The characteristics and evolution of pulmonary fibrosis in COVID-19 patients as assessed by AI-assisted chest HRCT



The characteristics and evolution of pulmonary fibrosis in patients with coronavirus disease 2019 (COVID-19) have not been adequately studied. AI-assisted chest high-resolution computed tomography (HRCT) was used to investigate the proportion of COVID-19 patients with pulmonary fibrosis, the relationship between the degree of fibrosis and the clinical classification of COVID-19, the characteristics of and risk factors for pulmonary fibrosis, and the evolution of pulmonary fibrosis after discharge. The incidence of pulmonary fibrosis in patients with severe or critical COVID-19 was significantly higher than that in patients with moderate COVID-19. There were significant differences in the degree of pulmonary inflammation and the extent of the affected area among patients with mild, moderate and severe pulmonary fibrosis. The IL-6 level in the acute stage and albumin level were independent risk factors for pulmonary fibrosis. Ground-glass opacities, linear opacities, interlobular septal thickening, reticulation, honeycombing, bronchiectasis and the extent of the affected area were significantly improved 30, 60 and 90 days after discharge compared with at discharge. The more severe the clinical classification of COVID-19, the more severe the residual pulmonary fibrosis was; however, in most patients, pulmonary fibrosis was improved or even resolved within 90 days after discharge.


Pulmonary fibrosis can occur as a serious complication of viral pneumonia, which often leads to dyspnea and impaired lung function. It significantly affects quality of life and is associated with increased mortality in severe cases [12]. Patients with confirmed severe acute respiratory syndrome coronavirus (SARS‐CoV) or Middle East respiratory syndrome coronavirus (MERS‐CoV) infections were found to have different degrees of pulmonary fibrosis after hospital discharge, and some still had residual pulmonary fibrosis and impaired lung function two years later. In addition, wheezing and dyspnea have also been reported in critically ill patients [35].

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel Betacoronavirus that is responsible for an outbreak of acute respiratory illness known as coronavirus disease 2019 (COVID-19). SARS-CoV-2 shares 85% of its genome with the bat coronavirus bat-SL-CoVZC45 [6]. However, there are still some considerable differences between SARS-CoV-2 and SARS‐CoV or MERS‐CoV. Whether COVID-19 can trigger irreversible pulmonary fibrosis deserves more investigation. George reported that COVID-19 was associated with extensive respiratory deterioration, especially acute respiratory distress syndrome (ARDS), which suggested that there could be substantial fibrotic consequences of infection with SARS-CoV-2 [7]. Moreover, it has also been shown that the pathological manifestations of COVID-19 strongly resemble those of SARS and MERS [8], with pulmonary carnification and pulmonary fibrosis in the late stages.

Chest X-rays and high-resolution computed tomography (HRCT) of the chest play important auxiliary roles in the diagnosis and management of patients with suspected cases of COVID-19 [910]. The newly applied artificial intelligence (AI)-assisted pneumonia diagnosis system has been described as an objective tool that can be used to qualitatively and quantitatively assess the progression of pulmonary inflammation [11]. At present, although COVID-19 has been classified as a global epidemic for months, the risk factors for and severity and evolution of pulmonary fibrosis have not yet been reported. In this study, this new technology was applied to investigate the pulmonary imaging characteristics and related risk factors in COVID-19 patients at the time of hospital discharge, as well as the evolution of pulmonary fibrosis 30, 60 and 90 days after discharge, with the aim of providing an important basis for the clinical diagnosis, treatment and prognostic prediction of COVID-19-related pulmonary fibrosis.

