key: cord-1032575-cwreauh8
authors: Hariri, Lida P.; North, Crystal M.; Shih, Angela R.; Israel, Rebecca A.; Maley, Jason H.; Villalba, Jullian A.; Vinarsky, Vladimir; Rubin, Jonah; Okin, Daniel A.; Sclafani, Alyssa; Alladina, Jehan W.; Griffith, Jason W.; Gillette, Michael A.; Raz, Yuval; Richards, Christopher J.; Wong, Alexandra K.; Ly, Amy; Hung, Yin P.; Chivukula, Raghu R.; Petri, Camille R.; Calhoun, Tiara F.; Brenner, Laura N.; Hibbert, Kathryn A.; Medoff, Benjamin D.; Hardin, C. Corey; Stone, James R.; Mino-Kenudson, Mari
title: Lung Histopathology in COVID-19 as Compared to SARS and H1N1 Influenza: A Systematic Review
date: 2020-10-07
journal: Chest
DOI: 10.1016/j.chest.2020.09.259
sha: aecf47bb76469d8f5eaa5522ae977a8dff88754f
doc_id: 1032575
cord_uid: cwreauh8

Background Patients with severe Coronavirus Disease 2019 (COVID-19) have respiratory failure with hypoxemia and acute bilateral pulmonary infiltrates, consistent with acute respiratory distress syndrome (ARDS). It has been suggested that respiratory failure in COVID-19 represents a novel pathologic entity. Research Question How does the lung histopathology described in COVID-19 compare to the lung histopathology described in SARS and H1N1 influenza? Study Design and Methods: We conducted a systematic review to characterize the lung histopathologic features of COVID-19 and compare them against findings of other recent viral pandemics, H1N1 influenza and SARS. We systematically searched MEDLINE and PubMed for studies published up to June 24, 2020 using search terms for COVID-19, H1N1 influenza and SARS with keywords for pathology, biopsy, and autopsy. Using PRISMA-IPD guidelines, our systematic review analysis included 26 articles representing 171 COVID-19 patients; 20 articles representing 287 H1N1 patients; and eight articles representing 64 SARS patients. Results In COVID-19, acute phase diffuse alveolar damage (DAD) was reported in 88% of patients, which was similar to the proportion of cases with DAD in both H1N1 (90%) and SARS (98%). Pulmonary microthrombi were reported in 57% of COVID-19 and 58% of SARS patients, as compared to 24% of H1N1 influenza patients. Interpretation DAD, the histologic correlate of ARDS, is the predominant histopathologic pattern identified in lung pathology from patients with COVID-19, H1N1 influenza and SARS. Microthrombi were reported more frequently in both patients with COVID-19 and SARS as compared to H1N1 influenza. Future work is needed to validate this histopathologic finding and, if confirmed, elucidate the mechanistic underpinnings and characterize any associations with clinically important outcomes.

The Coronavirus Disease 2019 pandemic, caused by SARS-CoV-2, has swept 98 throughout the world and captured our undivided attention. 1, 2 The novelty of the virus and 99 massive burden of respiratory failure associated with it have led to urgent questions about its 100 disease pathogenesis and pulmonary pathology. In both the scientific literature and media, it has 101 been suggested that respiratory failure in COVID-19 represents a novel entity. 3, 4 However, 102 clinical case series of patients with COVID-19 describe respiratory failure with moderate to 103 severe hypoxemia and acute bilateral pulmonary infiltrates consistent with prior reports of acute 104 respiratory distress syndrome (ARDS), the most severe form of acute lung injury (ALI). 1,2,5 105

Histopathologically, ALI is associated with a variety of manifestations that include diffuse 106 alveolar damage (DAD), acute fibrinous and organizing pneumonia (AFOP), and organizing 107 pneumonia (OP). 6 108 109 DAD lies on the severe end of the ALI spectrum and is the histopathologic pattern typically 110 associated with clinical ARDS. DAD is caused by "endothelial and alveolar lining cell injury 111 which leads to fluid and cellular exudation," culminating in physical disruption of the blood-air 112 barrier. 7 DAD is divided into three histopathological phases that generally correlate with the time 113 from pulmonary injury: acute (exudative) phase, subacute (organizing) phase, and chronic 114 (fibrotic) phase. [6] [7] [8] The acute phase of DAD ( Figure 1A ) occurs within one week of the initial 115 injury and is characterized by intra-alveolar hyaline membranes, edema, and alveolar wall 116 thickening without significant inflammation, unless it arises in conjunction with acute 117 pneumonia. 6, 7, 9 Importantly, vascular thrombosis and microthrombosis are frequently observed in 118 DAD, even in the absence of a systemic hypercoagulable state, and are thought to result from 119 J o u r n a l P r e -p r o o f local inflammation. 6, 7, 9, 10 Angiographic studies have also confirmed that thrombosis occurs early 120 in ARDS of diverse etiology. 11 121 122

