key: cord-0821452-8n9ee57a
authors: Giesen, Nicola; Sprute, Rosanne; Rüthrich, Maria; Khodamoradi, Yascha; Mellinghoff, Sibylle C.; Beutel, Gernot; Lueck, Catherina; Koldehoff, Michael; Hentrich, Marcus; Sandherr, Michael; Bergwelt-Baildon, Michael von; Wolf, Hans-Heinrich; Hirsch, Hans H.; Wörmann, Bernhard; Cornely, Oliver A.; Köhler, Philipp; Schalk, Enrico; Lilienfeld-Toal, Marie von
title: Evidence-based Management of COVID-19 in Cancer Patients – Guideline by the Infectious Diseases Working Party (AGIHO) of the German Society for Haematology and Medical Oncology (DGHO)
date: 2020-09-21
journal: Eur J Cancer
DOI: 10.1016/j.ejca.2020.09.009
sha: a07fdc156158be6dac13d96791cd081121f796cc
doc_id: 821452
cord_uid: 8n9ee57a

Since its first detection in China in late 2019 the novel coronavirus SARS-CoV-2 and the associated infectious disease COVID-19 continue to have a major impact on global health care and clinical practice. Cancer patients, in particular those with haematological malignancies, seem to be at an increased risk for a severe course of infection. Deliberations to avoid or defer potentially immunosuppressive therapies in these patients need to be balanced against the overarching goal of providing optimal antineoplastic treatment. This poses a unique challenge to treating physicians. This guideline provides evidence-based recommendations regarding prevention, diagnostics and treatment of SARS-CoV-2 infection and COVID-19 as well as strategies towards safe antineoplastic care during the COVID-19 pandemic. It was prepared by the Infectious Diseases Working Party (AGIHO) of the German Society for Haematology and Medical Oncology (DGHO) by critically reviewing the currently available data on SARS-CoV-2 and COVID-19 in cancer patients applying evidence-based medicine criteria.

specialists certified in haematology, medical oncology, infectious diseases, critical care, emergency 119 medicine, and virology. 120

After definition of topics and formation of subgroups, a systematic search of MEDLINE for 122 publications in English language was performed using one of the following search terms: 123 "coronavirus", "SARS-CoV-2", or "COVID-19". Given the current dynamic of research into 124 publications on the pre-print server www.medRxiv.org were also evaluated, however, the lack of 125 formal peer-review in these cases was taken into consideration with regard to grading of quality of 126 evidence. Publications were evaluated that appeared online until August 19 th 2020. 127 J o u r n a l P r e -p r o o f Guideline process 128

Relevant literature was thoroughly reviewed, the data extracted and rated. Based on the results of 129 data assessment, preliminary recommendations were first discussed within subgroups and then 130 discussed and revised in a step-by-step process by the specialist panel. Strength of recommendation 131 and quality of evidence were graded applying the scale proposed by the European Society of Clinical 132

Microbiology and Infectious Diseases (ESCMID) ( Table 1) . 23 In short, recommendations were graded 133 as follows: A -AGIHO strongly supports a recommendation for use, B -AGIHO moderately supports 134 a recommendation for use, C -AGIHO marginally supports a recommendation for use, and D -135 AGIHO supports a recommendation against use. The final recommendations presented in this 136 guideline were discussed and agreed upon by the AGIHO general assembly in a web meeting on June 137 23 rd 2020 and again on July 9 th 2020. 138

139 Cancer patients are generally assumed to be at an increased risk of severe illness by respiratory virus 140

infections when compared to healthy individuals, amongst others as they tend to be older and more 141 frequently suffer from comorbidities than the general population. 24 However, in case of SARS-CoV-2, 142 both healthy and immunocompromised individuals are immunologically naïve to this infection. Data 143 on SARS-CoV-2 infection rates vary among patients with malignant diseases. 1,13,25-28 144 Overrepresentation of cancer patients among hospitalized patient populations may contribute to a 145 higher reported prevalence of SARS-CoV-2 infections among cancer patients compared to the general 146 population, which is supported by a study showing similar infection rates in hospitalized patients 147 with haematological malignancies and a comparator group of health care workers (HCWs). 29 148

In cancer patients, uncontrolled malignancy seems to confer a higher risk of severe or even fatal 149 outcome of 30 With regard to specific cancer types, both haematological malignancies 150 and lung cancer were repeatedly identified as factors for poor prognosis compared to other (solid) 151 cancers. 12, [29] [30] [31] [32] [33] [34] [35] Interestingly, myeloid or lymphoid malignancies as underlying disease do not appear 152 J o u r n a l P r e -p r o o f to differ in their impact on COVID-19 mortality. 36 Among cancer patients, advanced stage 11, 12 and 153 recent antineoplastic therapy within the last 2-4 weeks were reported as risk factors. [37] [38] [39] However, 154 data on the impact of different cancer treatment modalities (immunotherapy, endocrine therapy, 155 targeted therapy, radiotherapy, chemotherapy, or surgery) on the outcome of 20, 39, 40 157 Of note, patients with lymphopenia 11,41-43 and granulocytosis 33,44 were reported to be at an increased 158 risk for severe or fatal COVID-19. Further factors with possible impact on COVID-19 course and 159 outcome are listed in Table 2 . 160 Prevention 161

Given the current lack of herd immunity, an effective vaccine, or antiviral prophylaxis, hygiene 163 measures and contact precautions are the cornerstones in preventing SARS-CoV-2 infection and 164 transmission (Table 3) . Community-wide face masks and physical distancing measures were effective 165 in several population-based studies and are thus strongly recommended (AII u ). [45] [46] [47] [48] [49] A distance of at 166 least 1.5m (6ft) is usually considered appropriate, however, depending on environmental conditions 167 a wider distance may be considered. 50 168

