key: cord-0991422-rigruto5
authors: Lommatzsch, Marek; Rabe, Klaus F.; Taube, Christian; Joest, Marcus; Kreuter, Michael; Wirtz, Hubert; Blum, Torsten Gerriet; Kolditz, Martin; Geerdes-Fenge, Hilte; Otto-Knapp, Ralf; Häcker, Brit; Schaberg, Tom; Ringshausen, Felix C.; Vogelmeier, Claus F.; Reinmuth, Niels; Reck, Martin; Gottlieb, Jens; Konstantinides, Stavros; Meyer, Joachim; Worth, Heinrich; Windisch, Wolfram; Welte, Tobias; Bauer, Torsten
title: Risk Assessment for Patients with Chronic Respiratory Conditions in the Context of the SARS-CoV-2 Pandemic Statement of the German Respiratory Society with the Support of the German Association of Chest Physicians
date: 2022-01-21
journal: Respiration
DOI: 10.1159/000518896
sha: 18b22842cc72fc364fb8f822900795fd46a56ffa
doc_id: 991422
cord_uid: rigruto5

Assessing the risk for specific patient groups to suffer from severe courses of COVID-19 is of major importance in the current SARS-CoV-2 pandemic. This review focusses on the risk for specific patient groups with chronic respiratory conditions, such as patients with asthma, chronic obstructive pulmonary disease, cystic fibrosis (CF), sarcoidosis, interstitial lung diseases, lung cancer, sleep apnea, tuberculosis, neuromuscular diseases, a history of pulmonary embolism, and patients with lung transplants. Evidence and recommendations are detailed in exemplary cases. While some patient groups with chronic respiratory conditions have an increased risk for severe courses of COVID-19, an increasing number of studies confirm that asthma is not a risk factor for severe COVID-19. However, other risk factors such as higher age, obesity, male gender, diabetes, cardiovascular diseases, chronic kidney or liver disease, cerebrovascular and neurological disease, and various immunodeficiencies or treatments with immunosuppressants need to be taken into account when assessing the risk for severe COVID-19 in patients with chronic respiratory diseases.

The current SARS-CoV-2 pandemic has created uncertainty regarding the question of how to adequately protect specific patient groups suffering from chronic respiratory conditions -both among physicians, who have a duty to provide patients with suitable and meaningful protective measures and among patients, who understandably wish to protect themselves optimally against COVID-19. Assessing the risk for specific patient groups is therefore of particular importance.

The SARS-CoV-2 virus responsible for COVID-19 can be transmitted also by asymptomatic carriers (according to current estimates, 15-31% of all infected persons remain asymptomatic) [1, 2] or by those infected before they develop symptoms [3] (Fig. 1) . This, in addition to the high contagiousness, contributes to the rapid spread of the virus. Most COVID-19 cases are mild to moderate (Fig. 1) , and patients are symptomatic for an average of 11.5 days (the most common symptoms are: cough, fever, loss of smell and taste, fatigue, and myalgia; gastrointestinal symptoms are also possible in some patients) [4, 5] . A minority of patients develops severe COVID-19 7-10 days after the onset of symptoms (Fig. 1) [4], with shortness of breath, pneumonia, and respiratory distress, which, in less than 25% of hospitalized patients [6] , requires intensive care (including mechanical ventilation) [7, 8] . Signs of progression to severe disease are shortness of breath, tachypnea, and/or drop in oxygen saturation below 94% [5] . In addition to pneumonia, severe COVID-19 can result in severe endothelial injury of the pulmonary vessels [9] with intravascular thrombosis and thromboembolic events [10, 11] , massive release of cytokines [12] , and multi-organ failure [4] .