For More Information:

Multi-layered transcriptomic analyses reveal an immunological overlap between COVID-19 and hemophagocytic lymphohistiocytosis associated with disease severity

Authors: Lena F. Schimkea,5, Alexandre H.C. Marquesa, Gabriela Crispim Baiocchia, Caroline Aliane de Souza Pradob Dennyson Leandro M. Fonsecab , Paula Paccielli Freirea , Desirée Rodrigues Plaçab , Igor Salerno Filgueirasa ,Ranieri Coelho Salgadoa, Gabriel Jansen-Marquesc, Antonio Edson Rocha liveirab
, Jean PierreSchatzmann Perona, José Alexandre Marzagão Barbutoa,d, Niels Olsen Saraiva Camaraa
, Vera Lúcia Garcia Calicha , Hans D. Ochse, Antonio Condino-Netoa, Katherine A. Overmyerf,g, Joshua J. Coonh,i, JosephBalnisj,k, Ariel Jaitovichj,k, Jonas Schulte-Schreppingl, Thomas Ulasm, Joachim L. Schultzel,m, Helder I.Nakayab, Igor Jurisican,o,p, Otavio Cabral-Marquesa,b,q

Clinical and hyperinflammatory overlap between COVID-19 and hemophagocytic lymphohistiocytosis (HLH) has been reported. However, the underlying mechanisms are unclear. Here we show that COVID-19 and HLH have an overlap of signaling pathways and gene signatures commonly dysregulated, which were defined by investigating the transcriptomes of
1253 subjects (controls, COVID-19, and HLH patients) using microarray, bulk RNA-sequencing (RNAseq), and single-cell RNAseq (scRNAseq). COVID-19 and HLH share pathways involved in cytokine and chemokine signaling as well as neutrophil-mediated immune responses that associate with COVID-19 severity. These genes are dysregulated at protein level across several
COVID-19 studies and form an interconnected network with differentially expressed plasma proteins which converge to neutrophil hyperactivation in COVID-19 patients admitted to the intensive care unit. scRNAseq analysis indicated that these genes are specifically upregulated across different leukocyte populations, including lymphocyte subsets and immature neutrophils.

Artificial intelligence modeling confirmed the strong association of these genes with COVID-19 severity. Thus, our work indicates putative therapeutic pathways for intervention.

More than one year of Coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome Coronavirus (SARS-CoV)-2, more than 197 million cases and 4,2 million deaths have been reported worldwide (July 30th 2021, WHO COVID-19 Dashboard). The clinical presentation ranges from asymptomatic to severe disease manifesting as pneumonia, acute respiratory distress syndrome (ARDS), and a life-threatening hyperinflammatory syndrome associated with excessive cytokine release (hypercytokinaemia)1–3 . Risk factors for severe manifestation and higher mortality include old age as well as hypertension, obesity, and diabetes4. Currently, COVID-19 continues to spread, new variants of SARS-CoV-2 have been reported and the number of infections resulting in death of young individuals with no comorbidities has increased the mortality rates among the young population 5,6. In addition, some novel SARS-CoV-2 variants of concern appear to escape neutralization by vaccine-induced humoral immunity7 . Thus, the need for a better understanding of the immunopathologic mechanisms associated with severe SARS-CoV-2 infection.

Patients with severe COVID-19 have systemically dysregulated innate and adaptive immune responses, which are reflected in elevated plasma levels of numerous cytokines and chemokines including granulocyte colony-stimulating factor (GM-CSF), tumor necrosis factor (TNF), interleukin (IL)-6, IL-6R, IL18, CC chemokine ligand 2 (CCL2) and CXC chemokine ligand 10
(CXCL10)8–10 , and hyperactivation of lymphoid and myeloid cells11. Notably, the hyperinflammation in COVID-19 shares similarities with cytokine storm syndromes such as those triggered by sepsis, autoinflammatory disorders, metabolic conditions and malignancies12–14 ,often resembling a hematopathologic condition called hemophagocytic lymphohistiocytosis
(HLH)15. HLH is a life-threatening progressive systemic hyperinflammatory disorder characterized by multi-organ involvement, fever flares, hepatosplenomegaly, and cytopenia due to hemophagocytic activity in the bone marrow15–17 or within peripheral lymphoid organs such as pulmonary lymph nodes and spleen. HLH is marked by aberrant activation of B and T lymphocytes and monocytes/macrophages, coagulopathy, hypotension, and ARDS. Recently, neutrophil hyperactivation has been shown to also play a critical role in HLH development18,19. This is in agreement with the observation that the HLH-like phenotype observed in severe COVID-19 patients is due to an innate neutrophilic hyperinflammatory response associated with available under aCC-BY-NC-ND 4.0 International license. (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.