Hand hygiene is crucial for infection control and regular washing of hands with water and soap is 169 strongly recommended for any population (AII t ). 51,52 Alcohol-based hand-rubs were shown to be 170 virucidal to SARS-CoV-2 if applied for at least 30 seconds at a concentration of ethanol or 2-propanol 171 ≥ 30%. 53 We strongly recommend hand disinfection for HCWs and cancer patients in health care 172 settings (AII u ). 173 SARS-CoV-2 can remain viable on surfaces for up to 3 days. 54, 55 We strongly recommend disinfection 174 of frequently touched surfaces such as doorknobs, elevator buttons or hand rails for cancer patients 175 in health care settings (AII r,u ) and moderatly outside of health care settings (BII r,u ) . 54-56 176 J o u r n a l P r e -p r o o f Surgical masks covering nose and mouths of an infected person reduce coronavirus RNA in expiration 177 air. 57, 58 Particulate-filtering facepieces such as the US regulated N95 respirators and the functionally 178 equivalent E.U. regulated FFP2 masks are characterized by a tighter fit and a finer mesh. Several 179 randomized trials in HCWs provide evidence of the protective effect of surgical masks against 180 respiratory virus infections with a potential additional benefit of FFP2/N95 respirators. [59] [60] [61] If worn to 181 prevent infection, FFP2/N95 masks may be equipped with an exhalation valve for greater comfort, 182 whereas in order to prevent transmission they must not have an exhalation valve. 22 183

We strongly recommend that cancer patients and HCWs wear a surgical mask to prevent SARS-CoV-2 184 transmission and infection (AII t ). 57-60 If caring for COVID-19 patients, we strongly recommend that 185

HCWs wear FFP2/N95 respirators (AII t ) and personal protective equipment including gloves, gowns 186 and eye protection such as goggles or face shields (AII r ). 22, [61] [62] [63] [64] Patients with COVID-19 are strongly 187 recommended to wear a surgical mask or FFP2/N95 respirator without exhalation valve (AII t ) taking 188 into account the protective equipment of their surroundings. 22,57,58 189 Cancer patients diagnosed with SARS-CoV-2 infection should undergo either self-quarantine, single 190 room or cohort isolation (AII t,u ). 65 While infectiousness of SARS-CoV-2 seems to decline significantly 191 within 7-8 days after onset of symptoms, 66,67 prolonged shedding of viral RNA for many weeks was 192 observed, especially in immunocompromised patients and in severe We strongly 193 recommend requirement of a negative SARS-CoV-2 PCR test result prior to discontinuation of 194 isolation (AII t,u ), which should be considered no earlier than 14 days after onset of symptoms and 2 195 days after cessation of symptoms. The possibility of false-negative test results must be kept in mind. 196 A positive test after one negative test was reported in up to 30% of which 197 declined to 5% after three consecutive negative tests. 68, 71 Requirement of more than one consecutive 198 negative test prior to discontinuation of isolation should therefore be considered, especially in 199 patients with risk factors for prolonged viral shedding. 200

With regard to participation in activities of daily life of cancer patients not in quarantine/isolation 201 due to suspected or confirmed SARS-CoV-2 infection, special consideration should be given to 202 J o u r n a l P r e -p r o o f current local epidemiology and requirements of local and national health authorities. As a general 203 recommendation, restriction of activities to places that have adequate hygiene concepts 204 implemented seems to be reasonable as well as a preference of outdoor versus indoor activities, 205 where possible. 206

Several large trials could not establish an association between renin-angiotensin-aldosterone-system 208 (RAAS) blockers and risk of SARS-CoV-2 infection or severe COVID-19 disease. 72-74 Discontinuation of 209 RAAS blockers is therefore not recommended (DII u selenium or vitamin C no conclusive data support supplementation with regard to Administration of intravenous immunoglobulin (IVIG) may be considered in cancer patients with 215 hypogammaglobulinaemia and COVID-19 (BII t,u ). 77 As specific antibodies against SARS-CoV-2 are most 216 likely absent in current products due to low herd immunity at the moment, IVIG will primarily act 217 against possible co-infections with other pathogens. However, with an increase of SARS-CoV-2 218 infections in populations over the course of the COVID-19 pandemic future IVIG preparations may 219 contain specific antibodies against SARS-CoV-2 possibly allowing for a broader use of IVIG in COVID-220 19 patients than according to present recommendations. 221

Prophylaxis with G-CSF might help in reducing vulnerability to infections due to shortened 222 neutropenia. However, G-CSF has also been associated with a risk of hyperinflammation during 223 neutrophil regeneration and cases of severe COVID-19 have been reported after G-CSF 224 administration. 44 We therefore do not recommend additional G-CSF prophylaxis on top of current 225 recommendations (DIII). 78 226 J o u r n a l P r e -p r o o f Several preclinical and early clinical trials on vaccine candidates against SARS-CoV-2 have shown 227 promising results. [79] [80] [81] As cancer patients are usually not included in these trials, it is too early to 228 make any specific deliberations on SARS-CoV-2 vaccine strategies in these patients. However, based 229 on experiences from other vaccines, depending on the type of vaccine, efficacy and/or safety might 230 be an issue in immunocompromised cancer patients, rendering vaccinations of HCWs, caregivers and 231 relatives especially important. 82 232

Organizational aspects

The prevention of nosocomial SARS-CoV-2 transmission is of major importance during treatment of 234 cancer patients. This relates to both inpatient and outpatient management. Therefore, we strongly 235 recommend the implementation of specific organizational pathways in hospitals and outpatient 236 clinics (AIII , Table 4 ). 21, 83, 84 This includes precise scheduling of in-person appointments to reduce 237 waiting times, increasing telemedical approaches including phone or video consultations when 238 clinically possible as well as special routing and zoning for cancer patients. Particularly with regard to 239 patient care in outpatient clinics we recommend to reduce the seating capacity in waiting areas and 240 treatment rooms to ensure a distancing of at least 1.5m. In order to reduce the number of visitors, 241 relatives and non-essential other attendants should be advised to stay outside the clinic during the 242 patient visit. In high-volume contact areas such as front desks, installation of transparent shields may 243 offer additional protection for HCWs . 244 In order to provide best care for cancer patients with COVID-19, ICU and respirator capacity should 245 be increased (BIII). If possible, dedicated treatment teams should be implemented to ensure 246 continued cancer care in case of infected medical personnel (AIII). 19 Early detection of infected staff 247 is crucial. Surveillance screening related to local epidemiology should be considered, especially in 248 inpatients, to prevent pre-symptomatic transmission of SARS-CoV2 (AII t,u ). 85 249