Most recent data based on reports of the Robert Koch Institute (RKI) in Germany show a hospitalization rate of 10% and case fatality rates between 2 and 4% (89% of the deceased were at least 70 years old) [2] . In an evaluation based on the health insurance data of 10,021 patients in 920 hospitals in Germany, 17% of patients received mechanical ventilation, their median age was 71, and 66% were male. Inhospital mortality was 22% (16% of the nonventilated and 53% of the ventilated patients) [6] . Based on a comparable analysis of health insurance data, this inhospital mortality is higher than in patients with community-acquired pneumonia (17%) [13] . The real mortality of COVID-19 is still unknown as it depends on the actual number of those infected, which is unknown. Current models from Europe assume a mortality rate of between 0.3% and 0.9% [14] [15] [16] [17] . Hence, the mortality rate in the current SARS-CoV-2 pandemic seems to be higher than that for seasonal influenza during a severe season (0.1%) [18] . However, in contrast to SARS-CoV-2, only direct deaths are considered as influenza-related deaths in patients infected with influenza viruses.

The following statements refer, in particular, to the risk of severe disease or death after SARS-CoV-2 infection ( Fig. 1) . They provide answers to frequently asked questions based on 13 exemplary cases.

Answer 1: Current data show that higher age is the most significant risk factor for severe COVID-19 or death. The mortality risk increases continuously from the 6th decade of life and is 20 times higher for an 80-year-old person than for a 50-year-old person [19] . This is also confirmed by data from Germany: while persons ≥70 years of age were only 16% of those infected, 89% of deaths occurred in this age-group [ The presence of more than one chronic disease or more than one risk factor significantly increases the risk of severe disease [23, 27] . The mortality risk is particularly high for nursing home residents because of their advanced age and high prevalence of multiple chronic diseases. In addition, the virus is easily transmitted in nursing homes as nursing staff care for multiple residents with close physical contact [28] .

Question 2 (mild to moderate asthma): I am a 58-year-old teacher and have moderate, wellcontrolled asthma; I regularly use my inhaled medications. Does this make me a risk patient? Is it safe for me to go to work during the coronavirus pandemic?