The subacute phase ( Figure 1B ) of DAD occurs approximately one week after the initial 123 pulmonary injury, and is characterized by microscopic organization of the fibrin followed by 124 fibroblast migration and secretion of young "loose" collagen. 6, 7, 9 Hyaline membranes become 125 slowly incorporated into organizing fibrotic tissue, which begins to appear in airspaces, alveolar 126 ducts, and alveolar walls. 6, 7, 9 Reactive atypical changes in Type II pneumocytes and squamous 127 metaplasia may be present. 6,7,9 Some cases of DAD will ultimately resolve, while others evolve 128 into a chronic fibrotic phase (weeks to months after the initial injury) with progressive 129 architectural remodeling and interstitial fibrosis. 6, 7, 9 In the extreme, these changes may resemble 130 usual interstitial pneumonitis, the histopathological correlate of idiopathic pulmonary fibrosis. 6,7,9 131 132 AFOP is characterized by formation of "fibrin balls" within the alveolar spaces, with 133 organization resulting from fibroblast migration and secretion of young collagen within fibrin 134 aggregates ( Figure 1C ). 6, 9, 12 It is well-established that DAD can have regions with AFOP 135 features. Therefore, the presence of hyaline membranes signifies a diagnosis of DAD, even if 136 AFOP features are also present. 6, 9, 12 OP can be seen in isolation or in combination with DAD 137 and/or AFOP and is characterized by intraluminal tufts of plump fibroblasts and young/immature 138 collagen tissue within alveolar ducts and distal airspaces ( Figure 1D ). 6, 9, 12 We conducted several literature natural language searches on MEDLINE, MedRxiv, arXiv, and 157

PubMed, using multiple logical search terms as appropriate and in accordance with the PRISMA 158 (Preferred Reporting Items for a Systematic Review and Meta-analysis) guidelines. 15 We 159 identified studies of COVID-19 lung histopathology through MEDLINE database searches for 160 "(COVID-19 OR SARS-CoV-2)" AND (Pathology OR Autopsy OR Biopsy)." Inclusion criteria 161 for the COVID-19 systematic review included: 1) confirmation of SARS-CoV-2 infection by 162 real-time reverse-transcriptase polymerase chain reaction (RT-PCR) assay; 2) clinical suspicion 163 of COVID-19 as the primary cause of death; and 3) sufficient histologic description of each 164 reported case within the study. Preprint studies were not included in our analysis due to the lack 165 of adequate peer-review at the time of publication. 166

We identified studies of 2009 H1N1 influenza lung histopathology through a PubMed search for 168 "H1N1 AND (Pathology OR Autopsy OR Biopsy)." Inclusion criteria for the H1N1 influenza Of the 26 studies included in the systematic review, 16 were case series 16, [20] [21] [22] 24, [26] [27] [28] [29] [30] [31] [32] [33] [35] [36] [37] and 10 201 were single case reports. 1, [17] [18] [19] 23, 25, 34, [38] [39] [40] Of the 171 patients reviewed, the majority consisted of 202 full or limited (lung only) autopsies (82%, n=138) [16] [17] [18] [19] [20] [21] [23] [24] [25] [26] [27] [28] [29] [30] [32] [33] [34] 36 with a minority of biopsy-based 203 post-mortem autopsies (18%, n=33). 1, 22, 31, 35, [37] [38] [39] [40] The studies evaluated cases from nine countries, 204 including the United States of America (n=37 patients), Italy (n=39), Germany (n=22), 205 Switzerland (n=22), China (n=17), Austria (n=11), Brazil (n=9), France (n=6), and Japan (n=1), 206 with one study describing a combined case series of patients from Germany and the USA (n=7). 207

