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The SARS-CoV-2 pandemic has already infected in excess of 50 million people worldwide and resulted in 1.2 million deaths. While the majority of those infected will not have long-term pulmonary sequelae, 5%-10% will develop severe COVID-19 pneumonia and acute respiratory distress syndrome (ARDS). The natural history of these severely affected patients is unclear at present, but using our knowledge of closely related coronavirus outbreaks like severe acute respiratory distress syndrome (SARS) and middle east respiratory syndrome (MERS), we would hypothesize that the majority will stabilize or improve over time although some patients will progress to advanced lung fibrosis or post-COVID interstitial lung disease (PC-ILD). Unlike the SARS and MERS outbreaks which affected only a few thousands, the sheer scale of the present pandemic suggests that physicians are likely to encounter large numbers of patients (potentially hundreds of thousands) with PC-ILD. In this review, we discuss the pathogenesis, natural history, and radiology of such patients and touch on clinical, laboratory, and radiographic clues at presentation which might help predict the future development of lung fibrosis. Finally, we discuss the responsible use of antifibrotic drugs such as pirfenidone, nintedanib, and some newer antifibrotics, still in the pipeline. The biological rationale of these drugs and the patient groups where they may have a plausible role will be discussed. We conclude by stressing the importance of careful longitudinal follow-up of multiple cohorts of post-COVID survivors with serial lung function and imaging. This will eventually help to determine the natural history, course, and response to therapy of these patients.

ABSTRACT Background: One of the most dreaded complications of COVID pneumonia is post-COVID residual lung fibrosis and lung function impairment. Objectives: To find out the extent and type of pulmonary function abnormality using spirometry, diffusion capacity, and 6-minute walk test and to co-relate with the clinical severity at the time of infection, in patients who have recovered from COVID19 pneumonia, in a tertiary care hospital in India. Materials and Methods: This is a prospective, cross-sectional study with a total 100 patients. Patients who have recovered from COVID pneumonia after one month of onset of symptoms and before 3 months who come for follow-up and have respiratory complaints undergo pulmonary function test will be recruited in the study. Results: In our study, the most common lung function abnormality detected was restrictive pattern in 55% of the patients (N = 55) followed by mixed pattern in 9% of patients (N = 9), obstructive in 5% of patients (N = 5), and normal in 31% of patients (N = 31). In our study, total lung capacity was reduced in 62% of the patients and normal in 38% of the patients and diffusion capacity of lung was reduced in 52% of the patients recovered from 52% of the individuals. Also, a 6-minute walk test was reduced in 15% of the patients and normal in 85% of the patients. Conclusion: Pulmonary function test can serve as an important tool in both diagnosis and follow-up of post-COVID lung fibrosis and pulmonary sequalae.

Post-COVID syndrome or long COVID is defined as the persistence of symptoms after confirmed SARS-CoV-2 infection, the pathogen responsible for coronavirus disease. The content herein presented reviews the reported long-term consequences and aftereffects of COVID-19 infection and the potential strategies to adopt for their management. Recent studies have shown that severe forms of COVID-19 can progress into acute respiratory distress syndrome (ARDS), a predisposing factor of pulmonary fibrosis that can irreversibly compromise respiratory function. Considering that the most serious complications are observed in the airways, the inhalation delivery of drugs directly to the lungs should be preferred, since it allows to lower the dose and systemic side effects. Although further studies are needed to optimize these techniques, recent studies have also shown the importance of in vitro models to recreate the SARS-CoV-2 infection and study its sequelae. The information reported suggests the necessity to develop new inhalation therapies in order to improve the quality of life of patients who suffer from this condition.

With the increasing cohort of COVID-19 survivors worldwide, we now realize the proportionate rise in post-COVID-19 syndrome. In this review article, we try to define, summarize, and classify this syndrome systematically. This would help clinicians to identify and manage this condition more efficiently. We propose a tool kit that might be useful in recording follow-up data of COVID-19 survivors.

In coronavirus disease 2019 (COVID-19) patients, dysregulated release of matrix metalloproteinases occurs during the inflammatory phase of acute respiratory distress syndrome (ARDS), resulting in epithelial and endothelial injury with excessive fibroproliferation. COVID-19 resembles idiopathic pulmonary fibrosis (IPF) in several aspects. The fibrotic response in IPF is driven primarily by an abnormally activated alveolar epithelial cells (AECs) which release cytokines to activate fibroblasts. Endoplasmic reticulum (ER) stress is postulated to be one of the early triggers in both diseases. Systemic sclerosis (SSc) is a heterogeneous autoimmune rare connective tissue characterised by fibrosis of the skin and internal organs. Interstitial lung disease (ILD) is a common complication and the leading cause of SSc-related death. Several corollaries have been discussed in this paper for new drug development based on the pathogenic events in these three disorders associated with pulmonary fibrosis. A careful consideration of the similarities and differences in the pathogenic events associated with the development of lung fibrosis in post-COVID patients, IPF patients and patients with SSc-ILD may pave the way for precision medicine. Several questions need to be answered through research, which include the potential role of antifibrotics in managing IPF, SSc-ILD and post-COVID fibrosis. Many trials that are underway will ultimately shed light on their potency and place in therapy.