Answer 2: Early general COVID-19 case series indicated that having asthma does not increase the risk for severe COVID-19 [6, [19] [20] [21] [22] [23] [24] [25] [26] . Subsequently, specific case series which included only patients with asthma from Spain [29] , Belgium [30] , France [31] , Brazil [32] , Russia [33] , Japan [34] , and the USA [35] [36] [37] [38] [39] [40] unanimously confirmed that asthma is not a risk factor for severe CO-VID-19 [41] . Even patients with severe asthma treated with biologics do not appear to be at an increased risk [42] [43] [44] [45] [46] [47] [48] [49] . One study from Korea suggested that the subgroup of patients with nonallergic asthma might have an increased risk of progression to severe disease [50] , but another study from Korea showed asthma not to be an independent risk factor for severe COVID-19 in Korea [51] . Based on the large number of data available today, it can be assumed that asthma (of all severities) is not an independent risk factor for severe COVID-19 [52] . There are even speculations that this risk may be lower in asthma [53] [54] [55] , in part due to a reduced expression of the ACE-2 receptor responsible for the uptake of SARS-CoV-2 in the airways [56] . This was observed, in particular, in patients with allergies and/or type 2 inflammation [57] [58] [59] [60] . Currently, there is also no evidence that treatment with low-or medium-dose inhaled corticosteroids (ICSs) to treat asthma increases the risk of developing severe COVID-19 [61] . Since ICS generally reduce the risk of asthma exacerbations and may additionally reduce the expression of the ACE-2 receptor in the airways [62] , a protective effect is instead suspected [63] . Discontinuation of ICS therapy Courses of SARS-CoV-2 infections. With a median incubation period of 5-6 days, SARS-CoV-2 has a longer incubation period than the influenza virus, but the risk of transmission from one person to another is higher. In addition, most infected have mild symptoms or are asymptomatic. During this incubation period or during a mild or asymptomatic course of the disease, those infected with SARS-CoV-2 can therefore spread the virus quickly and unnoticeably, with virus transmission peaking around the day of onset of symptoms. In contrast to severe influenza-related pneumonia, severe courses of COVID-19 rarely cause an abrupt deterioration of the patient's general condition after the incubation period. On average, it is only after 1 week of relatively mild symptoms that shortness of breath and respiratory distress may appear (only in very few cases, a rapid deterioration can occur directly after symptom onset). Signs of progression to severe disease are shortness of breath, tachypnea, and/or a drop in oxygen saturation below 94% [4, 5]. DOI: 10.1159/000518896 may lead to severe asthma exacerbations and contribute to a severe course of the disease in the event of a SARS-CoV-2 infection. Therefore, inhalation therapy, and in particular with ICS, should be continued in patients with well-controlled asthma during the SARS-CoV-2 pandemic: there are separate and detailed statements on this topic by the DGP (statement on asthma therapy with ICSs, www.pneumologie.de) and by the GINA (https://ginasthma.org/recommendations-for-inhaled-asthma-controller-medications). Allergen immunotherapy (allergen-specific immunotherapy) should also be continued: A separate EAACI statement is available in this regard [64] . We therefore suggest that patients with asthma who have no acute symptoms and no COVID-19-relevant comorbidities can work in schools as long as the RKI-recommended hygiene measures (AHA-L rules of physical distancing and hygiene: keep physical distance, observe hygiene procedures, wear a face mask, ventilate indoor areas) are observed. Answer 3: Currently, there is no evidence that patients using biologics would generally be at a higher risk of developing severe COVID-19 [65, 66] . Patients with severe asthma treated with biologics do not appear to be at an increased risk of a severe disease [42] [43] [44] [45] [46] [47] [48] [49] . The only published patient with severe asthma under biologic therapy who died of COVID-19 had 4 typical COVID-19 risk factors (age, male gender, hypertension, and diabetes), which explained the severe course of the disease [29] . However, there is evidence that treatment with systemic steroids [19] or high-dose ICS [61] (which can be equivalent to a low-dose therapy with systemic steroids [67] ) may increase the risk of severe COVID-19. In patients with severe asthma, it is therefore of particular importance during the coronavirus pandemic to avoid longterm or repeated systemic steroid therapy, by following a guideline-based therapy, for example, with biologics. It is therefore recommended to continue the biologic therapy in patients with severe asthma, especially to avoid the necessity of systemic corticosteroid therapy and/or exacerbation-related hospitalizations. A separate DGAKI statement on this topic is available (https://dgaki.de/ biologika-therapie-u-covid-19). Patients with wellcontrolled severe asthma, without acute symptoms, can work outside their homes, as long as the RKI-recommended behavioral measures (AHA-L rules of physical distancing and hygiene) are strictly observed. Self-administration of a biologic at home (which is possible and approved for omalizumab, mepolizumab, benralizumab, and dupilumab) should be encouraged to reduce contact with medical facilities and thus minimize the risk of contact with patients infected with SARS-CoV-2.

Question 4 (COPD): I am a 68-year-old pensioner with COPD. I had a heart attack 3 years ago, and I suffer from high blood pressure. Currently, I still smoke 3-4 cigarettes per day. Can I continue to take my high blood pressure medication (e.g., ramipril) and continue with inhalations? Should I be vaccinated against pneumococci? Should I shelter at home for the duration of the coronavirus pandemic?