The histopathologic findings from these 171 patients with COVID-19 are summarized in Table  208 1. We also identified six COVID-19 studies that described incidental histopathologic changes in 209 14 asymptomatic patients who incidentally underwent resection of a lung nodule. As infection 210 with COVID-19 prior to biopsy could not be verified for most cases, these cases did not meet our 211 criteria for inclusion and are described separately. 41 Table 2 . 252 253 Reported histopathology findings in COVID-19, 2009 H1N1 influenza, and SARS 254 J o u r n a l P r e -p r o o f DAD, acute phase: Of the published autopsy cases of patients with COVID-19, the acute phase 255 of DAD was the predominant pulmonary pathology, reported in 88% of cases (n=151 , Table  256 1). 1,16-21,24-40 The described features included prominent hyaline membranes with edema, mild 257 interstitial inflammatory infiltrates, and desquamated pneumocytes with reactive pneumocyte 258 hyperplasia. The acute phase of DAD was the most common histopathologic finding in both 259 H1N1 and SARS, reported in 90% of H1N1 cases (n=258, Supplemental their illness and, therefore, it is possible that hyaline membranes were not observed due to 266 limitations of the sampling method. Five additional studies, including 12 patients, describe 267 COVID-19 autopsy cases with regions of AFOP in a background of hyaline membranes, which 268 were ultimately categorized in the reports as DAD. 25, 26, 28, 35, 40 AFOP was also a rare finding in 269 H1N1 with only one case (0.3%) identified as pure AFOP. 63 In SARS, no patients were 270 identified as having pure AFOP. In one case series, AFOP was identified as the predominant 271 pattern in six (9%) cases that were diagnosed in the report as AFOP. 72 However, these cases 272 were described to have a background of hyaline membranes, and therefore, DAD may have been 273 a more appropriate diagnosis. autopsy cases (n=89). 17, 18, 21, 22, 24, 26, 27, [29] [30] [31] [32] [33] [35] [36] [37] 40 In most cases, organizing fibrosis was described 279 as either focal or in the setting of mixed acute and organizing phases of DAD, indicating an early 280 transition to the subacute organizing phase of DAD. Organizing fibrosis was reported in 40% of 281 H1N1 cases (n=115) 16, [48] [49] [50] [51] [52] [54] [55] [56] [57] [59] [60] [61] [62] [63] [64] Three of these patients were > 4 weeks from symptom onset, 68 while one was 19 days from 290 symptom onset but was mechanically ventilated for over two weeks at the time of death. 75 291 292 Microthrombotic disease: Of the COVID-19 cases, 57% (n=97) were reported to have 293 microthrombotic disease in capillaries and small and medium-sized vessels. 16, [19] [20] [21] [24] [25] [26] [27] [28] [29] [30] [31] 34, 36, 37, 39 In 294 H1N1, microthrombi were described in 24% (n=70) of cases. 16, 48, [50] [51] [52] 55, 57, 59, 60, 62, 64, 65 Similar to 295 COVID-19, among the SARS cases, microthrombi were reported in 58% (n=37) of cases. 68-75 296 297 Pulmonary Thrombosis: Thrombosis in large pulmonary vessels was reported in 15% of COVID-298 19 autopsy cases (n=25). 16, 20, 27, 30, 34, 36 In the H1N1 cases, 6% (n=18) had medium and/or large 299 vessel thrombosis. 16, 50, 51, 58, 60 The reported rate of thrombosis was higher in SARS, with 28% 300 (n=18) of cases describing thrombi in medium and/or large vessels. 69-72,75 301 302 Acute neutrophilic pneumonia: Secondary bacterial infections have been reported in patients 303 with COVID-19 with varying incidence. 76, 77 In this systematic review, 32% (n=55) reported 304 histologic features suggestive of acute pneumonia in COVID-19 patients. 18,21,26,27,29-33,35-37 305 Similar rates of superimposed pneumonia were reported in H1N1 cases (30%, n=86) 48-53,55,57-306 59,61,64,65 and SARS cases (31%, n=20). 68, 69, 71, 72, 74, 75 Clinical data identifying pneumonia etiology 307 was not consistently available across all case reports in an unbiased manner, and is therefore not 308 reported here. reports. 1, 16, 17, 19, 21, 24, [27] [28] [29] [30] [31] [32] [33] [35] [36] [37] [38] [39] [40] EM was performed on 31 patients in eight studies. 16, 21, 24, 29, 30, [37] [38] [39] Of 316 those, two cases in one study were not sufficient for analysis due to autolysis. 30 Viral particles 317 were found by EM in 18 of the remaining 29 patients (62%). 16,21,24,29,37-39 RT-PCR for SARS-318