It is made bioRxiv preprint doi: ttps://; this version posted August 1, 2021. The copyright holder for this preprint
virus-induced hypercytokinaemia which is dominant in patients with an unfavorable clinical course17 . Thus, HLH has been proposed as an underlying etiologic factor of severe COVID191,3,20. HLH usually develops during the acute phase of COVID-191,20–27 . However, a case of HLH that occurred two weeks after recovery from COVID-19 has recently been reported as the cause
of death during post-acute COVID-19 syndrome28
The familial form of HLH (fHLH) is caused by inborn errors of immunity (IEI) in different genes encoding proteins involved in granule-dependent cytotoxic activity of leukocytes such as AP3B1, LYST, PRF1, RAB27A, STXBP2, STX11, UNC13D29–31. In contrast, the secondary form (sHLH) usually manifests in adults following a viral infection (e.g., adenovirus, EBV, enterovirus, hepatitis viruses, parvovirus B19, and HIV)32,33, or in association with autoimmune /rheumatologic, malignant, or metabolic conditions that lead to defects in T/NK cell functions and excessive inflammation16,31. fHLH and sHLH affect both children and adults, however, the clinical and genetic distinction of HLH forms is not clear since immunocompetent children can develop sHLH 34,35, while adult patients with sHLH may also have germline mutations in HLH genes36. Of note, germline variants in UNC13D and AP3B1 have also been
identified in some COVID-19 patients with HLH phenotype37, thus, indicating that both HLH forms may be associated with COVID-19.

Here, we characterized the signaling pathways and gene signatures commonly dysregulated in both COVID-19 and HLH patients by investigating the transcriptomes of 1253 subjects (controls, COVID-19, and HLH patients) assessed by microarray, bulk RNA-sequencing (RNAseq), and single-cell RNAseq (scRNAseq) (Table 1). We found shared gene signatures and cellular signaling pathways involved in cytokine and chemokine signaling as well as neutrophilmediated immune responses that associate with COVID-19 severity.

For More Information:

Pathophysiology of acute respiratory syndrome coronavirus 2 infection: a systematic literature review to inform EULAR points to consider

Authors: Aurélie Najm1 Alunno2, Xavier Mariette3,4 Terrier5,6 De Marco7,8, Jenny Emmel9, Laura Mason9, Dennis G McGonagle7,10 and M Machado11,12,13


Background The SARS-CoV-2 pandemic is a global health problem. Beside the specific pathogenic effect of SARS-CoV-2, incompletely understood deleterious and aberrant host immune responses play critical roles in severe disease. Our objective was to summarise the available information on the pathophysiology of COVID-19.

Methods Two reviewers independently identified eligible studies according to the following PICO framework: P (population): patients with SARS-CoV-2 infection; I (intervention): any intervention/no intervention; C (comparator): any comparator; O (outcome) any clinical or serological outcome including but not limited to immune cell phenotype and function and serum cytokine concentration.

Results Of the 55 496 records yielded, 84 articles were eligible for inclusion according to question-specific research criteria. Proinflammatory cytokine expression, including interleukin-6 (IL-6), was increased, especially in severe COVID-19, although not as high as other states with severe systemic inflammation. The myeloid and lymphoid compartments were differentially affected by SARS-CoV-2 infection depending on disease phenotype. Failure to maintain high interferon (IFN) levels was characteristic of severe forms of COVID-19 and could be related to loss-of-function mutations in the IFN pathway and/or the presence of anti-IFN antibodies. Antibody response to SARS-CoV-2 infection showed a high variability across individuals and disease spectrum. Multiparametric algorithms showed variable diagnostic performances in predicting survival, hospitalisation, disease progression or severity, and mortality.

Conclusions SARS-CoV-2 infection affects both humoral and cellular immunity depending on both disease severity and individual parameters. This systematic literature review informed the EULAR ‘points to consider’ on COVID-19 pathophysiology and immunomodulatory therapies.