Answer 4: According to current data, COPD patients are at a moderately increased risk of severe COVID-19 [22, 26, 68] . Patients with COPD and cardiovascular comorbidities are at a significantly increased risk [22, 69] . Inhalation therapy according to current guidelines should generally be continued. So far, there is no evidence that ICSs might negatively impact the prognosis of patients with COPD. A study of almost 150,000 patients with COPD from the UK suggested an increased mortality in patients with COPD treated with ICS. However, the authors concluded that this was probably the result of patient selection (bias by indication) rather than treatment [61] . High blood pressure therapy, including ACE inhibitors (such as ramipril) or sartans, should be continued; there is no evidence that these drugs increase the risk of severe disease [70, 71] . It is strongly recommended to stop smoking cigarettes. Vaccination against pneumococci is also strongly recommended, if not already done. As long as there are no signs of COVID-19 disease, sheltering at home is unnecessary. However, the RKI recommendations (AHA-L rules of physical distancing and hygiene) should be strictly observed. In the current situation, get-togethers with children or grandchildren should be avoided as much as possible, and keeping in touch over the phone or by video conference should be preferred. Answer 5: The published number of COVID-19 cases in patients with cystic fibrosis (CF) continues to be very limited [72] . An update published by the "Cystic Fibrosis Registry Global Harmonization Group" reports 181 cases with SARS-CoV-2 from 19 countries in which approximately 85,000 CF patients reside (update: June 13, 2020) [73] . Among the infected patients, there were 32 transplanted patients (mostly status post lung transplant). A total of 11 (of which 7 were transplanted) patients required intensive care: 7 (of which 3 were transplanted) patients died. The authors conclude that a severe course was associated with increased age, CF-associated diabetes, poorer lung function, and status post organ transplant [73] . Although 46% of the included patients were hospitalized and 23% required supplemental oxygen, the course of the disease in this cohort was better than expected and more favorable than in other cohorts of patients with chronic lung diseases, which may be related to the protective effect of the relatively young age of CF patients [73] . In addition, these patients generally also practice very good basic hygiene, regardless of the SARS-CoV-2 pandemic. However, due to the fact that patients with CF in general have a significant increased risk for hospitalization, multiple comorbidities as well as a considerably shortened life expectancy compared to peers, immunization against SARS-CoV-2 is strongly encouraged and accordingly CF was explicitly included as a disease justifying immunization against SARS-CoV-2 with high priority in Germany. It is generally recommended that patients with CF or bronchiectasis of other etiology continue their primary therapy including pharmaceutic and nonpharmaceutic measures. This also applies to chest physiotherapy, which should be performed alone by the patient, whenever possible. Separate DGP recommendations are available on hygiene measures during the SARS-CoV-2 pandemic in connection with outpatient chest physiotherapy [74] . Many therapists offer treatment by video sessions in addition or as an alternative to in-person visits and have been permitted to re-quest reimbursement for these therapies in Germany. Likewise, clinically indicated outpatient or inpatient antibiotic therapies and regular follow-ups at specialized outpatient centers should be continued. Close monitoring of laboratory parameters and clinical follow-ups are mandatory when starting CFTR modulator therapy (after week 2 and 6 and every 12 weeks thereafter in the first year of therapy) [75] . If initiation of a CFTR modulator therapy is already planned, the inherent risk of regular visits to CF outpatient centers (which in Germany usually follow very high hygiene standards) should be weighed against the benefit of an often significantly improved lung function and a lower exacerbation rate [76] . It is unnecessary for patients who show no signs of COVID-19 to stay at home permanently (and this is also not reasonable considering the many positive aspects of physical exercise). However, the RKI's behavioral recommendations (AHA-L rules of physical distancing and hygiene) should be strictly observed. In summary, the potential damage caused by failing to adhere to the CF-specific routine measures according to European standards of CF care appears to be greater than the potential damage caused by CO-VID-19. Answer 6: ILD, especially pulmonary fibrosis, is believed to be associated with a higher risk of severe CO-VID-19. If hospitalization becomes necessary, ILD patients are at a significantly increased risk for severe CO-VID disease [77] . This is especially true for patients with idiopathic pulmonary fibrosis (IPF), particularly those with advanced disease stages or obesity. Even though there are limited data available, it should be considered that a temporary suspension of an otherwise indicated immunosuppressive therapy is associated with the risk of a worsening of the underlying condition (which will then require even higher doses of immunosuppressive therapy). The indication for immunosuppression should be reviewed in all types of ILD (includ-DOI: 10.1159/000518896 ing sarcoidosis) [78] treated by immunosuppressive therapy. If a continuation of the therapy is indicated, it should be continued without modification at the lowest possible dose. Only if the patient or a household member tests positive for SARS-CoV-2, immunomodulators such as azathioprine or methotrexate should be discontinued temporarily (in accordance with the DGRh recommendations, see www.dgrh.de) until clinical improvement is achieved. A prednisolone therapy should be continued at the lowest possible dose. Since antifibrotic agents in IPF or IPF-like behaving diseases protect against acute exacerbations that may develop in ILD in the context of a viral infection, this therapy should be continued. It is unnecessary for patients who show no signs of COVID-19 to stay at home permanently (and this is also not reasonable considering the many positive aspects of physical exercise). However, the RKI's behavioral recommendations (AHA-L rules of physical distancing and hygiene) should be strictly followed. Oxygen therapy should be continued without modification. There is still insufficient data regarding the nature, prognosis, and therapy of COVID-19-induced ILD. Studies are currently being conducted in this regard. Whether an antifibrotic or steroid therapy might be useful in these cases needs to be determined [79] . Answer 7: In a study from New York, sarcoidosis was not an independent risk factor for severe COVID-19. The risk was however increased in patients with moderately or severely impaired lung function [80] . An international registry study on 600 COVID-19 patients suffering from chronic inflammatory systemic diseases (including 10 patients with sarcoidosis) identified a higher risk of hospitalization for patients on glucocorticoid therapy receiving treatment with ≥10 mg prednisolone equivalent per day, but not for patients on bi-ologics, DMARDs, or NSAIDs [81] (in a subsequent analysis, the authors identified no risk of severe disease progression in 41 sarcoidosis patients in relation to the glucocorticoid therapy) [82] . Two monocentric, sarcoidosis-specific observational studies detected proven COVID-19 infections in 5 (out of 238) and 10 (out of approximately 1,000) patients with sarcoidosis, respectively. Clinical courses were favorable: only 2 patients were hospitalized, one of these 2 patients (with cardiac sarcoidosis, and no immunosuppressive medication prior to infection) died due to pulmonary embolism [83, 84] . Likewise, 2 survey-based studies yielded low COVID-19 infection rates in a large international cohort of sarcoidosis patients [85] and a mixed regional Italian patient cohort with rheumatic diseases/sarcoidosis treated with biologics/DMARDs [86] (a reporting bias cannot be excluded in these studies). The key factors regarding the risk for patients with sarcoidosis are:

(1) impaired lung function, (2) extrapulmonary organ involvement, (3) comorbidities, and (4) ongoing immunosuppressive therapy. In accordance with the recommendations of the European League Against Rheumatism (EULAR) and of the German Society of Rheumatology (DGRh) (www.dgrh.de), regarding the treatment of rheumatic conditions as well as the sarcoidosis-specific recommendations of an international panel of sarcoidosis experts, we recommend continuing immunosuppressive or immunomodulatory therapy at the lowest effective dose in patients with clinically stable sarcoidosis who do not have COVID-19. However, the indication for a therapy should be subject to a strict review. These patients can also continue to go to work as long as the RKI's behavioral recommendations (AHA-L rules of physical distancing and hygiene) are observed. In patients with active disease or impending organ complications, the initiation/continuation of immunosuppressive or immunomodulatory therapy should be carefully assessed under risk-benefit aspects. In most cases however it should be initiated or continued. In patients with sarcoidosis and acute COVID-19 disease, immunosuppressive or immunomodulatory sarcoidosis therapy should be suspended. If the decision is made to continue prednisolone, the therapy should be reduced to the lowest possible effective maintenance dose. This does not affect the indication and timing of a COVID-19-specific dexamethasone therapy [78, 87] Respiration 2022;101:307-320 DOI: 10.1159/000518896