CoV-2 was conducted on 80 cases (69 lung tissue samples and 11 bronchial swabs) in 12 studies, 319 75 of which were positive (94%). 1, 17, 19, 27, [30] [31] [32] [33] [35] [36] [37] 39 The expression of SARS-CoV protein by Some reports have identified microthrombi as a prominent feature of lung injury in 378 patients with 16, 21, 28 causing speculation that SARS-CoV-2 has a predilection for 379 endothelial cells, which may increase the incidence of microthrombotic complications and 380 contribute to hypoxemia. Vascular thrombosis and microthrombosis are frequent findings in 381 DAD, resulting from local inflammation even in the absence of a systemic hypercoagulable 382 state. 6, 7, 9, 10, 16 Angiographic studies have confirmed that thrombosis occurs early in ARDS of 383 diverse etiology. 11 In addition, it has been suggested that a heightened index of suspicion for 384 acute embolism may improve outcomes in pediatric ARDS. 11 In this systematic review, 385 pulmonary microthrombi were reported in approximately half of COVID-19 patients (57%), 386

which is similar to that reported in patients with SARS (58%, Table 2 ). This is higher than the 387 incidence of microthrombi reported in patients with H1N1 influenza (24% of patients), which 388 closely parallels the 24% incidence of microthrombi described in a large-scale histopathologic 389 autopsy study of DAD. 78 This is an interesting finding that may suggest that coronaviruses in 390 J o u r n a l P r e -p r o o f general could be associated with increased pulmonary microthrombi. However, the biases 391 inherent in published case reports require further prospective investigational studies to validate 392 these histopathologic findings. If validated, further work is needed to elucidate the 393 pathophysiologic mechanisms driving microthrombotic formation in coronavirus infections and 394 ascertain their clinical relevance as compared to other viral and non-viral causes of lung injury. 395

The main strength of this study is that it provides a comprehensive systematic review of 397 reported COVID-19 associated lung pathology with comparison to the reported lung pathology 398 associated with other recent viral pandemics, namely the 2009 H1N1 influenza and SARS. 399

Nevertheless, there are several limitations. First, some of the reported case series are biopsy-400 based (11% of SARS, 18% of COVID-19, and 19% of H1N1 reports) rather than full autopsies, 401 which may introduce systematic biases based on sub-optimal tissue evaluation. Second, cases 402 that were sent for biopsy or autopsy by the clinician may have been systematically different from 403 cases that did not have tissue sampling -for example, more severe disease stage -which could 404 introduce additional biases by not representing the full spectrum of COVID-19 associated lung 405 pathology. Thus, this is not a random sampling. However, the reported case series is the most 406 comprehensive description of COVID-19 associated lung pathology to date and thus provides 407 important insights for clinicians and researchers. It is also important to note that this bias applies 408 equally to all three viral pneumonias, not just COVID-19. Third, while RT-PCR confirmation of 409 SARS-CoV-2 and H1N1 influenza was uniformly present, not all SARS comparison cases were 410 confirmed by RT-PCR for SARS-CoV. Though it is possible that some SARS cases diagnosed 411 solely by clinical criteria were misclassified, this is unlikely to influence the overall conclusions 412 of this systematic review. The number of SARS case reports is also fewer than the COVID-19 or 413 J o u r n a l P r e -p r o o f H1N1 influenza case reports, which could bias the comparison. However, the systematic review 414 of COVID-19 and SARS, both of which are coronavirus infections, arrived at similar results. 415 416 Another important limitation is that detailed clinical characteristics were not reported in 417 all case series, including but not limited to comorbid conditions, duration of illness, timing of 418 biopsy, and mechanical ventilation strategies, all of which could influence lung pathology. 419

Physicians treating patients with COVID-19 have also been using a range of experimental 420 therapies, such as immunomodulatory agents, based on a variety of indications. Since the use of 421 these medications has not been consistently reported in the published literature, these data are not 422 available to characterize the extent to which these therapies influence histologic findings. 423

Additionally, there is not yet comparison between the pathology described in these case series 424 and histopathologic details from: 1) patients who recover from severe ALI; 2) patients with 425 milder respiratory disease and radiologic abnormalities who do not require intubation; and 3) 426 patients with no symptomatic disease but with radiologic abnormalities. Thus, it is possible that 427 COVID-19 patients have a spectrum of ALI patterns, but the proportions and extent of disease in 428 these patients remain a histologic mystery. Moreover, patients who recover from DAD are at risk 429 of developing progressive architectural remodeling and interstitial fibrosis, 6 but data on the long-430 term effects of COVID-19 associated lung injury are not currently available. As this pandemic 431 continues, it is crucial for forthcoming pathology reports to describe detailed clinical 432 information, including demographics, medical comorbidities, concomitant therapies and use of 433 invasive and non-invasive mechanical ventilation to further place these important histopathologic 434 reports into the appropriate clinical context. 