One of the common long-term consequences observed in survivors of COVID-19 pneumonia is the persistence of respiratory symptoms and/or radiological lung abnormalities. The exact prevalence of these post-COVID pulmonary changes is yet unclear. Few authors, based on their early observations, have labeled these persistent computed tomography (CT) abnormalities as post-COVID lung fibrosis, which appears to be an overstatement. Lately, it is being observed that many of the changes seen in post-COVID lungs are temporary and tend to show resolution on follow-up, with only a few developing into lung fibrosis. Thus, based on the presumptive diagnosis of lung fibrosis, these patients should not be blindly started on anti-fibrotic drugs. One must not forget that these drugs can do more harm than good, if used injudiciously. It is better to use the term \"post-COVID interstitial lung changes\", which covers a broader spectrum of pulmonary changes seen in patients who have recovered from COVID-19 pneumonia. At the same time, it is essential to identify the sub-set of COVID-19 survivors who are at an increased risk of developing lung fibrosis and to carefully chalk out management strategies so as to modify the course of the disease and prevent irreversible damage. Meticulous and systematic longitudinal follow-up studies consisting of clinical, laboratory, imaging, and pulmonary function tests are needed for the exact estimation of the burden of lung fibrosis, to understand the nature of residual pulmonary changes, and to predict the likelihood of development of lung fibrosis in COVID-19 survivors.

Introduction: Radiological phenotypes are radiological patterns or observable characteristics of COVID-19 pneumonia. Various phenotypic classifications have been reported in literature. CT severity radiological phenotypes are widely used and universally accepted radiological phenotypic methods. Robust data is available regarding role of HRCT in COVID-19 pneumonia and we have evaluated role of CT severity in assessing natural course of COVID-19 illness during its evolution sand follow-up. Methods: Prospective, Observational study, included 3000 COVID-19 RT-PCR confirmed cases with lung involvement documented and radiological severity phenotypes categorized on HRCT thorax as mild, moderate and severe as per lung segment involvement bilaterally (scoring tool 0-25 score, mild 1-7, moderate 8-15 and severe 16-25). Radiological CT severity phenotypes were   evaluated in correlation with interventions such as oxygen support and oxygen plus ventilatory support requirement during hospitalization. Age, gender, Comorbidity, laboratory parameters and use of BIPAP/NIV in COVID-19 cases and outcome as with or without lung fibrosis were key observations. Final radiological outcome documented in follow up CT thorax imaging done at six months of discharge from hospital. Statistical analysis is done by using Chi square test.  Results: In study of 3000 cases, ‘mild, moderate and severe’ radiological CT severity phenotypes were documented as 13.33%, 48.33% & 38.34 % respectively. CT severity has documented significant association with duration of illness at entry point [p<0.00001] Duration of illness (<7 days, 7-14 days and >14 days) plays a crucial role in predicting radiological CT severity phenotypes. CT severity has documented significant association with laboratory parameters at entry point (d-dimer, CRP, IL-6) [p<0.00001] and interventions required in indoor unit. [p<0.00001] Post COVID-19 lung fibrosis or sequelae has significant association with radiological CT severity phenotypes. [p<0.00001] Covariates such as age, gender, diabetes mellitus, IHD, Hypertension, COPD, Obesity has significant association with radiological CT severity phenotypes. [p<0.00001] Conclusion: Radiological CT severity phenotypic differentiation has documented very crucial role in initial assessment and during triaging of these cases in indoor and outdoor setting. Although CT severity is best predictor of severity it has showed ‘inconstancy’ in predicting disease severity, targeting interventions and predicting early and long-term outcomes in COVID-19 pneumonia. J MEDICINE 2024; 25: 46-57

