As a result of the novel coronavirus disease 2019 (COVID-19), there have been widespread changes in healthcare access. We conducted a retrospective population-based study in Alberta, Canada (population 4.4 million), where there have been approximately 1550 hospital admissions for COVID-19, to determine the impact of COVID-19 on hospital admissions and emergency department (ED visits), following initiation of a public health emergency act on March 15, 2020.We used multivariable negative binomial regression models to compare daily numbers of medical/surgical hospital admissions via the ED between March 16-September 23, 2019 (pre COVID-19) and March 16-September 23, 2020 . We compared the most frequent diagnoses for hospital admissions pre/post COVID-19 public health measures. A similar analysis was completed for numbers of daily ED visits for any reason with a particular focus on ambulatory care sensitive conditions (ACSC).There was a significant reduction in both daily medical (incident rate ratio (IRR) 0.86, p<0.001) and surgical  admissions through the ED in Alberta post COVID-19 public health measures. There was a significant decline in daily ED visits  including ACSC . The most common medical/surgical diagnoses for hospital admissions did not vary substantially pre and post COVID-19 public health measures, though there was a significant reduction in admissions for chronic obstructive pulmonary disease and a significant increase in admissions for mental and behavioral disorders due to use of alcohol.Despite a relatively low volume of COVID-19 hospital admissions in Alberta, there was an extensive impact on our healthcare system with fewer admissions to hospital and ED visits. This work generates hypotheses around causes for reduced hospital admissions and ED visits which warrant further investigation. As most publicly funded health systems struggle with health-system capacity routinely, understanding how these reductions can be safely sustained will be critical. Extensive changes to healthcare systems have been seen globally since the beginning of the coronavirus disease 2019 (COVID-19) outbreak and subsequent pandemic. What initially began as an outbreak of pneumonia cases in Wuhan, China in December 2019 quickly spread from country to country with the first North American case in the United States (US) in January 2020 [In addition to a shift to virtual healthcare, COVID-19 also influenced hospital admissions and visits unrelated to COVID-19 itself. There is emerging evidence from other countries that there are variations in healthcare utilization patterns due to COVID-19. For example, studies from both Spain and Italy have shown a reduction in admissions and procedures related to myocardial infarction and acute coronary syndrome , 4. A reAlberta is a Canadian province with a population of approximately 4.4 million people that is serviced by one health care system for hospital and specialty care–Alberta Health Services (AHS). As of November 16, 2020, Alberta has had approximately 1550 cases of COVID-19 requiring hospitalization over the past several months, and a total of approximately 36405 cases. In Alberta, a state of public health emergency due to COVID-19 was declared under the public health act on March 15, 2020. Elective surgeries were postponed, and in-person healthcare visits were discouraged except where urgent. The public health emergency act expired on June 15, 2020 and elective surgeries commenced again. However, given that COVID-19 is a fluctuating circumstance, many elective surgeries have continued to be delayed as COVID-19 cases increase and virtual care remains a large component for many outpatient practices. Despite these reductions in outpatient service and elective surgeries, patients would presumably still require inpatient management for their acute and chronic medical conditions requiring admission through the ED, and the impact of the emergency measures on overall hospital use is uncertain. Moreover, if outpatient health care access was adversely impacted, an increase in ED visits for ambulatory care sensitive conditions (ACSC) would be expected .In order to better understand the impact of changes associated with the COVID-19 pandemic on overall hospital use and patient safety, we conducted a population-based study to determine the impact on hospital and ED visits, assess markers of patient safety, and explore changes in diagnoses contributing to hospitalizations.In order to examine daily hospital admissions and ED visits, we used a retrospective population-based design examining the adult (≥18 years) population of Alberta, Canada prior to the COVID-19 pandemic , until the COVID-19 pandemic started and the public health emergency act was implemented –March 16 to September 23, 2020. We included data from January 1, 2019-March 15, 2020 to account for any seasonal variation that may have occurred in ED visits and hospital admission rates. At the time of this study, data was only available until September 23, 2020.AHS analytics provided the numbers of daily hospital admissions from the Discharge Abstract Database (DAD), which includes all inpatient encounters within the province and provides detailed information on discharges, clinical information, diagnoses and procedures . We obta10threvision (ICD-10) codes which represent the diagnosis resulting in the most hospital resources consumed and/or largest contributor to hospital length of stay.The National Ambulatory Care Reporting System (NACRS) was utilized to explore rates of visits to the ED (which may or may not have resulted in admission). The most responsible diagnosis for admissions and visits extracted from DAD and NACRS were identified by International Statistical Classification of Diseases and Related Health Problems– Patient characteristics and demographics pre and post COVID-19 public health measures were compared using the student’s t-test, stratified by medical and surgical hospital admissions. Patient characteristics included length of stay (LOS), in-hospital mortality, medical complexity as defined by the Charlson comorbidity index .The primary outcome of this study was changes in number of hospital admissions and ED visits pre and post COVID-19. Changes in numbers of hospital admissions, for any reason including COVID-19, were compared pre and post COVID-19 using multivariable negative binomial regression models controlling for age, sex, Charlson comorbidity index and seasonality. This modeling approach was used to account for overdispersion observed within the hospitalization data. Two different models were conducted. The first explored the outcome of hospital admissions per day (reported as an incident rate ratio (IRR) with corresponding 95% confidence intervals (CI)) comparing the time period of March 16-September 23, 2019 to March 16-September 23, 2020. The second explored the same outcome but expanded the pre COVID-19 timeframe  versus March 16-September 23, 2020 in order to account for seasonality. All models were also stratified by medical versus surgical admissions. A sensitivity analysis utilizing an interrupted time series approach  was usedThe number of ED visits per day for any reason were calculated and compared between March 16-September 