Answer 8: To date, there is no published data indicating that lung transplant patients are infected more frequently with SARS-CoV-2. The risk of severe COVID-19 in patients with lung transplants appears to be increased due to the required immunosuppression therapy. On the other hand, in vitro data for ciclosporine and tacrolimus indicate that both drugs have an inhibitory effect on virus replication. Several case series on patients with lung transplants with COVID-19 have been published so far. The first case published worldwide was of a German patient with COVID-19 after lung transplantion who had a moderate course [88] . In a large US multicenter cohort study including 482 organ transplant patients with CO-VID-19 (of which 30 were lung transplants), 78% of patients were hospitalized, 31% were intubated, and 21% died [89] . In other case series of transplant patients who had COVID-19 (which did not include patients with lung transplants) 25-28% of those infected died [90] [91] [92] , including 2 patients who were not initially thought to require hospitalization [90] . Therefore, increased attention is required for transplant patients on days 7-10 after symptom onset, even if the clinical symptoms are initially mild (Fig. 1) . A prophylactic adjustment of the immunosuppressive therapy is not recommended in the context of the coronavirus pandemic, and this is also not generally recommended for lung transplanted patients with SARS-CoV-2. Only in case of COVID-19, a temporary discontinuation of mycophenolate mofetil, sirolimus/ everolimus, and azathioprine within a triple drug regimen is recommended under close inhospital monitoring. Interactions of immunosuppressants, antivirals, and additional medication administered to treat COVID-19 need to be considered when treating patients after lung transplantation. It is unnecessary for these patients to stay at home permanently (and this is also not reasonable considering the many positive aspects of physical exercise). However, the RKI's behavioral recommendations (AHA-L rules of physical distancing and hygiene) should be strictly observed. Patients with lung transplants should wear FFP-2 masks used for personal protection in special risk situations if pulmonary function is not significantly impaired. Answer 9: Based on current knowledge, cancer patients, in general, are at a higher risk of developing severe COVID-19 [93] [94] [95] [96] [97] [98] . Data on the course of the infection from over 1,000 patients with COVID-19 have been collected in a major international scientific database (TERA-VOLT: http://teravolt-consortium.org) [99, 100] . A first analysis of this database shows that severe COVID-19 courses (32% of patients recorded in the database died from COVID-19) are associated with factors such as poor general health (the most significant risk factor), advanced age, glucocorticoid therapy, current smoking, advanced disease stage, and the type of therapy [101, 102] . These risk factors were confirmed by evaluating 105 SARS-CoV-2-infected patients with lung cancer from New York (in this case series, 62% of the patients were hospitalized, 25% of the patients died) [103] . On the other hand, it was hypothesized that, in some patients, immunosuppression as part of the cancer therapy might prevent the massive cytokine release typical of severe COVID-19 and thus counteract progression to a severe disease state [104] . Due to the many different subtypes of cancer, cancer stages, therapies and prognoses, and the range of lung cancer types, a risk assessment and recommendation can only be made on a case-by-case basis. In general, surgeries, systemic therapies, or radiotherapy are vital for patients and should therefore neither be postponed nor canceled [105] . Moreover, local (e.g., DGHO, www.dgho.de) and global organizations such as ASCO (www.asco.org) and ESMO (www.esmo.org) have issued separate recommendations for the treatment of cancer in the context of the SARS-CoV-2 pandemic, with the latter providing highly specific, hierarchically structured recommendations (3 graded levels) for diagnostics and all types of local/systemic tumor therapies in lung cancer. In addition, detailed recommendations for the treatment, diagnosis, and management of patients with lung cancer and other malignant diseases were developed and discussed in an ESMO consensus statement [106] . The RKI's behavioral recommendations (rules of physical distancing and hygiene) also apply for patients with lung cancer and should also be strictly observed by all visitors. Regarding contact DOI: 10.1159/000518896 restrictions, the decision whether visits by relatives or friends should be allowed should be made on a case-bycase basis depending on the patient's prognosis; a general ban on visits is not appropriate. Question 10 (sleep apnea syndrome): I am 74 years old and weigh 120 kg. I never smoked and, apart from high blood pressure, have no other conditions. In the past, I used to feel extremely exhausted when I woke up in the morning and was very tired during the day. Since regularly using my CPAP therapy, I feel refreshed when I wake up in the morning and am able to work in my garden all day. Do I belong to a high-risk group for severe coronavirus disease? Will I soon be able to host a barbecue party in my garden again?