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See:

For More Information:

Complement Anaphylatoxins and Inflammatory Cytokines as Prognostic Markers for COVID-19 Severity and In-Hospital Mortality

Authors: Bandar Alosaimi1,2Ayman Mubarak3, Maaweya E. Hamed3Abdullah Z. Almutairi4Ahmed A. Alrashed5, Abdullah AlJuryyan6, Mushira Enani7,Faris Q. Alenzi8 and Wael Alturaiki9*

COVID-19 severity due to innate immunity dysregulation accounts for prolonged hospitalization, critical complications, and mortality. Severe SARS-CoV-2 infections involve the complement pathway activation for cytokine storm development. Nevertheless, the role of complement in COVID-19 immunopathology, complement‐modulating treatment strategies against COVID-19, and the complement and SARS‐CoV‐2 interaction with clinical disease outcomes remain elusive. This study investigated the potential changes in complement signaling, and the associated inflammatory mediators, in mild-to-critical COVID-19 patients and their clinical outcomes. A total of 53 patients infected with SARS-CoV-2 were enrolled in the study (26 critical and 27 mild cases), and additional 18 healthy control patients were also included. Complement proteins and inflammatory cytokines and chemokines were measured in the sera of patients with COVID-19 as well as healthy controls by specific enzyme-linked immunosorbent assay. C3a, C5a, and factor P (properdin), as well as interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor (TNF)-α, and IgM antibody levels, were higher in critical COVID-19 patients compared to mild COVID-19 patients. Additionally, compared to the mild COVID-19 patients, factor I and C4-BP levels were significantly decreased in the critical COVID-19 patients. Meanwhile, RANTES levels were significantly higher in the mild patients compared to critical patients. Furthermore, the critical COVID-19 intra-group analysis showed significantly higher C5a, C3a, and factor P levels in the critical COVID-19 non-survival group than in the survival group. Additionally, IL-1β, IL-6, and IL-8 were significantly upregulated in the critical COVID-19 non-survival group compared to the survival group. Finally, C5a, C3a, factor P, and serum IL-1β, IL-6, and IL-8 levels positively correlated with critical COVID-19 in-hospital deaths. These findings highlight the potential prognostic utility of the complement system for predicting COVID-19 severity and mortality while suggesting that complement anaphylatoxins and inflammatory cytokines are potential treatment targets against COVID-19.

For More Information:

Endothelial dysfunction contributes to COVID-19-associated vascular inflammation and coagulopathy

Authors: Jun Zhang 1Kristen M Tecson 1Peter A McCullough 1 2 3

Great attention has been paid to endothelial dysfunction (ED) in coronavirus disease 2019 (COVID-19). There is growing evidence to suggest that the angiotensin converting enzyme 2 receptor (ACE2 receptor) is expressed on endothelial cells (ECs) in the lung, heart, kidney, and intestine, particularly in systemic vessels (small and large arteries, veins, venules, and capillaries). Upon viral infection of ECs by severe acute respiratory syndrome coronarvirus 2 (SARS-CoV-2), ECs become activated and dysfunctional. As a result of endothelial activation and ED, the levels of pro-inflammatory cytokines (interleukin -1, interleukin-6 (IL-6), and tumor necrosis factor-α), chemokines (monocyte chemoattractant protein-1), von Willebrand factor (vWF) antigen, vWF activity, and factor VIII are elevated. Higher levels of acute phase reactants (IL-6, C-reactive protein, and D-dimer) are also associated with SARS-CoV-2 infection. Therefore, it is reasonable to assume that ED contributes to COVID-19-associated vascular inflammation, particularly endotheliitis, in the lung, heart, and kidney, as well as COVID-19-associated coagulopathy, particularly pulmonary fibrinous microthrombi in the alveolar capillaries. Here we present an update on ED-relevant vasculopathy in COVID-19. Further research for ED in COVID-19 patients is warranted to understand therapeutic opportunities.

