Bridging the evidence gap: expert consensus on management of SARS-CoV-2 acute infection and post–COVID-19 condition in immunocompromised patients

Bridging the evidence gap: expert consensus on management of SARSCoV-2 acute infection and posteCOVID-19 condition in immunocompromised patients Lorenzo M. Canziani 1 , * , Antonella d'Arminio Monforte 2 , Maddalena Giannella 3 , 4 , Jesús Rodríguez-Ba~ no 5 , 6 , Evelina Tacconelli 1 1) Division of Infectious Diseases, Department of Diagnostics and Public Health, University of Verona, Verona, Italy 2) Icona Foundation, Milan, Italy 3) Infectious Diseases Unit, Department for Integrated Infectious Risk Management, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy 4) Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, Bologna, Italy 5) Unidad Clínica de Enfermedades Infecciosas y Microbiología, Hospital Universitario Virgen Macarena; Departamento de Medicina, Universidad de Sevilla; Instituto de Biomedicina de Sevilla (IBiS)/CSIC, Seville, Spain 6) CIBERINFEC, Instituto de Salud Carlos III, Madrid, Spain article info Article history: Received 2 May 2025 Accepted 4 May 2025 Available online 13 May 2025 Editor: L. Leibovici Keywords: COVID-19 Delphi survey Expert opinion Immunocompromized patient Long COVID The COVID-19 pandemic highlighted the inherent temporal disparity between the generation of reliable scientific evidence and the urgent clinical needs of patients, particularly those exhibiting significant, albeit less prevalent, comorbidities. This temporal lag frequently resulted in therapeutic decision-making under conditions of evidentiary scarcity. Immunocompromised individuals exhibit an elevated susceptibility to SARS-CoV-2 infection. However, the intersection of specific immunosuppressive comorbidities and COVID-19 is rarely characterized within COVID-19 research. This underrepresentation stems not only from the relatively low prevalence of these combined conditions but also from the inherent methodological complexities associated with conducting robust clinical investigations, particularly randomized controlled trials, within patient populations often characterized by high mortality rates and clinical heterogeneity. In May 2023, WHO officially declared the end of the COVID-19 pandemic as a global health emergency, largely due to the widespread implementation of mass vaccination campaigns and the availability of effective medical therapies. Since then, the incidence of new COVID-19 cases has significantly declined worldwide, and guidelines developed during the pandemic have quickly become overly restrictive or outdated. Meanwhile, the dynamic evolution of clinical needs, particularly for immunocompromised individuals, has outpaced the generation of timely and high-quality evidence to inform optimal management strategies. In this post-pandemic setting, clinicians frequently encounter complex decision-making scenarios in which current evidence offers limited direct guidance. Within ORCHESTRA (“Connecting European cohorts to increase common and effective response to SARS-CoV-2 pandemic”), a Horizon2020-funded project (https://orchestra-cohort. eu/)[1], a series of four Delphi survey were conducted to address critical knowledge gaps concerning COVID-19 management in key immunocompromised populations: solid organ transplants [2], hematologic malignancies [3], rheumatological diseases [4], and people with HIV [5]. The Delphi method is a well-established technique that employs iterative questionnaires with aggregated feedback from expert panellists to elicit informed opinion, particularly in areas characterized by evidence gaps. The main topics explored in these surveys included the identification of high risk for developing severe COVID-19, the diagnostic algorithms employed, the utilization of early antiviral therapy (including anti-spike monoclonal antibodies, remdesivir, nirmatrelvir/ritonavir, and molnupiravir), the interaction between COVID-19 and the relevant comorbidity, and posteCOVID-19 condition (PCC). Notably, the This article was published as part of a supplement supported by the ORCHESTRA project. The ORCHESTRA project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 101016167. The views expressed in this article are the sole responsibility of the author and the Commission is not responsible for any use that may be made of the information it contains. *Corresponding author: Lorenzo M. Canziani, Division of Infectious Diseases, Department of Diagnostics and Public Health, University of Verona, Piazzale L. A. Scuro 10, 37134, Verona, Italy. E-mail address: [email protected] (L.M. Canziani). Contents lists available at ScienceDirect Clinical Microbiology and Infection journal homepage: www.clinicalmicrobiologyandinfection.com https://doi.org/10.1016/j.cmi.2025.05.008 1198-743X/©2025 The Authors. Published by Elsevier Ltd on behalf of European Society of Clinical Microbiology and Infectious Diseases. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Clinical Microbiology and Infection 31 (2025) S1eS2 questions pertaining to PCC were standardized across all four Delphi surveys, and the findings have been published separately [6]. Drawn from international expertise, consensus was reached on 64 statements. They represent a collaborative synthesis of expert opinion supported by the available literature, offering practical guidance on key patient care areas in the selected immunocompromised populations. A key insight derived from this experience was the reaffirmed importance of patient-centred care as the overarching guiding framework. Assessing the immediate risks for an individual patientdparticularly when balancing the typically mild trajectory of SARS-CoV-2 infection against a pre-existing, clinically significant comorbiditydrequires nuanced clinical judgment. This decisionmaking process involves the integration of numerous patientspecific variables that are best synthesized by the treating physician. In such complex scenarios, expert opiniondinformed by literature and real-world clinical experiencedplays a crucial role in outlining a range of reasonable, context-specific approaches rather than a single prescriptive pathway. The second theme emerging from the survey is the recognition of increased risk of SARS-CoV-2 infection and severe COVID-19 that is still present in these immunocompromised patients. This increased vulnerability underscores the need to prioritize these populations in public health strategies, including resource allocation for vaccination campaigns, early antiviral treatment access, and targeted preventive interventions. At the individual patient level, it reinforces the importance of maintaining vigilant clinical follow-up, personalized risk assessment, and timely therapeutic decision-making to mitigate complications and improve outcomes. Reflecting the survey's emphasis on patient-centred care and the need for targeted approaches in immunocompromised individuals, regarding the diagnostic process, it has been emphasized that both antigen and PCR-based tests maintain adequate positive predictive value in the current epidemiological scenario. Because of the lower incidence of COVID-19, testing should be limited to only symptomatic patients rather than universal screening at hospital admission. The use of early antiviral therapy in clinical practice continues to be considered valuable by the panel, although its implementation remains constrained by several factors. Molnupinavir is not available in many countries right now, whereas the effectiveness of antispike monoclonal antibodies for prevention and treatment depends on the susceptibility of circulating variants. Remdesivir requires intravenous administration, posing logistical challenges, and the use of nirmatrelvir/ritonavir is frequently limited by drugedrug interactions. Nevertheless, specific prescribing patterns for early antiviral therapy appear to be emerging from expert experience: combination therapy has generally been avoided, and in severely immunocompromised patientsdparticularly those with B-cell depletiondthe emerging clinical scenario of persistent COVID-19 symptoms has led to the practice of administering additional antiviral dosing. This trend highlights an important gap in the current evidence base and underscores the need for tailored therapeutic strategies in this high-risk population. Temporary discontinuation of immunosuppressive agentsdsuch as anti-CD20 monoclonal antibodies and antimetabolitesdis generally recommended. Glucocorticoids, however, are typically excluded from this approach, as they remain the cornerstone of treatment in moderate to severe COVID-19. The timing of medical procedures in patients with COVID-19 has become more flexible, reflecting the increased manageability of the disease; short postponements are often sufficient, and extended