Answer 10: For patients with obstructive sleep apnea syndrome who need to use CPAP therapy every night, an increased risk can neither be excluded nor confirmed based on currently available data. In addition, a statement issued by the German Sleep Society (DGSM) notes that there is no conclusive evidence on whether CPAP therapy may worsen a COVID-19 infection: The therapy should therefore be continued [107] . However, the combination of obesity and arterial hypertension is generally associated with an increased risk of severe COVID-19 [6, [19] [20] [21] [22] [23] [24] [25] [26] . The RKI's behavioral recommendations (rules of physical distancing and hygiene) should therefore be strictly observed, and parties or social gatherings with friends should be avoided for the time being. The coronavirus pandemic should also be seen as an opportunity to tackle weight reduction, which offers many benefits in every respect. Answer 11: Patients with neuromuscular diseases who require noninvasive ventilation (NIV) suffer from a severe ventilatory insufficiency. Although epidemiological data in the context of the SARS-CoV-2 pandemic are not yet available for this patient group, a significantly increased risk of severe COVID-19 must be assumed as these patients lack ventilatory compensation capacity in COVID-19 pneumonia. Therefore, these patients may need to be intubated earlier as long as no therapy goal restrictions apply. On the other hand, a transfer to the intensive care unit does not necessarily have to involve intubation. A graduated concept can be applied in this case, including alternating oxygen administration via nasal high-flow and intensified noninvasive ventilation to avoid intubation [8, 108] . In the case of invasive ventilation, significant problems can be expected when weaning these patients from the respirator. This further impacts their prognosis, even if ventilation in intensive care is primarily successful [109] . These patients' quality of life may already be reduced by the underlying condition and may even be further impaired after suffering an extended period of COVID-19 pneumonia. This should be discussed in detail on a caseby-case basis [110] . Patients should be encouraged to draw up a comprehensive and specific advance directive after consultation with their attending respiratory physician and after careful consideration. Answer 12: There is little data on SARS-CoV-2 infections in patients who have recovered from tuberculosis. The likelihood of developing severe COVID-19 after a successfully treated tuberculosis without persistent lung damage is probably not increased. However, if tuberculosis has led to sequelae such as bronchiectasis, fibrosis, or COPD [111, 112] , an increased risk of severe COVID-19 cannot be excluded (see also answers to questions 1, 4, 5, and 6 of this statement). Published data suggest a more severe COVID-19 course in patients infected with SARS-CoV-2 during active tuberculosis [113] [114] [115] . However, due to the small number of published cases, we are not yet in a position to provide a definite statement. In addition, comorbidities need to be taken into consideration [116] . For the success of tuberculosis therapy, it is of utmost im-Respiration 2022;101:307-320 DOI: 10.1159/000518896 portance that patients keep all necessary doctor's appointments and avoid therapy interruptions, despite the challenges of the current pandemic [117] . Therefore, both the German Central Committee against Tuberculosis (DZK) [118] , and the WHO (https://www.who.int/ teams/global-tuberculosis-programme/covid- 19) strongly recommend that all possible effort should be made to maintain tuberculosis services in the context of the SARS-CoV-2 pandemic. Epidemiological data have led to the hypothesis that vaccination against tuberculosis (BCG) may protect against SARS-CoV-2 infections and severe disease [119] [120] [121] . Heterologous protective effects against other virus infections have been described [122] . However, whether these can also be assumed for SARS-CoV-2 has not yet been proven and is currently being investigated in randomized trials. Answer 13: COVID-19 is associated with a significantly increased risk of thrombosis and pulmonary embolism [10, 11, [123] [124] [125] . Laboratory parameters (such as elevated d-dimers), which indicate a risk to develop blood clots as a result of the strong inflammatory response, were seen in over 50% of cases [4, 126] . The percentage of patients with confirmed pulmonary embolism, deep vein thrombosis, and/or microembolisms with subsequent organ dysfunction (e.g., of the kidneys, heart, central nervous system) is also high and on average 25% [127] [128] [129] (probably even higher [125] ), although the data obtained until now were obtained without a control group and are therefore not very robust. The mortality rate of hospitalized COVID-19 patients could be significantly reduced by early thromboprophylaxis [130] . Prophylactic anticoagulation is currently recommended for all hospitalized CO-VID-19 patients, irrespective of a history of thrombosis or embolism. In contrast, therapeutic anticoagulation is indicated in confirmed thrombosis/embolism and, in certain situations, in COVID-19 patients in intensive care (e.g., ECMO). An administration of semi-therapeutic doses of low-molecular heparin or even full anticoagulation may be considered for ICU patients depending on the clinical severity and procoagulatory activity (e.g., significantly elevated or increasing d-dimers) [131] [132] [133] . According to currently available information, patients with a history of thrombosis or pulmonary embolism, who are generally at risk of recurrence, do not appear to have an increased risk of thrombosis in the context of COVID-19 compared to the general population. Consequently, there is no indication for routine prophylactic antithrombotic treatment in COVID-19 patients managed at home. Patients with a history of pulmonary embolism who are no longer taking anticoagulants should generally and especially during the COVID-19 epidemic, follow the general precautions such as avoiding extended immobilization and ensuring adequate fluid intake. When presenting with suspected COVID-19 symptoms to their primary care physician or the emergency department of a hospital, it is of utmost importance that patients mention their history of pulmonary embolism or venous thrombosis. This will ensure that thrombosis prophylaxis is initiated without delay as soon as the COVID-19 suspicion has been confirmed and the patient is hospitalized [134, 135] .