23, 2019 and March16-September 23, 2020. Rates of Ambulatory Care Sensitive Conditions (ACSC) were also explored using the Canadian Institute for Health Information ACSC indicator algorithm . This inThe top 10 most responsible diagnoses from March 16-September 23, 2019 for both surgical and medical admissions were compared to the top 10 most responsible diagnoses from March 16-September 23, 2020. A student’s t-test was used to determine if there were significant changes in the frequency of any of these diagnoses between the two time periods.Significance for all tests was determined as a p-value <0.05. All analyses were performed using Stata 16 .This research was approved by the University of Calgary Health Research Ethics Board (REB 20–0805). Informed consent for this study was waived by the ethics board.The characteristics of patients admitted to hospital in Alberta pre and post COVID-19 public health measures are reported in The number of medical and surgical admissions decreased significantly after implementation of public health measures March 16, 2020 Figs  demonstrThe interrupted time series analysis corroborated the findings of the negative binomial multivariable regression and demonstrated a reduction of approximately 11 surgical admissions per day  and 69 medical admissions per day  via the ED. This translates into a reduction of approximately 20% of admissions per day via the ED.The number of ED visits for any reason decreased significantly post COVID-19 public health measures  . The numThe top most responsible diagnoses for hospital admissions post COVID-19 public health measures  were very similar to top diagnoses pre COVID-19  which is demonstrated in Our work demonstrated a significant reduction in both daily medical and surgical hospital admissions following the period of COVID-19 . There was also a significant decline in visits to the ED for any reason as well as for ACSC specifically. The overall ten most common medical and surgical diagnoses for hospital admissions did not substantially change prior to COVID-19 and post COVID-19 public health measures. The proportion of total admissions accounted for by certain medical conditions did change, with COPD being significantly reduced but mental and behavioral disorders due to use of alcohol, and acute pancreatitis , significantly increased. Surgical admissions were generally not significantly reduced though certain surgical admissions such as cholecystitis and forearm fracture significantly increased.We determined that post COVID-19 public health measures there was a statistically significant decrease in the medical complexity of admitted patients (as defined by the Charlson Comorbidity Index). However, the change in the Charlson Comorbidity Index was small for both medical and surgical admissions and is unlikely to reflect a substantial difference clinically in patient comorbidities. Hospital LOS did decrease by approximately two days for both medical and surgical admissions, which is expected given pressure to reduce LOS in order to reduce patient exposure to COVID-19 in the hospital and retain bed capacity. The RIW decreased post COVID-19 public health measures which may reflect fewer tests and procedures being done given restricted access. Since we did not observe an increase in hospitalizations during the study period, the shorter LOS and fewer tests may have been appropriate, though longer-term analyses are required.There have been an increasing number of publications available globally on changes in overall admissions due to health system changes required due to the COVID-19 pandemic , 6. OtheAnother study also examining volume of visits to the ED found a significant reduction once the COVID-19 pandemic began . They foIn Alberta, we observed substantial reductions in hospital admissions through the emergency department for both medical and surgical issues. While the top diagnoses seen in the ED were similar both pre and post COVID-19, there were significantly fewer medical admissions during COVID-19 for exacerbation of COPD and pneumonia of unspecified organism specifically. It is possible that enhanced personal hygiene practices and social distancing resulted in fewer viral respiratory infections, which are a known trigger for such medical conditions , 15. AltOur work did demonstrate an increase in medical admissions due to mental and behavioral disorders due to use of alcohol and pancreatitis which can be triggered by alcohol consumption. A recent survey study demonstrated that there was an increase in adult alcohol consumption during the COVID-19 pandemic . AlcoholOther potential explanations for the overall reduction in admissions, include the emotional toll of COVID-19 and the fear associated with it, and with seeking medical care , 18, andOur work has several strengths. As mentioned above, previous studies have explored the impact of COVID-19 on certain types of admissions such as cardiac , 4, or iOur study should be interpreted considering its limitations. Data were only available for March to September 2020, and we are currently not able to assess long-term impacts on the healthcare system due to COVID-19. It is possible that moving forward admission rates will increase and there will be negative outcomes from a lack of earlier interventions and medical care. In fact, it can be seen from Figs Our work demonstrated that in a population that has relatively few cases of COVID-19 compared to other jurisdictions globally , there wS1 Table(DOCX)Click here for additional data file.


Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected millions of people worlwide and caused a pandemic that is still ongoing. The virus can cause a disease named as COVID-19, which is composed of multi systemic manifestations with a pulmonary system predominance. As the time passes, we are dealing more and more with a wide variety of effects and complications of the disease in survivors as far as with concerns about the clinical outcome and the timeline of symptoms in different patients. Since the lungs are the most involved organs and the post-COVID prolonged and persistent effects are mainly related to the pulmonary system, it is crucial to define and predict the outcome and to determine the individuals that can progress to fibrosis and loss of function of lungs. This review summarizes the current literature regarding the pulmonary complications in post-COVID syndrome and the management of these conditions. Our learning process about the COVID-19 disease, first observed in Wuhan city of Hubei province of China since the beginning of December 2019 and announced to the world by the WHO China Office on 31 December 2019 and whose agent was identified on 7 January 2021, still continues. The long-term effects and complications are better understood day by day. After being discharged from the hospital, some symptoms such as cough, exertional dyspnea, muscle aches, and fatigue are observed, sometimes lasting for months, especially in some of the patients who have experienced severe COVID-19. Chronic respiratory failure and permanent lung fibrosis may develop in patients who have been intubated with acute respiratory distress syndrome (ARDS) and received invasive mechanical ventilation (IMV) therapy. Non-pulmonary systemic conditions such as diabetes mellitus, neuromuscular problems, and cardiac pathologies are also experienced. In this article, in the light of current literature, long-term follow-up of COVID-19 patients and the management of the problems observed in this process will be reviewed in terms of post-COVID pulmonary complications. Currently, the best known and most common post-COVID syndrome (PCS) is pulmonary involvement. In this section, this important issue will be reviewed and discussed into six subsections, namely, post-COVID periods and characteristics, post-COVID syndrome definition pathogenesis from postacute COVID to organ dysfunction, postconcussion symptoms (PCS) clinical features, multisystem inflammatory syndrome in adults (MIS-A), and lung complications management in PCS.Siddiqi HK et al. proposed a 3-stage grading system for the symptomatic disease of COVID-19 including the increasing severity corresponding to different clinical manifestations, response to treatment, and clinical course [1]. Accordingly, the first stage (mild/early infection) is characterized by mild nonspecific symptoms such as fever, malaise and dry cough following infection and incubation. The virus replicates mainly focused on the respiratory system. At this stage, symptomatic treatment is essential. Trial treatments with some antivirals have been applied to prevent progression, reduce transmission, and accelerate recovery. Most patients recover in this stage [1].The second stage  is characterized by viral pneumonia. The virus continues to replicate and settles in the lungs. Fever, cough, hypoxia, radiological infiltrates, lymphopenia, and acute inflammatory markers are elevated. Most patients at this stage require hospitalization and treatment. Antivirals are used for trial purposes. In the absence of hypoxia (Stage IIa), corticosteroid use should be avoided. When hypoxia develops (Stage IIb), corticosteroid and oxygen therapies are provided [1].Extrapulmonary systemic hyperinflammation is observed in the third stage (severe/systemic hyperinflammation stage) in a small number of patients. IL-2, IL-6, IL-7, GCSF, macrophage inflammatory protein 1-alpha, TNF-alpha, CRP, ferritin, D-dimer are increased. Troponin and pro-BNP may also be elevated. Shock, vasoplegia, respiratory failure, cardiopulmonary collapse may develop. Systemic involvements such as myocarditis may occur. At this stage, immunomodulatory treatments  or anakinra (IL-1 receptor antagonist), intravenous immune globulin) are used to suppress systemic inflammation and prevent multiorgan failure that may develop afterwards [1].Patients become symptomatic 2–14 days after exposure (mean time: day 5). It usually gets better in 7–10 days or it starts to get worse 7 days after the onset of symptoms, often at day 9–10. Intensive care unit (ICU) support may be required and death usually occurs 14–28 days after the onset of symptoms. In symptomatic, severe cases, symptoms may last up to 6 months after recovery. Permanent sequelae and pulmonary fibrosis may develop in patients who have been treated in the ICU, who have developed acute respiratory distress syndrome (ARDS) and who have undergone IMV. Poor prognostic factors reported in patients are as follows: advanced age, comorbidities, smoking, obesity, genetic predisposition, pregnancy, excessive increase in inflammatory markers, lymphopenia, and treatment-resistant hypoxemia [2–6].According to the definitions used in the NICE guideline that includes the acute and chronic stages of the disease, the symptoms are listed below: Acute COVID-19: Presence of signs and symptoms of COVID-19 from onset to 4 weeks. Ongoing symptomatic COVID-19: Signs and symptoms of COVID-19 between 4 and 12 weeks. Post-COVID-19: Signs and symptoms lasting more than 12 weeks and not explained by an alternate diagnosis. Long COVID-19: Refers to the association of both ongoing and post-COVID-19 [7].When diagnosing post-COVID-19 the following criteria are taken into account: the patient’s symptoms that started in the acute period persist, worsen, recur, or new symptoms develop; worsening, loss of quality of life and functional status happens when compared to pre-COVID-19 and the presence of permanent or progressive radiological pathologies and abnormal laboratory findings in the lungs [8].However, there are many confounding situations that make the definition of post-COVID-19 difficult. It is not easy to define a timeline for acute and chronic symptoms. It is also difficult to distinguish between post-COVID-19 and the previously known post-intensive care , post-ARDS, post-mechanical ventilation  and post-intubation complications . In order to distinguish between previous comorbidities and the effects of COVID-19, it is necessary to know the patient’s pre-COVID-19 baseline status. It is important to distinguish if the clinical outcome is due to post-COVID-19 or post viral infection complications , or whether it is a post-secondary infection . Problems after corticosteroid use , osteoporosis, infections, adrenal suppression, etc.), post immunosuppression effects (anti-IL-6/1), post traumatic syndrome , post thrombotic , stroke), pulmonary embolism (PE), etc.), and post-ischemic  conditions should also be considered.In a study in the USA, it was shown that only 6.75% of COVID-19 patients returned to their previous health level 14–21 days after a positive test result [9]. Again, of the 233 cases of COVID-19 in the USA, most of which were mild and only 8 patients were hospitalized, 43.4% were shown to have symptoms lasting longer than 30 days, and 24.1% still had at least one symptom after 90 days. When compared to more severe COVID-19 cases, these rates were higher: 59.4% at 30 days and 40.6% at 90 days. In the acute period, complications persisted for 30 days or longer in 14.3% of even mild and asymptomatic cases [10]. It was revealed that 87.4% of COVID-19 patients in Italy still complained of at least one symptom 60 days after discharge [11]. Approximately 10%–20% of patients hospitalized with the diagnosis of COVID-19 required rehospitalization after discharge [12–13]. Of the 47,780 patients discharged from hospital after acute COVID-19 in the UK, who were followed-up at an average of 140 days, around a third of individuals were readmitted  and more than 1 in 10  died after discharge [14].Patients at high risk of long-term complications were treated in ICU or care units, received long-term high-flow oxygen therapy (HFO), non-invasive mechanical ventilation  and were discharged on oxygen therapy [15].The rationale behind the long-term follow-up of patients treated with a diagnosis of COVID-19 consists of identification and monitorization of the early, medium, and long-term respiratory complications; early detection and treatment of life-limiting complications such as pulmonary fibrosis and pulmonary vascular disease; assessment of patients’ dyspnea, oxygen requirement, provision of rehabilitation, palliative care, symptom management and psychosocial support; ensure radiological resolution of clinically recovered patients and identify and manage previous undiagnosed respiratory disease. This detailed evaluation is recommended to be done after every contact with the patient to detect the complications in the early period and manage permanent symptoms in the future [15].We still do not have clear information on the optimal timing of the follow-up of these patients. The follow-up period and intervals may vary from patient to patient. Follow-up planning will change according to the severity of the acute disease, the age of the patient, and the accompanying diseases. Young, non-comorbid and outpatient, mild patients who recover without treatment or hospitalization may not require routine follow-up unless they request. In patients who are elderly and have comorbidities and moderate to severe disease but do not require hospitalization should be given an appointment 3 weeks after the onset of the disease. In more severe cases treated at the hospital, the first visit is recommended as soon as within 1 week after discharge or 2–3 weeks at the latest.In the controls of the cases who have had the COVID-19 disease, first of all, detailed anamnesis is taken and physical examinations are performed in order to determine the current symptoms and signs. Subsequently, their COVID-19 disease histories  are questioned. Comorbid diseases, chronic medical conditions and the treatments they are receiving are assessed. The range of laboratory tests and imaging together with functional measurements can be planned according to the clinical findings. Appropriate medical treatments are arranged for the existing symptoms or comorbid chronic conditions and a plan is made for a regular follow-up. If worsening of symptoms occurs, the patients should be recommended to come earlier and not wait for the next visit. Education is provided on possible symptoms after persistent COVID-19 and the need for rehabilitation is evaluated [8].In the light of the information we have obtained from the community-acquired pneumonia, patients diagnosed with COVID-19 pneumonia will have a decrease in fever in approximately 1 week. The complaints of chest pain and sputum are expected to decrease in 4 weeks, and cough and shortness of breath will be greatly reduced in 6 weeks. Usually by 3 months, most of the symptoms will show improvement, but fatigue can last up to 6 months and most people return to their normal condition within 6 months [7].The respiratory system is the most severely affected system during COVID-19 [16]. It is known that the disease, which has a largely asymptomatic or minimally symptomatic course, can be complicated by ARDS in the acute phase in some cases and may require intensive care. Immediately after the infection of the alveolar epithelium, thrombosis characterized by alveolar wall damage, edema, hyaline membranes, leukocyte infiltration and microangiopathic changes predominates, while proinflammatory cytokine release triggered by pattern recognition receptors and cell damage, and an uncontrolled inflammatory process may develop afterwards [17]. In addition to immune responses, especially kinin-kallikrein system, renin-angiotensin and coagulation system play an important role in the worsening of the clinical outcome [18]. In patients with ARDS, long periods of follow-up in the intensive care unit and mechanical ventilation might be required.After the first four-week period, recovery can be achieved in most of the cases with severe disease, but unfortunately, organ damage can become permanent with prolonged symptoms, various pathologies and chronic processes. These post-acute complications include secondary infections, pulmonary function test disorders, pulmonary thromboembolism, pulmonary hypertension, and lung fibrosis [16].Post-COVID secondary infections can change the course of recovery [19]. It is suggested that a dysregulation in immunological mechanisms develops and an immunosuppressive state occurs during the control of this response before it progresses to organ damage especially following the hyperinflammatory acute period that develops in COVID-19, which resembles the state of immunosuppression that develops after sepsis [8]. However, although these secondary infections play a role in complicating the clinical outcome, it is suggested that they are not associated with permanent organ dysfunction [20].It has been reported that a decline in the measurements obtained in pulmonary function tests develop after COVID-19, which may continue for up to 12 months, and may even become permanent especially in cases with fibrosis or in relation to angiopathic changes [21–22]. It is stated that among the test variables, especially the decrease in carbon monoxide diffusion capacity is more prominent, which can be seen even in cases with normal lung volumes and can be a result of vascular pathologies. Respiratory muscle weakness, developing fibrosis, thrombosis and angiopathies, especially the ones associated with underlying diseases and intensive care follow-up processes, are some risk factors for the decline of pulmonary function [22–23].It is known that vascular microangiopathic processes, micro and macro thrombosis are common from the early stages of COVID-19, and this condition is more common than in the other ARDS and viral infections [20]. It is known that the damage, inflammation and hypoxia that occurs during viral infection activates the coagulation cascade, and this process results in platelet activation with an increase in the level of mediators such as von Willebrand factor and P-selectin, as well as direct endothelial damage [24–26]. Increasing the complement system activation with the addition of factors such as antibody development may also contribute to the process [27]. It is seen that this hypercoagulability may continue in the post-acute period, and D-dimer levels, as an indicator of ongoing fibrin formation and degradation, can give an idea regarding this process. There are publications on cases diagnosed with pulmonary embolism in the post-acute and chronic period of infection [28–31]. Stasis, endothelial damage and hypercoagulability, the classical Virchow triad, might help understand the mechanism [32]. It can be estimated that the cases whose mobilization is impaired due to the ongoing disease state and symptoms in the post-acute period are especially at high risk and there is not enough information about when endothelial damage heals. There are comments that thrombomodulin levels can provide an information about the continuation of the endothelial damage [24]. It has been reported that inflammation continues in a prolonged period in some of the cases, and a prolonged inflammation state associated with IL-6 and Lipocalin-2 is observed [33–34]. It is suggested that hypercoagulability may be triggered continuously, especially by ongoing inflammation, and the antiphospholipid antibodies may also contribute to this situation [35]. However, since it is already known that transient antiphospholipid antibody positivity can be observed after infections, information about the prolonged period is far from certain, and further studies are needed [36].Unfortunately, one of the most serious complications of the post-acute period is the development of fibrosis. It has been reported that fibrosis can be detected from the early period regardless of the pre-disease condition of the lung and the severity of the disease . TGF-b, which is the most important factor in the healing process of the developing parenchymal damage and during the regression of inflammation, is thought to be the cytokine that plays the most important role in the progression to fibrosis in the post-COVID period [38–39]. The increase in TGF-b level leads to a decrease in ACE-2 expression and increase in Angiotensin-II levels that promotes proliferation of fibroblasts, migration to tissue, transformation into myofibroblasts, activation of myofibroblasts and ultimately extracellular matrix accumulation [38]. Since it is known that SARS-CoV-2, like other coronaviruses, increases TGF-b levels with a direct viral effect [40], it is understood that the development of fibrosis begins in the early stages, becomes aggravated by changes in angiotensin levels, and becomes evident during the resolution of inflammation. It has been suggested that fibrotic processes are more common especially in cases requiring mechanical ventilation in the early period, and this may be related to oxidative stress caused by high oxygen fractions and trauma caused by positive airway pressure, and these factors further facilitate the progression to fibrosis [38].ın Yılmaz)The radiological findings obtained in this study and indicated in Figure 1 are as follows: Figures 1a, 1c, 1e, and 1g show the radiological findings of a patient with dyspnea at admission, whereas Figures 1b, 1d, 1f, and 1h show the radiological improvement of the same lung slices at 13 weeks post-COVID-19 after the patients received the corticosteroid treatment. , pulmonary embolism and chronic cough, whereas cavitary lesions, small airway disease and development of pulmonary hypertension are mentioned as rare conditions. Cough, which is among the initial symptoms of acute COVID-19 disease, is a condition that is also frequently encountered in post-COVID syndrome, along with symptoms such as chronic fatigue, headache, and widespread pain. The prevalence of cough was reported as 7%–10% in two studies [47–48]. The reason of cough in some patients is not clear. However, unlike cough that persists after a cold or flu, chronic cough in post-COVID syndrome is often accompanied by other multisystemic manifestations that may indicate multifactorial pathogenesis or common mechanisms underlying these symptoms. Cough may result from invasion of vagal sensory neurons by SARS-CoV-2, or from a neuroinflammatory response, or both, and may lead to peripheral and central hypersensitivity in the cough pathways [49]. After the differential diagnosis of chronic cough is made (according to the guidelines), treatment can be started. However, although guidelines serve as a reference for current approaches to acute and chronic cough, the optimal management of cough associated with COVID-19 remains unclear.In the NICE guideline, opioid-derived antitussives are recommended in acute COVID, but attention should be paid to their addictive potential and central nervous system side effects [7]. Oral or inhaled steroids can be given to asthmatic patients. Chronic refractory or unexplained cough in post-COVID syndrome may result from neuroinflammation leading to larynx and tracheal hypersensitivity. Neuromodulator agents such as gabapentin and pregabalin can be recommended. Antimuscarinic drugs such as tiotropium can be used to control COVID-19 cough as they can reduce cough sensitivity in acute viral upper respiratory tract infection. Speech and language therapy offered as part of a multimodal therapy in synergy with other aspects of pulmonary rehabilitation can help patients recover from post-COVID syndrome [49].Studies are needed to provide insights into the epidemiology of post-COVID chronic cough and its impact on quality of life as well as cough hypersensitivity.The radiological specific findings of COVID-19 disease are unilateral/bilateral ground-glass opacities with peripheral distribution, fine reticular opacities, and vascular thickening [50]. The cavity is an air-filled space formed within the area of pulmonary consolidation, mass, or nodule as a result of liquefaction of the necrotic portion of the lesion and evacuation of this necrotic material through the bronchial tree. It is rare for viral pneumonias (including SARS-CoV and MERS-CoV) to cause pulmonary cavitation even in severe and advanced viral infection [51]. However, cavitary lesions have been published as case series in the prolonged symptomatic period (4–12 weeks) in COVID-19 disease. In a series of 12 cases (1.7%) within the 689 COVID-19 pneumonia patient group reported by Zoumot Z et al., the mean time from the first symptom onset to the detection of cavitation was 36 (21–54) days, and all patients had bilateral peripheral ground glass opacities on their first chest tomography. Consolidation and air bronchograms were detected in most of the patients and cobblestone appearance with interlobular septal thickenings in half of them [52]. Tocilizumab and steroid therapy, which cause immunosuppression, were administered to patients followed up in the intensive care unit with severe COVID-19 pneumonia, but bacterial agents that could cause cavitary lesions were detected in only 4 patients. While simultaneous hemoptysis and pneumothorax developed in 2 patients, a total of 4 patients had in addition radiological findings compatible with invasive aspergillosis. The authors describe the development of cavitation in these patients as a result of multifactorial reasons such as: bacterial and fungal coinfection, immunosuppressive effects of glucocorticosteroids and tocilizumab, inflammatory pathways specific to SARS-CoV-2, susceptibility to COVID-19 related venous thromboembolism and micro-infarctions or infarctions causing cavitary lesions. They also emphasized that the natural course of these cavities in survivors is uncertain [52].Tuberculosis disease, which is endemic in our country and usually presents with a cavity, has also been reported in several publications as a co-infection with COVID-19. Both diseases have common risk factors such as underlying comorbidities  and low socio-economic status, air pollution, living in crowded environments, and both of them are important infectious pathogens that continue to threaten the world population. Presence of active or previous history of tuberculosis has been found to be associated with the development of COVID-19 and might worsen the prognosis of acute infection [53].It has been found that proinflammatory cytokines such as TNF-α, IL-6, IL-10, IL-1β and chemokines increase in COVID-19 patients (18). Increasing IL-10, Th1 suppression, and suppression of IL-6 level by tocilizumab used during the cytokine storm period increase the risk of invasive pulmonary aspergillosis, which progresses with a cavity and has a very poor prognosis in the follow-up period in COVID-19 patients [54–55].Although there is no standard diagnosis or treatment algorithm in the management of cavitary lesions, which we encounter mostly in the prolonged symptomatic period in post-COVID syndrome, attention should be paid to fungal infections especially aspergillosis, tuberculosis, differential laboratory, and microbiological examinations should be performed and the appropriate treatment should be started as soon as possible.ın Yılmaz)Below, in Figure 2a the CT findings of a patient presenting with a cavitary lesion are shown, and Figure 2b shows the remaining changes in lungs after antibiotic treatment.  in post-COVID syndrome is a very new clinical condition. A study, which is still in the publication stage and included 100 patients, tried to show if there is a correlation between air trapping measured with quantitative thorax computed tomography (CT) and pulmonary function test [56]. Although it is difficult to define small airways on CT, studies have found that air trapping detected on CT can be a biomarker of functional SAD [57]. In this study, it was stated that SARS-CoV-2 infection itself causes functional SAD and air trapping, whereas restrictive lung disease and deterioration in gas exchange are caused by lung damage and ARDS, regardless of the underlying cause. The underlying mechanism is explained as follows:The angiotensin-converting enzyme 2 (ACE2) receptor, which facilitates SARS-CoV-2 entry in cells, is expressed throughout the airway, including the small airways. Therefore, the functional SAD observed in patients in the post-COVID syndrome may result from direct infection of the small airways by SARS-CoV-2, even in patients with mild acute infection. In this case, post-COVID SAD may result from an ongoing damage-repair process, cellular debris, and/or abnormal mucus production. Conversely, the immune response induced by SARS-CoV-2 can directly induce post-COVID SAD even in the absence of infection. Regardless of the underlying mechanism, the development of functional SAD months after acute infection is of concern for airway remodeling and fibrosis.In one study, no correlation was observed between pulmonary function tests, quantitative CT measurements of ground glass opacities, air trapping and the period time from diagnosis. The median time from diagnosis to pulmonary function measurements and chest CT imaging was approximately 75 days. Multicenter, prospective studies are needed for the frequency of SAD and treatment recommendations in post-COVID syndrome.ın Yılmaz)Below, in Figure 3a, diffusion capacity and pulmonary function tests of a patient at admission, and, in Figure 3b, the improvement of these tests values after receiving corticosteroid treatment are shown.  has increased [58]. In the COVID-19 disease, the pulmonary artery wall thickness increased twice as compared to the H1N1-infected individuals as showed in autopsies. Pulmonary vascular thickening in COVID-19 is thought to have a vital role in the development of acute respiratory failure, and based on this result, we can think that patients recovering from COVID-19 may be prone to develop PAH and right heart failure [59–60].Multisystem inflammatory syndrome (MIS) is a finding that is observed in the prolonged course of COVID-19 but is not very common according to the available data. This syndrome, which was stated to affect children for the first time in articles published in March 2020 in England and the USA, was named as MIS-C (child) [61–63]. Shortly after MIS-C was defined (June 2020), a clinical picture compatible with MIS was reported also in adults and was defined as MIS-A(adult) [64–66]. Among the inflammatory syndromes secondary to COVID-19, Kawasaki-like syndrome has also been reported especially in children. Case reports that describe Kawasaki-like syndrome in adults are also available in the literature [67]. Most et al. also mention about the myocarditis-like syndrome in adults as another post-COVID inflammatory syndrome in their review [68]. A detailed Venn diagram of the overlap of symptoms and signs of Kawasaki disease, MIS, and acute cardiovascular syndrome is included in another part of this review. Here, only MIS-A will be discussed in details.Cardiovascular, gastrointestinal, dermatological and neurological symptoms without serious respiratory disorders are reported in the first published cases with the diagnosis of MIS-A. In the course of MIS-A, diagnosis is challenging due to the heterogeneity of symptoms and findings. SARS-CoV-2 PCR or antigen test positivity may not be detected in the diagnosis of MIS-A, and antibody test positivity may be the only evidence that the case has COVID-19 disease [69].The pathogenesis of the relationship between acute COVID-19 disease and MIS-A is not clearly understood, thus making it difficult to prevent the unwanted complications such as MIS-A. According to the data obtained from published case reports, the definition of MIS-A is made by the following five criteria [69]:1. Presence of severe disease requiring hospitalization in an individual >21 years of age, 2. positive test result of SARS-CoV-2 infection ; 3. presence of severe dysfunction in one or more extrapulmonary organs/systems , 4. elevated inflammatory parameters , 5. no serious respiratory problems (organ dysfunctions not associated with tissue hypoxia). MIS-A cannot be excluded in the presence of mild respiratory symptoms.As of May 2021, as of the time of writing this article, the number of full-text articles accessed with the keyword “MIS-A and COVID-19” in the PubMed index was determined as 186. All of these articles were case series. These numbers indicate that MIS-A has been seen or reported relatively less, when compared to the numerous articles on COVID-19 published since the beginning of the pandemic.Although hyperinflammation and extrapulmonary organ dysfunction are common in hospitalized adults with severe COVID-19, respiratory failure is often present in these severe cases. In MIS-A, there may be only mild respiratory symptoms, mild hypoxemia or rare radiological abnormalities. Although the pathophysiology of MIS is not fully known, it suggests that multi-organ/system involvement such as heart, brain, liver, kidney and gastrointestinal involvement is associated with endothelial damage, thromboinflammation, dysregulated immune responses, and renin-angiotensin-aldosterone system dysregulation [69].The interval between COVID-19 infection and the development of MIS-A is not known. It may be a prolonged clinical manifestation of an acute infection or a postacute phenomenon. Dyspnea may become prominent on days 5–8 of the Covid-19 infection, whereas the critical illness occurs usually 10–12 days after symptom onset. On the other hand, MIS-A is reported usually within 2–5 weeks after infection.In their review, Vogel et al. defined cases according to the levels of diagnostic certainty within four different groups as definitive, probable, possible case and case with insufficient evidence for MIS-C/A. This classification is a useful definition as it includes demographics, symptoms, signs and laboratory results [70].Level 1: Definitive caseAge < 21 years (MIS-C) and ≥21 years (MIS-A); fever for ≥3 consecutive days; the presence of two or more of the following clinical features: mucocutaneous findings, gastrointestinal symptoms, shock/hypotension, neurological findings; elevation in any of inflammatory markers ; the presence of two or more of disease activity markers: increased BNP or NT-pro BNP or troponin, neutrophilia, lymphopenia or thrombocytopenia, detection of cardiac involvement by echocardiography, EKG changes consistent with myocarditis or myo-pericarditis and the confirmation of active SARS-CoV-2 infection by laboratory or having a history of confirmed COVID-19 in the past 12 weeks or a history of close contact with a known case of COVID-19 in the last 12 weeks or a recent SARS-CoV-2 vaccination history.Level 2: Probable case: Same criteria as Level 1, except for disease activity measurements; a history of known or strongly suspected COVID-19 in the last 12 weeks or a close contact with a known or strongly suspected COVID-19 case in the last 12 weeks or a recent SARS-CoV-2 vaccination.Level 2aLevel 2b: Presence of the same criteria as Level 1 except fever that has lasted for 1–2 days or that can be subjective.Level 3: Possible caseLevel 3a: Age < 21 years (MIS-C) and ≥21 years (MIS-A); fever for >3 consecutive days; two or more of the following clinical features: mucocutaneous, gastrointestinal, shock/hypotension, neurological, physical examination findings of heart failure: gallop rhythm or rales, lower extremity edema, jugular venous engorgement, hepatosplenomegaly; absence of elevated inflammatory markers and a history of known or strongly suspected COVID-19 in the last 12 weeks or close contact with a known or strongly suspected COVID-19 case in the last 12 weeks or a recent SARS-CoV-2 vaccination.Level 3b: Presence of the same criteria as Level 2a except fever that lasted for 1–2 days and that can be subjective.Level 4: Insufficient evidenceA case that does not fully meet the case definitions in levels 1–3. The treatment for MIS-A is supportive, but there may also be a need for intensive care. The current protocol includes biological agents such as intravenous immunoglobulin (IVIG), corticosteroids, tocilizumab, anakinra or infliximab. It is reported that the treatment response is rapid, and the patient can improve dramatically within days. However, it may also result in unresponsiveness to treatment and death [71]. It is important for the clinician to notice the early findings and approach them in a proper way. Because it is a clinical condition that can be overlooked and antibody tests are not widely used yet, a careful and systematic approach is required for the diagnosis of MIS-A, with a good collaboration of multidisciplinary specialists.As more than one year has passed since the pandemics of SARS-CoV-2 started, we gained knowledge about the long-term pulmonary complications of COVID-19 disease. Experience with longer follow-ups will further shape the approach to PCS patients. Viral pneumonia is the most common and the most severe problem in the course of the disease. It is not yet clear whether disseminated COVID-19 pneumonia can have long-term effects resulting in persistent fibrosis in the lungs. The number of studies and reviews written on post-COVID pulmonary fibrosis is increasing day by day. Post-COVID pulmonary fibrosis is referred to as Post-COVID interstitial lung disease (PC-ILD) in most articles. In this article, the abbreviation PC-ILD will be used. In an article published from India in March 2021, PC-ILD was defined as ‘the tsunami that will follow the earthquake’ . Although it is reported that there are three possible different clinical courses, the frequency of each is not known. According to this review, most lung involvements heal without sequelae, some heal with minimal fibrosis without worsening, and a few progress to advanced fibrosis that requires antifibrotic treatment. Advanced age, severe pneumonia, prolonged ICU stay and prolonged MV duration, smoking and chronic alcoholism history are some of the predictors for PC-ILD development. High CRP, IL-6 and LDH levels in the acute phase may lead to activation of fibroblast proliferation in the repair process of lung injury .In order to minimize the risk factors for PC-ILD development shortening the length of stay in the intensive care unit, avoiding invasive mechanical ventilation support if possible, managing the case with low airway pressure in case of forced MV, proper management of concomitant diseases and prevention of bacterial superinfections are some of the measures that can be taken.Treatment options can be listed as follows based on the available evidence [74]:Antivirals: The close relationship between the development of lung fibrosis and high viral load is known, and the effectiveness of early antiviral treatments  to reduce viral load has been shown in some studies [74]. The necessity of effective antivirals in pandemic control is indisputable. However, there is no specific antiviral agent developed for the SARS-CoV-2 agent yet and many studies are ongoing in order to develop effective drugs.Anti-inflammatory drugs: The efficacy of systemic steroids has been proven in the treatment of severe disease in the acute period. World Health Organization (WHO). Corticosteroids for COVID-19. Available from:https://www.who.int/publications/item/WHO-2019-nCoV-Corticosteroids-2020 [Accessed 06/2021]. However, there is insufficient evidence for long-term use in the prevention of PC-ILD. There are studies suggesting that 20–30 mg/day prednisolone should be started in the presence of diffuse ground glass opacities in the prevention of lung fibrosis and continued until radiological improvement is achieved [74].: As mentioned above, lung involvement should be monitored for up to 3 months in the post-COVID period, and it should be kept in mind that there may be a possibility for regression. In other words, it is not necessary to rush for the antifibrotic treatment. If fibrosis still persists at the end of the 12th week, there is a rationale for the use of these agents in the treatment of PC-ILD, although there is not enough data yet. Pirfenidone or nintedanib should be used for at least 1–3 months for a clear measurement of the antifibrotic response. In addition to clinical findings, response to antifibrotics should be evaluated objectively with HRCT, DLCO and 6MWT [75]. Concomitant use of steroids and antifibrotics is also being tried, and the long-term results are not yet known.AntifibroticsPulmonary rehabilitation (PR): PR is a vital treatment approach that can also be applied at home. Since PC-ILD may also cause hypoxemia, long-term use of oxygen and PR at home can help in recovery [7].Other supportive treatments: Anticoagulation, psychiatric support, family support, pneumococcal and influenza vaccinations are required until the patient is fully mobile, and evaluation of progressive and persistent PC-ILD for lung transplantation in selected cases is recommended [7].After the acute phase of the disease, the state of hypercoagulation may last for a long time, so long-term prophylaxis may be recommended in cases with severe disease. However, this issue is not very clear yet. In cases with severe disease and accompanying pulmonary embolism, anticoagulation administration is required according to the recommendations by the specific guidelines. It is recommended to evaluate the patient for the development of pulmonary hypertension (PHT) at the end of 12 weeks, and to discontinue the treatment at the end of the 3rd month if PHT has not developed. Lastly, the measurement and follow-up of D-Dimer level, which is also an acute phase reactant and is not specific for COVID-19, for chronic embolism is controversial [74]. T.C Sağlık Bakanlığı, COVID-19 enfeksiyonu antisitokin-antiinflamatuar tedaviler, koagülopati yönetimi. Available from: https://covid19.saglik.gov.tr [Accessed 06/2021]ın Yılmaz)CT findings of a patient presenting with bilateral pulmonary embolism are shown in Figure 4. Figure 4a shows a centrally located thrombus on the right pulmonary artery, whereas Figure 4b and 4c show the presence of thrombus in segmental branches of the left and right pulmonary arteries, respectively. (From archives of AydCOVID-19 disease is not just an acute infection, but is a complex entity with post-infection complications and long effects especially involving the pulmonary system, which emphasizes the fact that the treatment of this disease continues even after the patients have been discharged. Further detailed studies are needed in order to identify biomarkers and risk factors for the individuals that can progress, thus enabling a prompt intervention and treatment to minimize the long term effects. There are still many unknowns regarding the pathophysiology of this new disease, which makes the approach to these patients difficult for the moment and COVID-19 specialized hospitals or centers might help for an optimized treatment and follow-up.


The coronavirus disease 2019 (COVID-19) pandemic has disrupted the health care delivery systems worldwide. Currently, Asian countries have had an upsurge in infections due to the spread of the Delta variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that started in India in April 2021 . As BangCurrently, over 1.3 million Rohingya refugees are living in highly congested camps with high risk of COVID-19 in Bangladesh . The majThe most effective responses to COVID-19 such as social distancing and quarantine concept are impossible in Rohingya refugee camps. The testing capacity is highly limited and treatment is usually late and inadequate. It has been estimated that a large-scale outbreak is very likely in the Rohingya camps with 70%–98% of the refugees expected to be infected, if no effective interventions are taken . The numThe first outbreak of COVID-19 in the Rohingya population was confirmed on May 14, 2020. A sharp increasing trend in cases among Rohingya refugees has been observed in July 2021. As of July 14th 2021, a total of 2147 patients from Rohingya refugees had COVID-19 and more than 70% of them were infected within the past few weeks [There have been 20 deaths in the Rohingya Refugees from COVID-19 and 60% were female  facilities available at refugee camps for severe and critical patients. Moreover, as of July 14th 2021, not a single dose of the COVID-19 vaccine has been administered to Rohingya refugees [An ideal environment exists for the SARS-CoV-2 to spread in the highly densely populated (120 000 refugees per square miles) Rohingya refugee camps. The poor living conditions that make it impossible to maintain social distancing and quarantining, delayed diagnosis, reduced access to medicine, and absolute lack of advanced treatment facilities can lead to increased occurrence, severity and case fatality of COVID-19 in Rohingya refugee camps. Moreover, the deadly Delta variant of COVID-19 is spreading at an alarming level in the host communities surrounding refugee camps exacerbating the fears of massive outbreaks. In fact, the numbers of severe COVID-19 cases and deaths in Rohingya camps jumped three times in recent weeks. The pattern of present outbreaks indicates that the scenario in the Rohingya camps may be worsened in coming days. Modeling studies have predicted that without appropriate actions COVID-19 will spread unchecked within the Rohingya refugee camps, causing high levels of morbidity and mortality . TherefoMathematical modeling has reported that proper distribution of COVID-19 vaccines could reduce coronavirus deaths . VaccinaBangladesh has begun the COVID-19 vaccination program nationally for its 167 million citizens. The COVID-19 Vaccines Global Access (COVAX) allocated 11 million doses of COVID-19 vaccine for Bangladesh and only a few of them have arrived in Bangladesh . While BUnder these realities, international stakeholders, particularly vaccine-producing countries such as the USA, China, UK, and Russia should step in to ensure that the Rohingya refugees who are most susceptible to the COVID-19 are given priority in vaccinations. There are some reasons to be hopeful for Rohingya refugees as most of these countries have immunized a significant number of their citizens. Any single country or all of these stakeholders are capable of immediately ensuring adequate COVID-19 vaccines for the refugees. A recent donor summit of G7 countries secured pledges for 1 billion doses of COVID-19 vaccines for poor countries . FurtherThere should some specific recommendations to handle the Rohingya population before the conditions of these refugee camps touch the point of no return.The COVID-19 preparedness of Rohingya refugees should be considered as special circumstances of a population devastated by prior genocide, leaving homes and wealth, with psychological torture.There should be special COVID-19 cell only for health education, case identification, and management of this population. The barrier of language, education status, and realizing health need should be considered for proper planning.They should get anti-SARS-CoV-2 vaccine as preferential basis because if the vaccine delivered based on the principle of distribution in Bangladesh, these vulnerable group would be endangered. All Rohingya population above the age of 12 years should be immediately vaccinated.As the movement of these people are restricted, the assessment of SARS-CoV-2 and management strategies should be provided by creating field hospitals adjacent to their camps. These facilities should have abundant oxygen supply and requisite drugs. Also, serious and complicated patients should be moved to tertiary treatment center at the district head quarter by special transportation. Adequate numbers of health personnel including physicians should be provided to ensure quality services.In case of fatality, proper measures must be ensured for funeral.The COVID-19 pandemic has highlighted clear discriminatory limitations on access to health care facilities particularly hospital beds, oxygen supplies, intensive care capacities and vaccination for Rohingya refugees. Preparedness for COVID-19 in the refugee camps are affected by the lack of human resources, inadequate management, and laboratory and hospital facilities for testing and treating COVID-19. Bangladesh, like many other resource constrained countries hosting millions of stateless people, needs to strengthen the treatment and vaccination facilities for refugees. However, it is almost impossible for Bangladesh to ensure such facilities for the huge number of Rohingya refugees. Therefore, it is essential for the government to work with international stakeholders and experts on refugee health to take urgent steps to ensure adequate medical facilities and vaccines against COVID-19 to protect the most devastated Rohingya people. Failure or delay to put in these efforts would leave these vulnerable populations dangerously unprotected.