delays are no longer routinely necessary in most clinical settings. In transplant settings, with the exception of lung grafts, SARS-CoV-2 positivityin donors is not considered a contraindication, and neither pre-emptive antiviral therapy nor alterations to induction immunosuppression are required. Recommendations on PCC in immunocompromised patients remain limited. The ORCHESTRA panel experts identified chronic fatigue as the most frequent presentation of PCC in the target populations. Key risk factors for the development of PCC include severe acuteCOVID-19, olderage, and femalesex. In case ofchronic fatigue or arthralgia of new onset, a diagnostic workup to rule out autoimmune disorders has been suggested. Preventive strategiesdincluding fullcourse vaccination and timely antiviral therapydshould be strongly encouraged to reduce the risk of PCC in this vulnerable population. Moving beyond the limitations of current evidence, this comprehensive effort, encompassing four distinct Delphi surveys, proactively addressed the urgentclinical needs ofimmunocompromised patients facingSARS-CoV-2 infection and its sequelae. The resulting consensus offers a valuable resource, empowering clinicians with expertinformed guidance to navigate the complexities of diagnosis, treatment, and long-term management in solid organ transplants, hematologic malignancies, rheumatological diseases, and people with HIV. The survey exercise not only provided practical recommendations but also helped to highlight critical gaps in the current evidence base. Notably, this approach not only addresses the immediate challenges of the recent pandemic but alsoprovides a valuable framework for future pandemic preparedness plans, ensuring that the unique needs of immunocompromised individuals are proactively considered and addressed in evolving health crises. However, reliance on expert consensus alone is not sufficient in the long term. There remains a pressing need for more advanced, agile methodologiesdcapable of integrating real-world data, adaptive trial designs, and multidisciplinary inputdto ensure that evidence keeps pace with emerging challenges and meets the nuanced needs of vulnerable patient populations. Funding This article was published as part of a supplement supported by the ORCHESTRA project. The ORCHESTRA project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement no. 101016167. The views expressed in this article are the sole responsibility of the author and the European Commission is not responsible for any use that may be made of the information it contains. Conflict of interest The authors declare that they have no conflicts of interest. References [1] Azzini AM, Canziani LM, Davis RJ, Mirandola M, Hoelscher M, Meyer L, et al. How European research projects can support vaccination strategies: the case of the ORCHESTRA project for SARS-CoV-2. Vaccines 2023;11:1361. https:// doi.org/10.3390/vaccines11081361. [2] Tazza B, Caroccia N, Toschi A, Pascale R, Gkrania-Klotsas E, Navarro PO, et al. ORCHESTRA Delphi consensus: diagnostic and therapeutic management of SARS-CoV-2 infection in solid organ transplant recipients. Clin Microbiol Infect 2025;31:S21e31. https://doi.org/10.1016/j.cmi.2025.02.010. [3] Canziani LM, Azzini AM, Salmanton-García J, Savoldi A, Caponcello MG, Pasquini Z, et al. ORCHESTRA Delphi consensus: diagnostic and therapeutic management of SARS-CoV-2 infection in haematological patients. Clin Microbiol Infect 2025;31:S32e42. https://doi.org/10.1016/j.cmi.2025.03.004. [4] Caponcello MG, Navarro PO, Bonazzetti C, Campoli C, Savoldi A, Gentilotti E, et al. ORCHESTRA Delphi consensus: diagnostic and therapeutic management of SARS-CoV-2 infection in patients with rheumatological diseases. Clin Microbiol Infect 2025;31:S14e20. https://doi.org/10.1016/j.cmi.2025.02.030. [5] Tavelli A, Vergori A, Cingolani A, Bai F, AzziniAM, Hara GL, et al. ORCHESTRA Delphi consensus: clinical management of SARS-CoV-2 infection in people with HIV. Clin Microbiol Infect 2025;31:S43e54. https://doi.org/10.1016/j.cmi.2025.03.006. [6] Gentilotti E, Canziani LM, Caponcello MG, Azzini AM, Savoldi A, De Nardo P, et al. ORCHESTRA Delphi consensus: diagnostic and therapeutic management of post-COVID-19 condition in vulnerable populations. Clin Microbiol Infect 2025;31:S3e13. https://doi.org/10.1016/j.cmi.2025.04.009. L.M. Canziani et al. / Clinical Microbiology and Infection 31 (2025) S1eS2S2