Key Clinical Message This case illustrates sarcoidosis as a potential complication of COVID‐19, highlighting the need for a comprehensive diagnostic approach, including histopathology and prolonged monitoring, to distinguish it from post‐COVID fibrosis. Further research is crucial to elucidate these associations and understand their underlying mechanisms. Severe Acute Respiratory Syndrome Coronavirus‐ 2 (SARS‐CoV‐2), a positive‐sense single‐stranded RNA virus, causes COVID‐19 and has been linked to autoimmune disorders. Sarcoidosis is a multi‐system disease that is frequently triggered by infections. It is characterized by non‐necrotizing granulomas in multiple organs. We present a case of sarcoidosis as rare sequelae of COVID‐19. A 26‐year‐old man presented with mild COVID‐19 symptoms, followed by prolonged fever and cough despite initial therapy, prompting a provisional diagnosis of post‐COVID fibrosis. A subsequent assessment at a tertiary hospital revealed dyspnea, weight loss, and abnormal chest imaging, all of which were consistent with pulmonary sarcoidosis with pulmonary tuberculosis as a differential diagnosis. A biopsy taken during bronchoscopy confirmed pulmonary sarcoidosis and treatment with inhalation steroids resulted in symptom relief, which was followed by remission with oral steroid therapy. Sarcoidosis is a systemic disease of unknown etiology, characterized by non‐necrotizing granulomas in multiple organs. It may be triggered by infections and involves an abnormal immune response. COVID‐19 can potentially initiate sarcoidosis, with both sharing common immune mechanisms. Diagnosis involves imaging and biopsy, and treatment typically includes glucocorticoids and regular monitoring. This case report emphasizes the potential link between COVID‐19 and autoimmune conditions like sarcoidosis, highlighting the need for a comprehensive diagnostic approach and long‐term observation to distinguish between sarcoidosis and post‐COVID fibrosis. Transverse section of contrast‐enhanced Computed Tomography (CT) of the chest revealing mild enhancement at the region of the nodule and consolidation.

Coronavirus-19 emerged about 3 years ago and has proven to be a devastating disease, crippling communities worldwide and accounting for more than 6.31 million deaths. The true disease burden of COVID-19 will come to light in the upcoming years as we care for COVID-19 survivors with post-COVID-19 syndrome (PCS) with residual long-term symptoms affecting every organ system. Pulmonary fibrosis is the most severe long-term pulmonary manifestation of PCS, and due to the high incidence of COVID-19 infection rates, PCS-pulmonary fibrosis has the potential of becoming the next large-scale respiratory health crisis. To confront the potentially devastating effects of emerging post-COVID-19 pulmonary fibrosis, dedicated research efforts are needed to focus on surveillance, understanding pathophysiologic mechanisms, and most importantly, an algorithmic approach to managing these patients. We have performed a thorough literature review on post-COVID-19 pulmonary symptoms/imaging/physiology and present an algorithmic approach to these patients based on the best available data and extensive clinical experience.

Introduction: Pulmonary fibrosis is an irreversible condition that may be caused by known (including viral triggers such as SARS-CoV-2) and unknown insults. The latter group includes idiopathic pulmonary fibrosis (IPF), which is a chronic, progressive fibrosing interstitial pneumonia of unknown cause. The longer the insult acts on lung tissue, the lower the probability of a complete resolution of the damage. An emerging clinical entity post-COVID-19 is pulmonary fibrosis (PCPF), which shares many pathological, clinical, and immunological features with IPF. The fibrotic response in both diseases—IPF and PCPF—is orchestrated in part by the immune system. An important role regarding the inhibitory or stimulatory effects on immune responses is exerted by the immune checkpoints (ICs). The aim of the present study was to analyse the similarities and differences between CD4+, CD8+, and NK cells in the peripheral blood of patients affected by fibrotic disease, IPF, and PCPF compared with sarcoidosis patients and healthy controls. The second aim was to evaluate the expression and co-expression of PD-1 and TIGIT on CD4, CD8, and NK cells from our patient cohort. Methods: One hundred and fifteen patients affected by IPF, PCPF, and sarcoidosis at the rare pulmonary disease centre of the University of Siena were enrolled. Forty-eight patients had an IPF diagnosis, 55 had PCPF, and 12 had sarcoidosis. Further, ten healthy controls were enrolled. PCPF patients were included between 6 and 9 months following hospital discharge for COVID-19. The peripheral blood samples were collected, and through flow cytometric analysis, we analysed the expression of CD4, CD8, NK cells, PD-1, and TIGIT. Results: The results show a greater depletion of CD4 and NK cells in IPF patients compared to other groups (p = 0.003), in contrast with CD8 cells (p < 001). Correlation analysis demonstrated an indirect correlation between CD4 and CD8 cells in IPF and sarcoidosis patients (p < 0.001 = −0.87 and p = 0.042; r = −0.6, respectively). Conversely, PCPF patients revealed a direct correlation between CD4 and CD8 cells (p < 0.001; r = 0.90) accentuating an immune response restoration. The expression of PD-1 and TIGIT was abundant on T and NK cell subsets of the two lung fibrotic groups, IPF and PCPF. Analogously, the co-expression of PD-1 and TIGIT on the surfaces of CD4 and CD8 were increased in such diseases. Conclusions: Our study shines a spotlight on the immune responses involved in the development of pulmonary fibrosis, idiopathic and secondary to SARS-CoV-2 infection. We observed a significant imbalance not only in CD4, CD8, and NK blood percentages in IPF and PCPF patients but also in their functional phenotypes evaluated through the expression of ICs.