The risk of transmission strongly correlates with the number of consultation and treatment 250 appointments. 21, 29, 86, 87 However, optimal control of the underlying malignancy is considered 251 J o u r n a l P r e -p r o o f favorable as patients with active cancer appear to have an increased risk of severe In 252 order to ensure high-quality cancer care, visits should by no means be avoided or unnecessarily 253 delayed, but reduced if possible without interfering with treatment goals. We strongly recommend 254 considering therapeutic strategies with the fewest and shortest clinic visits adapted to curative or 255 palliative intent taking the patient's individual situation and risk into account (AIII). This might e.g. 256 include substitution of intravenous by oral regimens (e.g. 5-fluorouracil/capecitabine) or 257 hypofractionated radiotherapy. Given the immunocompromising effect of many cancer therapies and the fact that most cancer 264 patients belong to high-risk groups regarding adverse outcome of COVID-19 it seems reasonable to 265 debate whether it may be the safer course of action to delay or discontinue certain antineoplastic 266 therapies. However, uncontrolled malignancy was identified as an independent risk factor for severe 267 COVID-19. 20 We therefore strongly recommend performing antineoplastic therapy to reach the best 268 possible remission (AII u , Table 5 ). 269

Routine delay or discontinuation of antineoplastic therapy in patients without suspected/confirmed 270 SARS-CoV-2 infection is not recommended even in times of pandemic (DII u ). 18, 20, 31, 33, 40, [92] [93] [94] In case of 271 suspected SARS-CoV-2 infection, e.g. due to contact with a confirmed case or a high incidence in the 272 area, we strongly recommend to quarantine the patient and delay antineoplastic therapy for up to 14 273 days, if not detrimental for cancer prognosis (AIII). Given the average incubation time of 3-5 days, a 274 delay for a shorter time period and (re-)start of antineoplastic therapy under quarantine conditions 275 may be considered especially in patients with significant prognostic impact of per-protocol 276 J o u r n a l P r e -p r o o f administration of treatment. Obviously, these patients should be tested for SARS-CoV-2 (AIII) but the 277 possibility of false-negative test results should be kept in mind. 278

Cytotoxic chemotherapy was reported as a risk factor for severe COVID-19 by some, 11, 13, 37, 39 although 279 not consistently across all studies. 20,40 We therefore moderately recommend to consider to 280 delay/discontinue chemotherapy in areas with high SARS-CoV-2 infection rates in patients with 281 controlled malignancy if no significant detrimental impact on cancer prognosis is to be expected 282 (BII u ). This might be especially relevant in the palliative setting, if the benefit of chemotherapy is 283 marginal, and if other risk factors for severe COVID-19 are present. Furthermore, dose reductions 284 might be a reasonable strategy in the palliative setting in order to reduce neutropenia. We do not 285 recommend to delay/discontinue radiotherapy, targeted therapy, endocrine therapy or surgery in 286 cancer patients without suspected/confirmed SARS-CoV-2 infection (DII u ) as no impact on mortality 287 of such prior treatments was seen in several large cohort studies of 20, 31, 40, 94 288 In patients with COVID-19, it is strongly recommended to delay/discontinue chemotherapy, if 289 possible, as chemotherapy within two weeks of admission was a major risk factor for severe COVID-290 19 in a large Chinese cohort study (AII u ). 11 Similarly, we strongly recommend delaying surgery in 291 COVID-19 patients (AII u ), as perioperative SARS-CoV-2 infection was associated with a high rate of 292 pulmonary complications and increased mortality. 95 We recommend to delay/discontinue 293 radiotherapy in patients with COVID-19 with moderate strength (BII u ) taking into account field size, 294 location and dosage. 11,12,31,40 295 A small cohort study in breast cancer patients with COVID-19 reported very favorable outcomes in 296 several patients who did not discontinue their endocrine therapy despite diagnosis of infection. 18 297 Given that endocrine therapy is usually not associated with significant immunosuppression, we do 298 not recommend to discontinue endocrine therapy in patients with COVID-19 (DIII). It is important to 299 note that this does not apply to CDK4/6 inhibitors jointly administered with endocrine therapy which 300 can induce significant neutropenia. 96 301 Targeted therapy was reported as a risk factor for severe COVID-19 in one study, although patient 302 numbers for this subgroup were small. 11 Given that many targeted agents adversely affect immune 303 function we marginally support discontinuation of targeted therapy in COVID-19 patients (CIII). In 304 support, a recent small German study on multiple myeloma (MM) patients with COVID-19 reported 305 favorable outcomes after discontinuation of various types of targeted anti-MM therapies until 306 resolution of symptoms. 17 However, the heterogeneity of drugs summarized as targeted therapy has 307 to be acknowledged and depending on the available data, substance specific recommendations 308 should be applied. 309

In the following we summarize current knowledge regarding specific cancer treatments. This 311 summary is in no way complete and subject to change as knowledge accumulates. 312

While corticosteroid therapy can be beneficial to treat severe COVID-19, 97 long term systemic 313 steroids were identified as a risk factor to develop severe COVID-19 in a large registry study of 314 patients with inflammatory bowel disease. 98 We marginally recommend considering to delay, 315 discontinue or reduce treatment with systemic steroids in cancer patients during the COVID-19 316 pandemic (CII t,u ). Any potential impact of steroid reduction on treatment success needs to be 317 carefully evaluated, most importantly in curative settings. 318