We would like to reiterate that patients with chronic respiratory diseases should generally observe the RKI recommendations (AHA-L rules of physical distancing and hygiene) and follow the vaccination recommendations (www.rki.de). With the start of the second lockdown in Germany in November 2020, the German sports association for disabled people (DBS) and the German Airways League (DAL) initially recommended the temporary suspension of all sports-based rehabilitation, including outpatient breathing exercises for groups [136] . As long as distancing rules, hygiene rules, and patients' current symptoms are strictly observed (no participation of patients with any acute symptoms), exercises for people with chronic respiratory conditions in small groups are currently permitted in many of the federal states of Germany. Since the regulations of the federal states and regional health authorities in Germany may change at short notice, it is advisable to inquire with local authorities, especially health authorities, whether rehabilitation measures in small groups are permitted. If this is not the case, patients should continue to exercise at home. Group training with structured training programs (e.g., NASA, CO- BRA) that are conducted at medical offices should not take place at the moment. However, the owners of such practices can offer customized instruction (at least in inhalation techniques) and refer to future training dates. The DAL is currently developing Internet-based training programs and offers comprehensive information for patients as well as training videos on inhalation techniques (www.atemwegsliga.de). Concerning the question of the clinical management of COVID-19, comprehensive, separate statements are available from both the DGP [137] and the RKI [133] .

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The authors are indebted to Mrs. Gunda Mundt for expert translational service.

The authors have no conflicts of interest to declare.

German Respiratory Society (DGP e.V.).

All authors corrected the initial draft of the manuscript.