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Supplemental Figure 1. Flow diagram of systematic literature review for

Supplemental Figure 2. Flow diagram of systematic literature review for SARS

Systematic review of lung histopathology features in 2009 H1N1 709 influenza studies. All reported numbers are the number of patients reported to have the 710 respective finding within each respective study. No.: Number of total patients in the study

Diffuse alveolar damage; AFOP: acute fibrinous and organizing pneumonia; PNA: pneumonia

Pulmonary thrombosis: pulmonary vessel thrombosis. NIV: National Institute of Virology

Centers for Disease Control and Prevention. * Cases referred to NIV in India, which is the WHO 714 referral center for H5N1. ** Cases referred to US CDC

Supplemental Table 2. Systematic review of lung histopathology features in SARS studies

Number of total patients in the study; DAD: Diffuse alveolar 719 damage; AFOP: acute fibrinous and organizing pneumonia; PNA: pneumonia; Pulmonary 720 thrombosis: pulmonary vessel thrombosis

Available clinical data for included studies, part 1. All reported numbers 725 of patients with each finding for the respective study. No.: number of patients; AF: atrial 726 fibrillation

CVA: cerebrovascular accident; CHF: chronic heart failure; CKD: chronic kidney disease; CLL: 728 chronic lymphocytic leukemia; COPD: chronic obstructive pulmonary disease; CPR: 729 cardiopulmonary resuscitation; CVD: cardiovascular disease; DM: diabetes mellitus; DVT: deep 730 vein thrombosis; DOAC: direct oral anticoagulant; ECMO: extracorporeal membrane 731 oxygenation; ESRD: end stage renal disease (dialysis dependent)

HCQ: hydroxychloroquine; HBV: hepatitis B viral 733 infection (chronic); HCV: hepatitis C viral infection (chronic); HFNC: high flow nasal cannula

HIV: Human Immunodeficiency Virus; HLD: hyperlipidemia; HSTC: hematopoietic stem cell 735 transplant; HTN: hypertension; MDS: myelodysplastic syndrome; MM: multiple myeloma

OA: osteoarthritis; OSA: 737 obstructive sleep apnea; PAD: peripheral arterial disease; PE: pulmonary embolism; PNA: 738 pneumonia; PMH: past medical history

UIP: usual interstitial pneumonia; VSD: ventricular septal defect

Acute (exudative) phase of DAD is characterized by architecturally 742 preserved alveolar parenchyma (A) with numerous hyaline membranes (B). (C) Fibromyxoid 743 proliferation within alveolar spaces (arrows) is consistent with organizing (proliferative) phase of

D) In this case, immunohistochemistry for SARS nucleocapsid protein highlights 745 numerous alveolar macrophages and pneumocytes (red chromogen) supporting the SARS-CoV-2

Organizing (proliferative) phase of DAD demonstrates poorly 749 organized fibrous proliferation in alveolar walls and within airspaces and limited hyaline 750 membranes. Numerous multinucleated giant cells are also seen (arrows) in this case

Multiple foci with peribronchiolar metaplasia suggest recent severe acute lung injury

Multiple fibrin thrombi in small pulmonary arteries (arrows) are often present in COVID-19 753 lungs as well as in those with conventional DAD

A) Neutrophils and histiocytes filling alveolar spaces (inset) consistent 756 with superimposed pneumonia are seen in a notable fraction of COVID-19 autopsy cases

Marked reactive cytologic atypia suggestive of cytopathic changes (arrows) are rare but may be 758 seen in pneumocytes and/or macrophages. (C) Capillary congestion, often with increased 759 megakaryocytes (D, arrows), is common in DAD

 Table 1 . Systematic review of lung histopathology features in COVID-19 studies. All reported numbers are the number of patients reported to have the respective finding within each respective study. No.: Number of total patients in the study; DAD: Diffuse alveolar damage; AFOP: acute fibrinous and organizing pneumonia; PNA: pneumonia; Pulmonary thrombosis: pulmonary vessel thrombosis. *also described findings consistent with aspiration pneumonia in a patient with positive SARS-CoV-2 nasopharyngeal swab but with no evidence of SARS-CoV-2 pulmonary infection.Only the patient with positive SARS-CoV-2 nasopharyngeal swab and clinical evidence of SARS-CoV-2 pulmonary infection was included in the analysis. ** One patient was excluded from the study with 10 patients due to negative RT-PCR for SARS-CoV-2. Only results from the 9 patients with positive RT-PCR for SARS-CoV-2 were included in the analysis J o u r n a l P r e -p r o o f