Immune checkpoint inhibitors were initially suspected to increase the risk of severe COVID-19. 12 319 However, later studies did not find a significant association after adjustment for smoking. 99,100 We 320 therefore do not recommend to delay/discontinue immune checkpoint inhibitors (DII u ). 321

Prior treatment with tyrosine kinase inhibitors (TKI) was not associated with adverse outcome in a 322 cohort study of lung cancer patients with COVID-19, although patient numbers in this subgroup were 323 small and no further details on the type of TKI were provided. 100 Routine delay/discontinuation of TKI 324 in lung cancer patients is thus not recommended (DII u The JAK inhibitor ruxolitinib was evaluated in a small randomized controlled trial (RCT) against 330 placebo for the treatment of severe COVID-19 given its anti-inflammatory properties. While no 331 statistically significant difference in outcome was observed, time to clinical improvement of patients 332 receiving ruxolitinib was numerically shorter. 103 Discontinuation of ruxolitinib in patients with COVID-333 19 is therefore not recommended (DII t ). 334

Further data on the risks of specific antineoplastic drugs with regard to COVID-19 is scarce at this 335 time. In a small case series of five patients with CML and COVID-19, TKI treatment could safely be 336 continued. 104 Regarding the impact of rituximab on COVID-19, several cases are published reporting 337 outcomes ranging from very mild to fatal. 105,106 B-cell depletion seems to be associated with 338 prolonged shedding of SARS-CoV-2. 68,105 Several case reports on lenalidomide-based therapies 339 describe severe to fatal outcomes of COVID-19. 107,108 However, it remains unclear whether this is 340 mainly due to the drug or the underlying malignancy. As hypersensitivity pneumonitis has been 341 reported as a rare side-effect of lenalidomide, an adverse impact on the course of COVID-19 is, 342 however, conceivable. 109 In contrast, a recent German study on MM patients on active therapy at 343 time of COVID-19 diagnosis including lenalidomide-, proteasome inhibitor-, and daratumumab-based 344 therapies reported favorable outcomes after therapy was discontinued in all patients until resolution 345 of symptoms with no fatalities. 17 346 Diagnostics 347 For diagnosis of SARS-CoV-2 infection, the AGIHO guideline panel categorized the following clinical 348 situations: a) asymptomatic cancer patients scheduled for antineoplastic treatment in whom delay is 349 likely to increase risk of death, b) asymptomatic cancer patients scheduled for antineoplastic 350 treatment in whom delay is unlikely to increase risk of death, and c) cancer patients presenting with 351 respiratory symptoms compatible with COVID-19. With regard to diagnosing SARS-CoV-2 infection 352

and COVID-19 there should be no differences between these groups. A comprehensive approach 353

should be applied to all cancer patients (Table 6) . 354

Upper respiratory samples obtained by nasopharyngeal or posterior oropharyngeal swab at the time 356 of symptom onset are standard to diagnose acute SARS-CoV-2 infection. 110,111 Sampling bias may be 357 decreased by combining a nasopharyngeal swab and an oropharyngeal swab in one universal 358 transport medium. 112 If a nasopharyngeal swab is contraindicated, expectorated sputum can be used, 359 in particular during thrombocytopenia or if nasopharynx tumors increase bleeding risks. 111 New 360 evidence has become available indicating that morning saliva may be a viable alternative, but data is 361 currently only available preprint. 113 In case of mechanically ventilated patients, lower respiratory 362 samples by tracheal aspirate or bronchoalveolar lavage are standard in the ICU population. 111 363 Tracheal aspirate is often preferred to limit droplet and aerosol exposure of HCWs. Generally, it has 364 to be emphasized that diagnostic material should be sampled from the focus of symptoms -that is, 365 samples from the upper respiratory tract for those with symptoms of URTID only and samples from 366 the lower respiratory tract for those with LRTID. 367

Currently, antigen assays for diagnosing SARS-CoV-2 infection are being developed and should only 368 be used in clinical studies. Antibody assays should not be used to diagnose active/ongoing SARS-CoV-369 2 infection, but depending on sensitivity and specificity may be helpful to identify patients with 370 previous SARS-CoV-2 infection. 114-116 A major caveat is the uncertainty associated with undetectable 371 or low antibody levels in individuals with a-/oligosymptomatic course of SARS-CoV-2 infection, the 372 level and duration of detectable antibodies in immunocompromised cancer patients, and the 373 protection from re-infection or severe disease. 374

We strongly recommend that all cancer patients prior to antineoplastic therapy receive upper 375 respiratory sampling to diagnose SARS-CoV-2 infection by PCR (AII u ), taking into account local 376 epidemiology, individual patient risk and potential for nosocomial transmission. In intubated 377 patients, we strongly recommend additional testing of tracheal aspirate (AII u ). If the above 378 techniques are contraindicated in individual patients, testing of saliva or expectorated sputum is 379 recommended with moderate strength (BII a,u ). 380

Imaging studies show characteristic findings and are highly sensitive to identify patients with COVID-382 19 LRTID in a timely manner. 117-119 They complement molecular testing strategies. Chest CT imaging 383 abnormalities can evolve rapidly from focal unilateral to diffuse bilateral ground-glass opacities, even 384 in asymptomatic patients. Ground-glass opacities may be accompanied by consolidations which 385 evolve during the course of disease. 119 386

We strongly recommend low-dose chest CT in all cancer patients with suspected COVID-19 to 387 diagnose LRTID due to SARS-CoV-2 (AII u ). 117-119 388 Treatment 389 Since the treatment of COVID-19 is a rapidly changing field, it is strongly recommended to include 390 patients into clinical trials if at all possible (AIII). To evaluate treatment indications and outcomes in 391 COVID-19, the WHO Ordinal Scale for Clinical Improvement should be applied (Suppl. Table 1 ). 120 It 392 summarizes disease severity during the course of COVID-19 from uninfected to ambulatory, 393 hospitalized with mild disease or severe disease or dead and allocates scores from 0-8. The WHO 394