For More Information:

Cytokine Storm in COVID-19: The Current Evidence and Treatment Strategies

Authors: Yujun Tang, Jiajia Liu, Dingyi ZhangZhenghao XuJinjun Ji,* and Chengping Wen*

Severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) is the pathogen that causes coronavirus disease 2019 (COVID-19). As of 25 May 2020, the outbreak of COVID-19 has caused 347,192 deaths around the world. The current evidence showed that severely ill patients tend to have a high concentration of pro-inflammatory cytokines, such as interleukin (IL)-6, compared to those who are moderately ill. The high level of cytokines also indicates a poor prognosis in COVID-19. Besides, excessive infiltration of pro-inflammatory cells, mainly involving macrophages and T-helper 17 cells, has been found in lung tissues of patients with COVID-19 by postmortem examination. Recently, increasing studies indicate that the “cytokine storm” may contribute to the mortality of COVID-19. Here, we summarize the clinical and pathologic features of the cytokine storm in COVID-19. Our review shows that SARS-Cov-2 selectively induces a high level of IL-6 and results in the exhaustion of lymphocytes. The current evidence indicates that tocilizumab, an IL-6 inhibitor, is relatively effective and safe. Besides, corticosteroids, programmed cell death protein (PD)-1/PD-L1 checkpoint inhibition, cytokine-adsorption devices, intravenous immunoglobulin, and antimalarial agents could be potentially useful and reliable approaches to counteract cytokine storm in COVID-19 patients.

For More Information:

SARS-CoV-2 infection: The role of cytokines in COVID-19 disease

Authors: Víctor J Costela-Ruiz 1Rebeca Illescas-Montes 1Jose M Puerta-Puerta 2Concepción Ruiz 3Lucia Melguizo-Rodríguez 1

COVID-19 disease, caused by infection with SARS-CoV-2, is related to a series of physiopathological mechanisms that mobilize a wide variety of biomolecules, mainly immunological in nature. In the most severe cases, the prognosis can be markedly worsened by the hyperproduction of mainly proinflammatory cytokines, such as IL-1, IL-6, IL-12, IFN-γ, and TNF-α, preferentially targeting lung tissue. This study reviews published data on alterations in the expression of different cytokines in patients with COVID-19 who require admission to an intensive care unit. Data on the implication of cytokines in this disease and their effect on outcomes will support the design of more effective approaches to the management of COVID-19.

For More Information:

Accumulating evidence suggests anti-TNF therapy needs to be given trial priority in COVID-19 treatment

Authors: Philip C Robinson, Duncan Richards, Helen L Tanner, Marc Feldmann

The COVID-19 pandemic continues to wreak havoc on global health-care systems and to claim an increasing number of lives. Although some treatments have shown promise, including dexamethasone and remdesivir, problems remain with access to medication and high mortality despite treatment. Patient selection also appears to be critical, with some patient groups benefitting from treatment, but not others. One potential treatment that deserves higher priority in COVID-19 trials, based on the documented evidence of its effects, is the biological agent anti-TNF.Feldmann and colleagues1 described the rationale for trialling anti-TNF therapies in COVID-19. These therapies neutralise TNF, a major component of the cytokine response that is part of the damaging excess inflammatory phase of COVID-19, which is termed hyperinflammation or cytokine release syndrome. This hyperinflammatory response in COVID-19 is characterised by elevated concentrations of serum TNF, interleukin (IL)-6, and IL-8, but relatively little IL-1.2 However, IL-1 has a short serum half-life, and mononuclear transcriptome data show that genes and pathways upregulated by TNF, IL-1β, and type I interferon predominate.3 A major component of deteriorating lung function in patients with COVID-19 is capillary leak, a result of inflammation driven by key inflammatory cytokines: TNF, IL-1, IL-6, and vascular endothelial growth factor. Administration of anti-TNF to patients for treatment of autoimmune disease leads to reductions in all of these key inflammatory cytokines.45 It is therefore conceivable that anti-TNF therapy could reduce inflammation-driven capillary leak in COVID-19 and have a major impact on the need for ventilation and mortality.

For More Information: