serial collection of biospecimens 369 to foster understanding of the long-term trajectory of COVID-19. Studies of such specimens may 370 support biomarker discovery and support efforts to predict the development of chronic disease. 371

Furthermore, collecting and analyzing specimens suitable for multi-omics, microbiome, and 372 virome studies can catalyze scientific discovery across disciplines. These efforts can lead to 373 collaborations between academic, industry, governmental, and patient advocacy organizations. 374

This enhances the power of any individual or institutional effort and allows for a more nuanced 375 understanding of the impact of regional, national, and international practices on post-COVID-19. 376

The COVID-19 pandemic has posed unprecedented challenges to the medical 379 community. While much focus necessarily remains on reducing transmission, case detection, 380 and management of acute COVID-19, we must work in parallel to address the needs of those 381 recovering from this illness. Effective and sustainable care models will need to leverage the 382 successes of telehealth and remote monitoring, employ creative strategies for multidisciplinary 383 engagement, and adapt to the shifting logistical landscape of the ongoing pandemic. 

World Health Organisation Coronavirus Disease Situation reports 138

Connecticut Department of Public Health COVID-19 Data Tracker

The plight of essential workers during the COVID-19 pandemic

Health Care Workers and Implications for Prevention Measures in a Tertiary Hospital in 432

Coronavirus Disease 2019 Case 437 Surveillance -United States

ACE-2 expression in the small airway epithelia of 440 smokers and COPD patients: implications for COVID-19. The European respiratory 441 journal

Tobacco Smoking Increases the Lung 443

Gene Expression of ACE2, the Receptor of SARS-CoV-2

Severe Covid-19

Human Kidney is a Target for Novel Severe Acute 447 Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection. medRxiv

Clinical features of patients infected with 2019 novel 450 coronavirus in Wuhan

COVID-19) -452 United States

Prone Positioning of Non-Intubated Patients 458 with COVID-19

Prone positioning in severe acute respiratory 460 distress syndrome

Extracorporeal Membrane Oxygenation for 462 Critically Ill Patients with COVID-19 Related Acute Respiratory Distress Syndrome: 463 Worth the Effort?

COVID-19: Gastrointestinal Manifestations and Potential Fecal-465 Oral Transmission

Neurologic Manifestations of Hospitalized Patients With 467

Coronavirus Disease 2019 in Wuhan, China. JAMA Neurol. 2020

Potential Effects of Coronaviruses 469 on the Cardiovascular System: A Review

The cytokine storm and COVID-19

The pathogenesis and treatment of the `Cytokine Storm' in 473 COVID-19

Autopsy Findings and Venous 475 Thromboembolism in Patients With COVID-19

Complement associated microvascular injury and 477 thrombosis in the pathogenesis of severe COVID-19 infection: A report of five cases

Pulmonary Arterial Thrombosis in COVID-19 With 480 Fatal Outcome: Results From a Prospective, Single-Center, Clinicopathologic Case 481 Series

Approach to Acute Cardiovascular 483 Complications in COVID-19 Infection

Clinical Characteristics of 138 Hospitalized Patients With 485 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China

Cardiovascular Implications of Fatal Outcomes of Patients 488

COVID-19)

Clinical course and risk factors for mortality of adult inpatients 490 with COVID-19 in Wuhan, China: a retrospective cohort study

Coagulation abnormalities and thrombosis in patients 493 with COVID-19. The Lancet Haematology

Incidence of thrombotic complications in 495 critically ill ICU patients with COVID-19

Hyperimmune IV immunoglobulin treatment: a 497 multicenter double-blind randomized controlled trial for patients with severe 2009 498 influenza A(H1N1) infection

Treatment of 5 Critically Ill Patients With COVID-19 With 500 Convalescent Plasma

Rationale and evidence on the use of 502 tocilizumab in COVID-19: a systematic review

Remdesivir for the Treatment of Covid-19 -504 Preliminary Report

Covid-19 in Critically Ill Patients in the 510 Seattle Region -Case Series

Chronic obstructive pulmonary disease is associated with severe 512 coronavirus disease 2019 (COVID-19)

OpenSAFELY: factors associated with 514 COVID-19 death in 17 million patients

Do chronic respiratory diseases or 516 their treatment affect the risk of SARS-CoV-2 infection?

A multinational report to characterise SARS-CoV-2 519 infection in people with cystic fibrosis

Pulmonary fibrosis is associated with an elevated 521 risk of thromboembolic disease

Outcome of Hospitalization for COVID-19 in 523 Patients with Interstitial Lung Disease: An International Multicenter Study. Am J Respir 524 Crit Care Med

Abnormal pulmonary function in COVID-19 patients at time of 526 hospital discharge

Anormal pulmonary function and residual CT 528 abnormalities in rehabilitating COVID-19 patients after discharge

Prediction of the Development of Pulmonary 530

Fibrosis Using Serial Thin-Section CT and Clinical Features in Patients Discharged after 531 Treatment for COVID-19 Pneumonia

Organizing pneumonia as 533 another pathological finding in pandemic influenza A (H1N1)

Essentials for Radiologists on 536 COVID-19: An Update-Radiology Scientific Expert Panel

Radiological Society of North America Expert 539 Consensus Statement on Reporting Chest CT Findings Related to COVID-19. Endorsed 540 by the Society of Thoracic Radiology, the American College of Radiology, and RSNA -541 Secondary Publication

Pulmonary fibrosis secondary to COVID-19: a 543 call to arms? The Lancet. Respiratory medicine

Chest CT manifestations of new coronavirus 545 disease 2019 (COVID-19): a pictorial review

Chronic Thromboembolic Pulmonary 547 Hypertension: Evolving Therapeutic Approaches for Operable and Inoperable Disease

Diagnosis of chronic thromboembolic 550 pulmonary hypertension after acute pulmonary embolism

Coronavirus as a possible cause of severe acute 552 respiratory syndrome

Isolation of a 554 novel coronavirus from a man with pneumonia in Saudi Arabia

Epidemic and Emerging Coronaviruses (Severe Acute Respiratory Syndrome 557 and Middle East Respiratory Syndrome)

The 1-year impact of severe acute respiratory 559 syndrome on pulmonary function, exercise capacity, and quality of life in a cohort of 560 survivors

Follow-up study on pulmonary function and lung radiographic 562 changes in rehabilitating severe acute respiratory syndrome patients after discharge

Follow-up chest radiographic findings in patients with 565 MERS-CoV after recovery

Correlation between Pneumonia Severity and Pulmonary 567 Complications in Middle East Respiratory Syndrome

Long-term clinical outcomes in survivors of 570 severe acute respiratory syndrome and Middle East respiratory syndrome coronavirus 571 outbreaks after hospitalisation or ICU admission: A systematic review and meta-572 analysis

One-year outcomes in survivors of the 574 acute respiratory distress syndrome

Functional Disability 5 Years after Acute 577 Respiratory Distress Syndrome

The fibroproliferative 580 response in acute respiratory distress syndrome: mechanisms and clinical significance

Pulmonary function and health-related 583 quality of life in survivors of acute respiratory distress syndrome

Improving long-term outcomes after 586 discharge from intensive care unit: Report from a stakeholders' conference

Association of 589 intensive care unit delirium with sleep disturbance and functional disability after critical 590 illness: an observational cohort study

Sleep Disturbance after Hospitalization and Critical 592 Illness: A Systematic Review

Persistent Symptoms 594 in Patients After Acute COVID-19

Clinical Characteristics and Outcomes for 596 7,995 Patients with SARS-CoV-2 Infection. medRxiv

Respiratory rehabilitation in elderly 598 patients with COVID-19: A randomized controlled study

Telemedicine is as effective as in-person 601 visits for patients with asthma

COVID-19 transforms health care 603 through telemedicine: evidence from the field

Discontinuation of Isolation for Persons with COVID-19 Not in Healthcare Settings

Persistent severe acute respiratory syndrome 608 coronavirus 2 detection after resolution of coronavirus disease 2019-associated 609 symptoms/signs