Ordinal Scale is foundation to most clinical trials on COVID-19 and allows to measure endpoints and 395 to facilitate interpretation of results across studies. 396

Prophylaxis 397

To date, there is no agent that has shown convincing efficacy as post-exposure prophylaxis. A double-398 blind RCT (N=821) compared post-exposure prophylaxis with hydroxychloroquine or placebo. The 399 incidence of either laboratory confirmed infection or illness compatible with COVID-19 within 14 days 400 did not differ between the groups. Participants receiving hydroxychloroquine experienced a higher 401 rate of adverse events, in particular gastrointestinal or neurological. 121 A retrospective study 402 evaluated umifenovir, an antiviral agent targeting haemagglutinin, as prophylaxis and reported an 403 effect in HCWs, albeit with small sample size. 122 Other compounds have not been tested so far. 404

Therefore, post-exposure prophylaxis with any drug with presumed antiviral activity outside of 405 controlled clinical trials is not recommended (DIII, for hydroxychloroquine DI, Table 7 ). 406

Remdesivir 408

A double-blind RCT (N=1063) compared intravenous remdesivir with placebo in adults hospitalized 409 with COVID-19 and evidence of LRTID. Preliminary results were published after the data and safety 410 monitoring board recommended to unblind. Remdesivir was superior to placebo in shortening the 411 time to recovery (11 days versus 15 days). This effect was most pronounced in patients requiring 412 oxygen but not mechanical ventilation (corresponding to WHO Scale 5) at presentation. The Meier estimates of mortality by 14 days were 7·1% with remdesivir and 11·9% with placebo which 414 was not statistically significant. 123 A second, open-label RCT compared remdesivir for 5 days with 415 remdesivir for 10 days. In patients with WHO Scale 3-5 the trial did not show a difference between 416 the short or longer course of remdesivir. However, as the study did not include placebo control the 417 degree of benefit cannot be determined. 124 418

We strongly support a recommendation for use of remdesivir for 10 days in patients with COVID-19 419 LRTID (WHO Scale 3-7) to shorten time to recovery in COVID-19 (AII t ). 420

Hydroxychloroquine 421

An open-label RCT (N=150) compared hydroxychloroquine with standard of care in mild to moderate 422 disease. Conversion rates to SARS-CoV-2 negative did not differ between the groups, patients on 423 active drug experienced a higher rate of gastrointestinal adverse events. 125 A cohort study (N=928) 424 found a 3-fold risk of death in cancer patients treated with hydroxychloroquine/azithromycin 425 combination for COVID-19. 20 426

We therefore recommend against hydroxychloroquine treatment of COVID-19 (DII u The effect of corticosteroids was studied in an open-label RCT with hospitalized COVID-19 patients 441 receiving standard of care (N=4321) compared to additional low-dose dexamethasone (N=2104). In 442 the entire cohort, application of dexamethasone showed a significant reduction in 28-day mortality 443 (rate ratio 0.83) and a shorter time to hospital discharge (12 days versus 13 days). The impact was 444 most pronounced in patients requiring mechanical ventilation with 28-day mortality reduced by one 445 third compared to a reduction of one fifth in patients only requiring non-invasive oxygen 446 supplementation. In contrast, patients not requiring oxygen had a numerically higher mortality when 447 treated with dexamethasone, however, without reaching statistical significance. 97 448

We strongly recommend dexamethasone in COVID-19 patients requiring oxygen or mechanical 449 ventilation (WHO Scale 4-7, AI). In contrast, all asymptomatic patients or those well enough to be on 450 ambient air should not receive low-dose dexamethasone for treatment of COVID-19 (DI). Clinicians 451 need to be aware of potential adverse effects of corticosteroid treatment. 452

Tocilizumab, a humanized monoclonal antibody against interleukin-6 showed mixed results in severe 454 We marginally recommend tocilizumab in patients with a severe course of COVID-19 likely due to 463 hyperinflammation (WHO Scale ≥ 5, CII u ). Further randomized trials are needed to confirm whether 464 tocilizumab is effective and, if so, identify subsets of patients most likely to benefit from the drug. 465

In a prospective cohort study (N=52) COVID-19 WHO Scale ≥4 patients received the human 466 interleukin-1 receptor antagonist anakinra and were compared to a historical control (N=44). Rates 467 of progression to mechanical ventilation or death were 25% vs 73%. 136 468

We therefore marginally recommend anakinra in COVID-19 patients with WHO Scale ≥4 (CII h,t ). 469

Baricitinib, an inhibitor of the JAK/STAT pathway commonly used in rheumatology patients, was 471 evaluated in a retrospective cohort study in patients with COVID-19 WHO Scale 3 (N=113). Patients 472 treated with baricitinib experienced a significantly lower case fatality rate and rate of ICU admission 473 as well as a higher rate of hospital discharge after two weeks. 137 In all hospitalized COVID-19 cancer patients (WHO Scale 3-6), we strongly recommend thrombosis 498 prophylaxis with LMWH (AII t ) to prevent thromboembolic complications. Despite prophylactic 499 anticoagulation, an increased incidence of thromboembolic disease associated with COVID-19 in ICU 500 patients was reported. 7,143 In a single-center cohort study, the use of therapeutic anticoagulation in 501 COVID-19 patients requiring ventilation (N=234) significantly reduced hospital mortality (29·1% 502 versus 62·7 %) compared to ventilated patients without anticoagulation (N=161). 144 We therefore 503 moderately recommend therapeutic anticoagulation in ventilated COVID-19 patients (WHO Scale 6-504 7) with cancer to reduce mortality while carefully weighing the risk-benefit ratio of bleeding (BII t ). 505 Health, personal fees from Jazz Pharmaceuticals, personal fees from MSD, personal fees from 538 NewConceptOncology, outside the submitted work. CL reports non-financial support from Jazz 539

Pharmaceuticals, non-financial support from Neovii, outside the submitted work. MH reports 540 personal fees from Amgen, personal fees from Janssen, personal fees from Celgene, personal fees 541 from Sanofi, personal fees from Takeda, outside the submitted work. MBB is the PI of the COVACTA 542 Comparison to RT-PCR. Radiology. 2020:200432. 873 118. Ai T, Yang Z, Hou H, Zhan C, Chen C, Lv W, et al. Correlation of Chest CT and RT-PCR Testing in 874 Coronavirus Disease 2019 (COVID-19) for COVID-19. Front Immunol. 2020; 11:1061. 899 130. Luo P, Liu Y, Qiu L, Liu X, Liu D, Li J. Tocilizumab treatment in COVID-19: A single center 900 experience. J Med Virol. 2020; 92(7):814-818. 901 131. Campochiaro C, Cavalli G, De Luca G, Ripa M, Boffini N, et al. Efficacy and safety 902 of tocilizumab in severe COVID-19 patients: a single-centre retrospective cohort study. Eur J Intern 903 Med. 2020; 76:43-49. 904 132 severe COVID-19 patients: a pilot study. medRxiv. 2020 .2003 .2016 J o u r n a l P r e -p r o o f medRxiv. 928 2020 medRxiv. 928 :2020 medRxiv. 928 .2005 medRxiv. 928 .2012 142. Lodigiani C, Iapichino G, Carenzo L, Cecconi M, Ferrazzi P, Sebastian T, et al. Venous and 930 arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in 931 Milan, Italy. Thromb Res. 2020; 191:9-14. 932 143. Helms J, Tacquard 

Higher neutrophil count associated with a higher risk for death 10,20

Increased risk of death was reported for patients of higher age, male sex and with limitations in daily activity and comorbidities. Both history of cancer and active cancer, particularly hematological and lung cancer and advanced-stage cancer, as well as lymphopenia and granulocytosis were associated with higher risk of death in COVID-19 patients.

Abbreviations: HR, hazard ratio; OR, odds ratio. 6 7 J o u r n a l P r e -p r o o f 

To prevent hospitalization and severe COVID-19

Discontinuation of RAAS inhibitors D II u 54,55

Abbreviations: SoR, strength of recommendation; QoE, quality of evidence; IVIG, intravenous 10 immunoglobulin; RAAS, renin-angiotensin-aldosterone system 11 12 J o u r n a l P r e -p r o o f J o u r n a l P r e -p r o o f

Clinical Characteristics of Coronavirus 564 Disease 2019 in China

A Novel Coronavirus from Patients with 566 Pneumonia in China

Self-reported olfactory 568 and taste disorders in SARS-CoV-2 patients: a cross-sectional study

Clinical features of patients infected with 570 2019 novel coronavirus in Wuhan

The issue of recurrently positive patients 750 who recovered from COVID-19 according to the current discharge criteria: investigation of patients 751 from multiple medical institutions in Wuhan

Renin-Angiotensin-Aldosterone System 753

Blockers and the Risk of Covid-19

System Inhibitors and Risk of Covid-19

Use 758 of renin-angiotensin-aldosterone system inhibitors and risk of COVID-19 requiring admission to 759 hospital: a case-population study

Vitamin D 761 concentrations and COVID-19 infection in UK Biobank

Effects of vitamin D supplementation on 763 the outcomes of patients with pulmonary tuberculosis: a systematic review and meta-analysis

Effect of regular intravenous 766 immunoglobulin therapy on prognosis of severe pneumonia in patients with COVID-19

Prophylaxis of 768 infectious complications with colony-stimulating factors in adult cancer patients undergoing 769 chemotherapy-evidence-based guidelines from the Infectious Diseases Working Party AGIHO of the 770

SARS-CoV-2 on Safety and Immunogenicity Outcomes: Interim Analysis of 2 Randomized Clinical 773

Safety, tolerability, and 775 immunogenicity of a recombinant adenovirus type-5 vectored COVID-19 vaccine: a dose-escalation, 776 open-label, non-randomised, first-in-human trial

Safety and 778 immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a 779 phase 1/2, single-blind, randomised controlled trial

Anti-infective 781 vaccination strategies in patients with hematologic malignancies or solid tumors-Guideline of the 782

Infectious Diseases Working Party (AGIHO) of the German Society for

Oncology (DGHO)

Effective strategies to prevent in-785 hospital infection in the emergency department during the novel coronavirus disease 2019 786 pandemic

Successful prevention and screening 788 strategies for COVID-19: focus on patients with haematologic diseases

SARS-CoV-2 Infections and Transmission in a Skilled Nursing Facility

Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA. 2020

ILROG emergency 795 guidelines for radiation therapy of hematological malignancies during the COVID-19 pandemic

Managing haematology 798 and oncology patients during the COVID-19 pandemic: interim consensus guidance

ESCMID* 32 guideline for the diagnosis and management of Candida diseases 2012: adults with haematological 33 malignancies and after haematopoietic stem cell transplantation (HCT)

Clinical impact of 36 COVID-19 on patients with cancer (CCC19): a cohort study

Clinical characteristics and risk factors 38 associated with COVID-19 disease severity in patients with cancer in Wuhan, China: a multicentre, 39 retrospective, cohort study

Case Fatality 41 Rate of Cancer Patients with COVID-19 in a New York Hospital System. Cancer Discov

Clinical outcome of 43 coronavirus disease 2019 in haemato-oncology patients

Clinical characteristics, outcomes, and 45 risk factors for mortality in patients with cancer and COVID-19 in Hubei, China: a multicentre, 46 retrospective, cohort study

High mortality 48 rate in cancer patients with symptoms of COVID-19 with or without detectable SARS-COV-2 on RT-49 PCR

COVID-19 in 51 patients with thoracic malignancies (TERAVOLT): first results of an international, registry-based, 52 cohort study

Cancer history is an independent risk factor 54 for mortality in hospitalized COVID-19 patients: a propensity score-matched analysis

Reply to 57 "COVID-19 in persons with haematological cancers": a focus on myeloid neoplasms and risk factors 58 for mortality

Patients with Cancer Appear More Vulnerable 62 to SARS-CoV-2: A Multicenter Study during the COVID-19 Outbreak

Survival study of 65 hospitalised patients with concurrent COVID-19 and haematological malignancies

A 68 systematic review and meta-analysis of cancer patients affected by a novel coronavirus. medRxiv

OpenSAFELY: 71 factors associated with COVID-19 death in 17 million patients

Clinical characteristics of COVID-19-73 infected cancer patients: a retrospective case study in three hospitals within Wuhan

Clinical characteristics and outcomes of cancer 19

CoV-2 infection in cancer patients undergoing active treatment: analysis of clinical features and 81 predictive factors for severe respiratory failure and death

Granulocyte-83 colony stimulating factor in COVID-19: Is it stimulating more than just the bone marrow? Am J 84 Hematol

Impact assessment of non-86 pharmaceutical interventions against coronavirus disease 2019 and influenza in Hong Kong: an 87 observational study

Evaluating the Effectiveness of Social Distancing Interventions to Delay or 89 Flatten the Epidemic Curve of Coronavirus Disease

Incidence, clinical 91 outcomes, and transmission dynamics of severe coronavirus disease 2019 in California and 92 Washington: prospective cohort study

The effect of control 94 strategies to reduce social mixing on outcomes of the COVID-19 epidemic in Wuhan, China: a 95 modelling study

Influence of wind and relative humidity on the social 97 distancing effectiveness to prevent COVID-19 airborne transmission: A numerical study

The role of community-wide 100 wearing of face mask for control of coronavirus disease 2019 (COVID-19) epidemic due to SARS-CoV-101 2

Efficacy of soap and 103 water and alcohol-based hand-rub preparations against live H1N1 influenza virus on the hands of 104 human volunteers

Single treatment with ethanol hand rub is ineffective against human rhinovirus--hand washing 107 with soap and water removes the virus efficiently

Acute Respiratory Syndrome Coronavirus 2 by WHO-Recommended Hand Rub Formulations and 110 Alcohols

Aerosol and Surface Stability of SARS-CoV-2 as Compared with SARS-CoV-1

Persistence of coronaviruses on inanimate 115 surfaces and their inactivation with biocidal agents

Environmental contamination of SARS-CoV-2 117 during the COVID-19 outbreak in South Korea

Medical masks vs N95 respirators for 119 preventing COVID-19 in healthcare workers: A systematic review and meta-analysis of randomized 120 trials. Influenza Other Respir Viruses

Surgical mask partition reduces 122 the risk of non-contact transmission in a golden Syrian hamster model for Coronavirus Disease 2019 123 (COVID-19)

Respiratory Infections in Healthcare Workers: A Systematic Review and Meta-Analysis

The 128 challenge of COVID-19 and hematopoietic cell transplantation; EBMT recommendations for 129 management of hematopoietic cell transplant recipients, their donors, and patients undergoing CAR 130 T-cell therapy

A cluster randomized 132 clinical trial comparing fit-tested and non-fit-tested N95 respirators to medical masks to prevent 133 respiratory virus infection in health care workers. Influenza Other Respir Viruses

Consensus of Chinese experts on 135 protection of skin and mucous membrane barrier for health-care workers fighting against 136 coronavirus disease 2019

Physical distancing, face 138 masks, and eye protection to prevent person-to-person transmission of SARS-CoV-2 and COVID-19: a 139 systematic review and meta-analysis

The Ocular Manifestations and 141 Transmission of COVID-19: Recommendations for Prevention

Respiratory virus 143 shedding in exhaled breath and efficacy of face masks

Effect of isolation practice on the 145 transmission of middle east respiratory syndrome coronavirus among hemodialysis patients: A 2-year 146 prospective cohort study

Decreased B cells on admission was associated with 148 prolonged viral RNA shedding from respiratory tract in Coronavirus Disease 2019: a case control 149 study

Temporal dynamics in viral shedding and 151 transmissibility of COVID-19

Immunosuppressed Renal Transplant Recipients: A Summary of 10 Confirmed Cases in Wuhan

Factors associated with prolonged viral RNA 156 shedding in patients with COVID-19

The issue of recurrently positive patients 158 who recovered from COVID-19 according to the current discharge criteria: investigation of patients 159 from multiple medical institutions in Wuhan

Effect of regular intravenous 161 immunoglobulin therapy on prognosis of severe pneumonia in patients with COVID-19

High-Dose Intravenous Immunoglobulin as a 163

Therapeutic Option for Deteriorating Patients With Coronavirus Disease 2019. Open Forum Infect 164 Dis

Vitamin D 166 concentrations and COVID-19 infection in UK Biobank

Effects of vitamin D supplementation on 168 the outcomes of patients with pulmonary tuberculosis: a systematic review and meta-analysis

Daily adjunctive 171 therapy with vitamin D3 and phenylbutyrate supports clinical recovery from pulmonary tuberculosis: 172 a randomized controlled trial in Ethiopia

Renin-Angiotensin-Aldosterone System 174 Blockers and the Risk of Covid-19

System Inhibitors and Risk of Covid-19

Use 179 of renin-angiotensin-aldosterone system inhibitors and risk of COVID-19 requiring admission to 180 hospital: a case-population study

Effective strategies to prevent in-182 hospital infection in the emergency department during the novel coronavirus disease 2019 183 pandemic

Successful prevention and screening 185 strategies for COVID-19: focus on patients with haematologic diseases

SARS-CoV-2-specific 187 antibody detection in healthcare workers in Germany with direct contact to COVID-19 patients

Presymptomatic 192 SARS-CoV-2 Infections and Transmission in a Skilled Nursing Facility

Screening for COVID-19 in Asymptomatic Patients With 195 Cancer in a Hospital in the United Arab Emirates

Implications of SARS-CoV-2 Infection and COVID-19 Crisis on Clinical Cancer Care: Report of the 198 University Cancer Center Hamburg

Safety at the Time of the 200 COVID-19 Pandemic: How to Keep our Oncology Patients and Healthcare Workers Safe

Care During the COVID-19 Pandemic: Agility and Collaboration Toward a Common Goal

Essential 206 Role of Patient Blood Management in a Pandemic: A Call for Action

Managing haematology 209 and oncology patients during the COVID-19 pandemic: interim consensus guidance

Increased thymidylate synthase (EC 212 2.1.1.45) activity in normal and neoplastic proliferation

Provision of cancer care during the COVID-19 pandemic

SARS-CoV-2 Transmission in Patients With Cancer at a 216 Tertiary Care Hospital in Wuhan, China

Clinical Characteristics of 138 Hospitalized 218 Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan

ILROG emergency 220 guidelines for radiation therapy of hematological malignancies during the COVID-19 pandemic. 221 Blood

Mortality and pulmonary complications in patients undergoing surgery 223 with perioperative SARS-CoV-2 infection: an international cohort study

Cancer patients in SARS-CoV-2 infection: 225 a nationwide analysis in China

Clinical course and outcomes of critically ill 227 patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, 228 observational study

Cancer treatment during the 230 coronavirus disease 2019 pandemic: Do not postpone, do it!

Philadelphia-positive acute 232 lymphoblastic leukaemia (ALL) in Italy during the COVID-19 pandemic: a Campus ALL study

Characteristics and 235 outcomes of patients with breast cancer diagnosed with SARS-Cov-2 infection at an academic center

COVID-19 mortality 238 in patients with cancer on chemotherapy or other anticancer treatments: a prospective cohort study

COVID-19 in breast 241 cancer patients: a cohort at the Institut Curie hospitals in the Paris area

Corticosteroids, but not TNF Antagonists, are Associated with Adverse COVID-19 Outcomes in 245 Patients With Inflammatory Bowel Diseases: Results from an International Registry

COVID-19 in patients 248 with lung cancer

Impact of PD-1 blockade on 250 severity of COVID-19 in patients with lung cancers. Cancer Discov

COVID-19 in persons with chronic 252 myeloid leukaemia

Protective role of Bruton 254 tyrosine kinase inhibitors in patients with chronic lymphocytic leukaemia and COVID-19

The BTK 257 inhibitor ibrutinib may protect against pulmonary injury in COVID-19-infected patients

Ruxolitinib in treatment of severe 260 coronavirus disease 2019 (COVID-19): A multicenter, single-blind, randomized controlled trial

Posterior oropharyngeal saliva 263 for the detection of SARS-CoV-2. Clinical Infectious Diseases

Detection of SARS-CoV-2 in Different Types of 265 Clinical Specimens

Sensitivity of Chest CT for COVID-19: 267 Comparison to RT-PCR

Correlation of Chest CT and RT-PCR Testing in 269

COVID-19) in China: A Report of 1014 Cases

Radiological findings from 81 patients with 271 COVID-19 pneumonia in Wuhan, China: a descriptive study

Saliva is more sensitive for SARS-CoV-2 detection in COVID-19 patients than nasopharyngeal swabs

Antibody Detection and Dynamic 276 Characteristics in Patients with COVID-19

CoV-2 in patients with COVID-19

Clinical infectious diseases : an official 282 publication of the Infectious Diseases Society of America. 2020:ciaa523. 283 96. WHO R&D blueprint novel coronavirus COVID-19 therapeutic trial synopsis. Geneva, 284 Switzerland: World Health Organization; 2020. 285 97

Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19

Remdesivir for the 289 Treatment of Covid-19 -Preliminary Report

Hydroxychloroquine in patients with 291 mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial

Dexamethasone in 294 Hospitalized Patients with Covid-19 -Preliminary Report

Tocilizumab treatment in COVID-19: A single center 296 experience

Anakinra for 298 severe forms of COVID-19: a cohort study

COVID-19) Patients with Convalescent Plasma

Time to Clinical Improvement in Patients With Severe and Life-threatening COVID-19: A Randomized 303 Clinical Trial

305 multicenter study on the impact of baricitinib in COVID-19 moderate pneumonia

A Trial of Lopinavir-Ritonavir in Adults 307 Hospitalized with Severe Covid-19

Efficacy and safety 309 of tocilizumab in severe COVID-19 patients: a single-centre retrospective cohort study

Outcomes in 312 Patients with Severe COVID-19 Disease Treated with Tocilizumab -A Case-Controlled Study

Cytokine Release Syndrome in hospitalized COVID-19 patients: survival and clinical outcomes

Tocilizumab in 318 patients with severe COVID-19: a retrospective cohort study

Tocilizumab for 320 treatment of mechanically ventilated patients with COVID-19

Thromboembolism Prophylaxis and Treatment in Patients With Cancer: ASCO Clinical Practice 323 Guideline Update

Venous and 325 arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in 326

Prevention of VTE in 328 nonsurgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American 329 College of Chest Physicians Evidence-Based Clinical Practice Guidelines

High risk of 332 thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study

Incidence of 335 thrombotic complications in critically ill ICU patients with COVID-19

Dose Anticoagulation with In-Hospital Survival Among Hospitalized Patients with COVID-19

Extracorporeal Life Support 340 Organization COVID-19 Interim Guidelines

patients with COVID-19. J Med Virol. 2020. 77 18. Tang LV, Hu Y. Poor clinical outcomes for patients with cancer during the COVID-19 78 pandemic. Lancet Oncol. 2020. 79

All authors actively participated in the guideline panel. NG coordinated the guideline panel and wrote the final version of the manuscript. All authors agreed upon guideline topics, performed a systematic literature search, extracted and rated the data, discussed and agreed upon the final recommendations, helped in writing and critically revised the first draft of the manuscript, and approved the final version of the manuscript.

☐ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.☒The authors declare the following financial interests/personal relationships which may be